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Single incision access: a novel surgical approach to the extraction of impacted inferior third molars
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The recent attention to quality of life and oral health care procedures reflects a renewed 'patient-based' approach to dealing with non-life-threatening conditions. In the current study, we proposed a novel surgical approach to the extraction of impacted inferior third molars (iMs3) through a randomised, blinded, split-mouth controlled clinical trial following the CONSORT guidelines. The novel surgical procedure, hereinafter referred to as single incision access (SIA), will be compared with our previously described flapless surgical approach (FSA). The predictor variable was the novel SIA approach, involving access through a single incision without removal of soft tissue, on the impacted iMs3. The primary endpoint was the acceleration of the iMs3 extraction healing time. The secondary endpoints were the incidences of pain and oedema as well as gum health (pocket probing depth and attached gingiva). The study was carried out on 84 teeth of 42 patients with both iMs3 impacted. The cohort was composed of 42% Caucasian males and 58% Caucasian females, aged 23.8 ± 7.9 (17-49) years. We observed faster recovery/wound-healing on the SIA side (33.6 ± 4.3 days) than at the FSA side (42.1 ± 5.4 days;
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"To review the literature on the effect of different surgical flaps upon patient morbidity (pain perception, trismus, swelling and osteitis) after impacted third molar extraction. An electronic and complementary search of main databases and grey literature was performed up to January 2019 to retrieve randomized clinical trials. The Cochrane risk of bias assessment tool was used for methodological appraisal. A random-effects meta-analysis was conducted of pain perception and trismus. From the initially 1314 screened studies, only 11 were included in the qualitative synthesis, and 5 in the meta-analysis. There were no statistically significant differences in pain between the envelope and triangular flap designs over time, except on the sixth postoperative day, when the envelope flap proved more painful. Regarding trismus, statistically significant differences were observed on the seventh postoperative day, with greater mouth opening in the envelope flap group than in the triangular flap group. There were no clear differences in swelling and osteitis among the flap designs. Despite its limitations, the present meta-analysis found no clear differences in patient morbidity between the different flap designs.",
"Pain, swelling, trismus, and alveolar osteitis often occur after removal of impacted third molar teeth. To minimize these complications a number of mucoperiosteal flap designs have been advocated, but, to date, a pedicle flap design has not been evaluated. In a randomized prospective split mouth study, 52 participants had bilateral symmetrically impacted mandibular third molars removed over two sessions. A buccal envelope or pedicle flap was randomly assigned to the left or right third molar site. Pre-and postoperative pain and swelling were recorded using a standardized visual analogue scale, trismus was measured as the maximum inter-incisal opening distance in millimetres and dry socket was assessed clinically. Greater continuous pain, pain on maximum opening, and oro-facial swelling were recorded with the pedicle flap design. Continuous pain resolved significantly faster with this flap design (p<0.05). Trismus was similar for both flap designs (p>0.05). Five cases of alveolar osteitis occurred with the envelope flap whilst no cases developed with the pedicle flap, but the incidence was too small for statistical analysis. The pedicle flap improved some aspects of postoperative pain experience and reduced the incidence of alveolar osteitis, but further investigation with a larger sample size is required to evaluate its significance.",
"The aim of this study was to investigate the effects of two commonly used flap designs (envelope and triangular) used for the removal of mandibular third molars (M3) on postoperative morbidity. 19 patients with bilateral symmetrically impacted mandibular M3 were studied using a split mouth design. Swelling, pain and trismus measures were recorded on days 2, 7 and 14; periodontal indices were recorded on days 7 and 14, one final measure of probing depth on the distal aspect of the mandibular second molar (M2) was taken at the last follow up appointment. Data were analysed using the χ(2) test, the Mann-Whitney U-test and Pearson's correlations. The mean age of the patients was 21.4 ± 2.3 years (± SD). Facial swelling and the reduction in mouth opening were significantly greater in the early postoperative period (P<0.05) with pyramidal flap designs. There was no significant difference in pain scores, plaque accumulation and bleeding on probing indices between the two flap designs (P>0.05). Probing depth was significantly greater with envelope flaps in the early postoperative period (P<0.005). In conclusion, flap design in mandibular M3 surgery has an effect on postoperative recovery."
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Anti-osteoporosis effects of a mixture of BPX and a tylenol
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Osteoporosis is a metabolic skeletal disease characterized by lowered bone mineral density and quality, which lead to an increased risk of fracture. The aim of this study was to evaluate the anti-osteoporosis effects of a mixture (called BPX) of
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"Osteoporosis diagnosis is based on bone mineral density (BMD) but bone remodeling is also a crucial issue. It can be assessed by bone turnover markers (BTMs). Their interest for the positive and etiological diagnosis of osteoporosis at baseline, and their predictive value for past asymptomatic vertebral fractures, were evaluated by a systematic review of the literature. Medline database was searched to identify all published reports analyzing BTMs and BMD or fractures. We conducted meta-analyses on BTMs levels according to osteoporotic status using random effects models. Moderate and negative correlations were found, mainly in postmenopausal women, between BTMs and BMD, especially with bone alkaline phosphatase (bone ALP), osteocalcin, serum C-terminal and urine N-terminal crosslinking telopeptides of type I collagen (sCTX and uNTX). Bone ALP and sCTX levels are higher in osteoporotic patients compared to controls. High levels of bone ALP in primary hyperparathyroidism and low levels of osteocalcin in endogenous hypercorticism are the most relevant data reported in endocrine diseases associated with osteoporosis. High levels of BTMs, especially osteocalcin, bone ALP or sCTX, may be associated with prevalent vertebral fractures. The diagnosis value of BTMs at baseline in osteoporosis is very low. The interest of BTMs for the etiological diagnostic of secondary osteoporosis has not been demonstrated. Data are lacking to address the interest of BTMs assessment to screen for vertebral fractures in asymptomatic patients with high risk factors of fractures.",
"Bone turnover markers (BTMs) reflect the metabolic activity of bone tissue and can be used to monitor osteoporosis therapy. To adequately interpret BTMs, method-specific reference intervals are needed. We aimed to determine reference intervals for serum concentrations of intact amino-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP) and carboxy-terminal telopeptide of type I collagen (CTX). We established a healthy reference population of 1107 men as well as 382 pre- and 450 postmenopausal women, who participated in the first follow-up of the Study of Health in Pomerania. Serum PINP, BAP and CTX concentrations were measured on the IDS-iSYS Automated System (Immunodiagnostic Systems, Frankfurt am Main, Germany). The reference interval was defined as the central 95% range. We determined age-specific reference intervals for PINP, BAP, and CTX for men by quantile regression. Reference intervals for women were age-independent. Reference intervals for men for PINP and CTX decreased with age (25-29year-old men: PINP 31.1-95.9ng/mL, CTX 0.12-0.83ng/mL; 75-79year-old men: PINP 15.7-68.1ng/mL, CTX 0.05-0.58ng/mL). The reference interval for men for BAP did not significantly change with age (25-29year-old men: 7.4-27.7ng/mL; 75-79year-old men: 7.6-24.4ng/mL). The reference intervals for 30-54year-old premenopausal women were: PINP 19.3-76.3ng/mL, BAP 6.0-22.7ng/mL, and CTX 0.05-0.67ng/mL. The reference intervals for 50-79year-old postmenopausal women were: PINP 18.2-102.3ng/mL, BAP 8.1-31.6ng/mL, and CTX 0.09-1.05ng/mL. An intensively characterized, large reference population free of bone-related diseases allowed us to determine robust reference intervals for serum concentrations of PINP, BAP and CTX. Our normative data may aid to interpret bone turnover in adult men and pre- and postmenopausal women.",
"Serum tartrate-resistant acid phosphatase (TRACP) 5b was investigated for use as a marker for diagnosis of giant cell tumor (GCT) of bone and for detection of its recurrence.Four patients with GCT of bone who were initially referred to our hospital were classified as a primary group. Three patients who had local recurrence following curettage were classified as a local recurrence group. Five with no recurrence were classified as a no-recurrence group. Eighteen patients with primary and metastatic malignant bone tumors were also enrolled in the study as a control group. Serum TRACP 5b was measured before the biopsy in all patients and was measured periodically after the operation in patients with GCT of bone. Student t-tests were used for statistical analyses.TRACP 5b was greater than 1500 Um/dL in all primary group patients. Mean TRACP 5b values decreased gradually with post-operative time, showing lower values until local recurrence. The mean value of TRACP 5b of the local recurrence group (753 ± 68.7 mU/dL) was significantly higher than that of the no-recurrence group (340.6 ± 78.3 mU/dL). The mean value of TRACP 5b of the control group (466.9 ± 130.3 mU/dL) was much lower than that of the primary group and markedly lower than that of the local recurrence group. However, no significant difference was found between the no-recurrence group and the control group.Serum TRACP 5b is a useful and convenient marker for diagnosing GCT of bone and for predicting its recurrence.",
"Background: Osteoporosis is a skeletal disease that is associated with a reduction in bone mass and microstructures and deterioration of bone tissue. It is also associated with an increased risk of fracture that is the most important complication of osteoporosis. The knowledge about costs and economic aspects of osteoporosis plays an important role in making policies and planning measures for the prevention and management of this disease; hence, this study systematically investigated the available evidence on the costs associated with osteoporosis worldwide. Methods: In this systematic review, electronic searches were performed on various online databases, including PubMed, Embase, Scopus, web of science, ProQuest, and Cochrane. The timeframe selected for searching articles was from 1980 to 2018. Results: Of a total of 1989 papers, 28 papers were included in the study on the basis of inclusion criteria. Based on the data extracted from the mentioned studies, the mean age of people with osteoporotic fractures was 50 years, with the highest costs associated with hip fractures. Conclusion: Our review indicated that the cost of osteoporosis carries a significant economic burden on countries in the world. The main cost drivers in this study were Fracture-related costs. The direct annual cost of treating osteoporotic fractures of people on average is reported to be between 5000 and 6500 billion USD in Canada, Europe and the USA alone, not taking into account indirect costs such as disability and loss of productivity. Prevention of this disease can significantly reduce the costs incurred by the health system.",
"Bone mass density (BMD) is still the gold standard for the diagnosis of osteoporosis, but bone turnover markers (BTMs) can provide helpful information regarding the bone remodeling process. The aim of this study was to determine the correlations between BMD and serum levels of BTMs (tartrate-resistant acid phosphatase-5b [TRAP-5b]), bone-specific alkaline phosphatase (BSAP), estradiol (E2), and magnesium (Mg[2+]) ion concentrations in postmenopausal osteoporotic women as compared to healthy postmenopausal subjects. The study included 132 women with postmenopausal osteoporosis and 81 healthy postmenopausal women without osteoporosis. Dual-energy X-ray absorptiometry scan assessed BMD at different skeleton sites. Serum levels of E2, BSAP, and TRAP-5b were measured by enzyme linked immunosorbent assay. Serum levels of Mg(2+) were determined using the colorimetric spectrometry technique. Serum levels of BTMs were significantly higher in osteoporotic women than in controls. BSAP has a moderate sensitivity (76.5%) and specificity (84.3%) (cutoff point 21.27 U/L). At a cutoff point of 3.45 U/L, TRAP-5b presented a sensitivity of 86.3% and a higher specificity of 90.6%. Osteoporotic patients showed significantly lower concentrations of serum Mg(2+) than the control group. Mg(2+) levels correlated positively with BMD values (r=0.747, P<0.0001). Furthermore, Mg(2+) concentrations correlated positively with E2 levels (r=0.684, P<0.0001). Spine BMD correlated negatively with BSAP levels (r=-0.36, P<0.0001). Our study showed that BMD correlates negatively with BTMs and positively with E2 and Mg(2+) levels. TRAP-5b presents a good specificity in identifying patients with postmenopausal osteoporosis.",
"Low bone mineral density (BMD) is a major determinant of fragility fractures (Fx), but its very long-term prediction is poorly documented. We analyzed the risk of Fx beyond 10 years in women. In a longitudinal cohort study (Os des Femmes de Lyon), we studied 867 women aged 40 years and older (mean age 59 ± 10 y) over 20 years. We assessed the risk of the first incident Fx according to the baseline BMD obtained by dual-energy X-ray absorptiometry, clinical risk factors, and the Fracture Risk Assessment Tool (FRAX). During a median (interquartile range) follow-up of 20 years (3), 245 women sustained one or more incident fragility Fx. Women who sustained a first Fx beyond 10 years (Fx 10-20, n = 109) were younger and had lower values of FRAX compared with those in the first 10 years (Fx 0-10, n = 136). After adjustment for age, they still had greater grip strength and BMD. Parental hip Fx was associated with an increased risk of Fx 10-20 but contrasting with Fx 0-10, the risk of Fx 10-20 was not associated with age, previous Fx, and FRAX except in women younger than 70 years. Each SD decrease of BMD at the spine, femoral neck, total hip, and ultradistal radius was associated with an increased risk of Fx 10-20 with adjusted odds ratios [95% confidence interval (CI)] of 1.43 (95% CI 1.12-1.82), 1.39 (95% CI 1.08-1.82), 1.47 (95% CI 1.14-1.89), and 2.00 (95% CI 1.47-2.7). Women with osteoporosis had an increased risk of both Fx 0-10 and Fx 10-20 compared with women with normal BMD, whereas osteopenia was not associated with a higher risk of Fx beyond 10 years. Low BMD in women is significantly associated with an increased risk of Fx over 20 years. Beyond 10 years, the prediction conferred by baseline BMD was better than that from clinical risk factors.",
"Monitoring bone turnover of the adult and aging skeleton is essential for optimal treatment of bone metabolic diseases, such as postmenopausal osteoporosis. Diagnosis of osteoporosis is based solely on dual-emission x-ray absorptiometry-based measurements of bone mineral density. However, within the last 20 years, biochemical markers of bone turnover have been implemented to a larger degree, and especially within the field of drug development. Numerous clinical studies have underscored that the markers have promise in terms of predicting patients at high risk of losing bone, future fracture events and importantly also the fracture efficacy of drugs in development. Furthermore, while classical methods often require years to monitor the changes, the bone turnover markers do so within a shorter time span. The aims of this article are to provide an update on the different biochemical markers of bone turnover, and to give an overview of their applications in epidemiological and clinical research especially in women. The main emphasis will be on their utility in clinical trials testing the efficacy of drugs for the treatment of osteoporosis, and their ability to supplement bone mass measurements. Finally, recent evidence suggests that biochemical markers may provide information on bone age that may indirectly relate to bone quality, and this is discussed together with future possibilities for measuring bone quality using bone turnover markers. In summary, a more targeted use of biomarkers could assist in the identification of high-risk patients, the process of drug discovery and monitoring of the efficacy of osteoporosis treatment in clinical settings."
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Rice blast caused by a biotic stress
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Rice is one of the staple foods for the majority of the global population that depends directly or indirectly on it. The yield of this important crop is constantly challenged by various biotic stresses. Rice blast, caused by
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"Recognition of pathogen-derived molecules by pattern recognition receptors (PRRs) is a common feature of both animal and plant innate immune systems. In plants, PRR signalling is initiated at the cell surface by kinase complexes, resulting in the activation of immune responses that ward off microorganisms. However, the activation and amplitude of innate immune responses must be tightly controlled. In this Review, we summarize our knowledge of the early signalling events that follow PRR activation and describe the mechanisms that fine-tune immune signalling to maintain immune homeostasis. We also illustrate the mechanisms used by pathogens to inhibit innate immune signalling and discuss how the innate ability of plant cells to monitor the integrity of key immune components can lead to autoimmune phenotypes following genetic or pathogen-induced perturbations of these components.",
"The aboveground parts of terrestrial plants, collectively called the phyllosphere, have a key role in the global balance of atmospheric carbon dioxide and oxygen. The phyllosphere represents one of the most abundant habitats for microbiota colonization. Whether and how plants control phyllosphere microbiota to ensure plant health is not well understood. Here we show that the Arabidopsis quadruple mutant (min7 fls2 efr cerk1; hereafter, mfec)1, simultaneously defective in pattern-triggered immunity and the MIN7 vesicle-trafficking pathway, or a constitutively activated cell death1 (cad1) mutant, carrying a S205F mutation in a membrane-attack-complex/perforin (MACPF)-domain protein, harbour altered endophytic phyllosphere microbiota and display leaf-tissue damage associated with dysbiosis. The Shannon diversity index and the relative abundance of Firmicutes were markedly reduced, whereas Proteobacteria were enriched in the mfec and cad1S205F mutants, bearing cross-kingdom resemblance to some aspects of the dysbiosis that occurs in human inflammatory bowel disease. Bacterial community transplantation experiments demonstrated a causal role of a properly assembled leaf bacterial community in phyllosphere health. Pattern-triggered immune signalling, MIN7 and CAD1 are found in major land plant lineages and are probably key components of a genetic network through which terrestrial plants control the level and nurture the diversity of endophytic phyllosphere microbiota for survival and health in a microorganism-rich environment.",
"Crop breeding aims to balance disease resistance with yield; however, single resistance (R) genes can lead to resistance breakdown, and R gene pyramiding may affect growth fitness. Here we report that the rice Pigm locus contains a cluster of genes encoding nucleotide-binding leucine-rich repeat (NLR) receptors that confer durable resistance to the fungus Magnaporthe oryzae without yield penalty. Among these NLR receptors, PigmR confers broad-spectrum resistance, whereas PigmS competitively attenuates PigmR homodimerization to suppress resistance. PigmS expression, and thus PigmR-mediated resistance, are subjected to tight epigenetic regulation. PigmS increases seed production to counteract the yield cost induced by PigmR Therefore, our study reveals a mechanism balancing high disease resistance and yield through epigenetic regulation of paired antagonistic NLR receptors, providing a tool to develop elite crop varieties.",
"Nucleotide-binding site leucine-rich repeat (NLR) receptors perceive pathogen effectors and trigger plant immunity. However, the mechanisms underlying NLR-triggered defense responses remain obscure. The recently discovered Pigm locus in rice encodes a cluster of NLRs, including PigmR, which confers broad-spectrum resistance to blast fungus. Here, we identify PIBP1 (PigmR-INTERACTING and BLAST RESISTANCE PROTEIN 1), an RRM (RNA-recognition motif) protein that specifically interacts with PigmR and other similar NLRs to trigger blast resistance. PigmR-promoted nuclear accumulation of PIBP1 ensures full blast resistance. We find that PIBP1 and a homolog, Os06 g02240, bind DNA and function as unconventional transcription factors at the promoters of the defense genes OsWAK14 and OsPAL1, activating their expression. Knockout of PIBP1 and Os06 g02240 greatly attenuated blast resistance. Collectively, our study discovers previously unappreciated RRM transcription factors that directly interact with NLRs to activate plant defense, establishing a direct link between transcriptional activation of immune responses with NLR-mediated pathogen perception.",
"The broad-spectrum rice blast resistance gene Pi9 was cloned using a map-based cloning strategy. Sequencing of a 76-kb bacterial artificial chromosome (BAC) contig spanning the Pi9 locus led to identification of six tandemly arranged resistance-like genes with a nucleotide-binding site (NBS) and leucine-rich repeats (LRRs) (Nbs1-Pi9-Nbs6-Pi9). Analysis of selected Pi9 deletion mutants and transformation of a 45-kb fragment from the BAC contig into the susceptible rice cultivar TP309 narrowed down Pi9 to the candidate genes Nbs2-Pi9 and Nbs3-Pi9. Disease evaluation of the transgenic lines carrying the individual candidate genes confirmed that Nbs2-Pi9 is the Pi9 gene. Sequence comparison analysis revealed that the six paralogs at the Pi9 locus belong to four classes and gene duplication might be one of the major evolutionary forces contributing to the formation of the NBS-LRR gene cluster. Semiquantitative reverse transcriptase (RT)-PCR analysis showed that Pi9 was constitutively expressed in the Pi9-resistant plants and was not induced by blast infection. The cloned Pi9 gene provides a starting point to elucidate the molecular basis of the broad-spectrum disease resistance and the evolutionary mechanisms of blast resistance gene clusters in rice.",
"Rice blast, caused by the fungal pathogen Magnaporthe oryzae, is a major constraint to rice production worldwide. In this study, we developed monogenic near-isogenic lines (NILs) NIL , NIL , and NIL carrying genes Pi9, Pizt, and Pi54, respectively, by marker assisted backcross breeding using 07GY31 as the japonica genetic background with good agronomic traits. Polygene pyramid lines (PPLs) PPL combining Pi9 with Pi54, and PPL combining Pizt with Pi54 were then developed using corresponding NILs with genetic background recovery rates of more than 97%. Compared to 07GY31, the above NILs and PPLs exhibited significantly enhanced resistance frequencies (RFs) for both leaf and panicle blasts. RFs of both PPLs for leaf blast were somewhat higher than those of their own parental NILs, respectively, and PPL + exhibited higher RF for panicle blast than NIL and NIL (P < 0.001), hinting an additive effect on the resistance. However, PPL exhibited lower RF for panicle blast than NIL (P < 0.001), failing to realize an additive effect. PPL + showed higher resistant level for panicle blast and better additive effects on the resistance than PPL . It was suggested that major R genes interacted with each other in a way more complex than additive effect in determining panicle blast resistance levels. Genotyping by sequencing analysis and extreme-phenotype genome-wide association study further confirmed the above results. Moreover, data showed that pyramiding multiple resistance genes did not affect the performance of basic agronomic traits. So the way to enhance levels of leaf and panicle blast resistances for rice breeding in this study is effective and may serve as a reference for breeders. Key Message: Resistant levels of rice blast is resulted from different combinations of major R genes, PPL + showed higher resistant level and better additive effects on the panicle blast resistance than PPL .",
"The japonica rice cultivar Hokkai 188 shows a high level of partial resistance to leaf blast. For mapping genes conferring the resistance, a set of 190 F2 progeny/F3 families was developed from the cross between the indica rice cultivar Danghang-Shali, with a low level of partial resistance, and Hokkai 188. Partial resistance to leaf blast in the F3 families was assessed in upland nurseries. From a primary microsatellite (SSR) linkage map and QTL analysis using a subset of 126 F2 progeny/F3 families randomly selected from the above set, one major QTL located on chromosome 1 was detected in the vicinity of SSR marker RM1216. This QTL was responsible for 69.4% of the phenotypic variation, and Hokkai 188 contributed the resistance allele. Segregation analysis in the F3 families for partial resistance to leaf blast was in agreement with the existence of a major gene, and the gene was designated as Pi35(t). Another QTL detected on chromosome 8 was minor, explained 13.4% of the phenotypic variation, and an allele of Danghang-Shali increased the level of resistance in this QTL. Additional SSR markers of the targeted Pi35(t) region were further surveyed in the 190 F2 plants, and Pi35(t) was placed in a 3.5-cM interval flanked by markers RM1216 and RM1003."
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[Myocardial infarction with non-obstructive coronary arteries].
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Myocardial infarction with Non Obstructive Coronary Arteries (MINOCA) is defined by patients presenting with signs and symptoms similar to acute myocardial infarction, but are found to have non-obstructive coronary arteries angiography. What was once considered a benign phenomenon, MINOCA has been proven to carry with it significant morbidity and worse mortality when compared to the general population. As the awareness for MINOCA has increased, guidelines have focused on this unique situation. Cardiac magnetic resonance (CMR) has proven to be an essential first step in the diagnosis of patients with suspected MINOCA. CMR has also been shown to be crucial when differentiating between MINOCA like presentations such as myocarditis, takotsubo and other forms of cardiomyopathy. The following review focuses on demographics of patients with MINOCA, their unique clinical presentation as well as the role of CMR in the evaluation of MINOCA.
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"This study investigated whether T1 mapping by cardiac magnetic resonance (CMR) reflects the clinical evolution of disease in myocarditis and supports its diagnosis independently of the disease stages. Acute viral myocarditis is characterized by a range of intracellular changes due to viral replication and extracellular spill of debris within days of viral infection. Convalescence may be characterized by a chronic low-grade inflammation leading to ventricular remodelling, but also a complete resolution of myocardial changes. Patients with clinical diagnosis of viral myocarditis (N = 165) underwent routine clinical CMR protocol (1.5- and 3.0-T) for assessment of cardiac function and structure, and tissue characterization with T2-weighted imaging and late gadolinium enhancement. T1 mapping was obtained in a mid-ventricular short-axis slice before and >20 min after administration of 0.2 mmol/kg of gadobutrol. Compared with control subjects (n = 40), T1 indexes were increased in patients with myocarditis. Patients with acute symptoms (n = 61) had higher values of T1 indexes compared with patients in clinical convalescence (n = 67). Native T1 is an independent discriminator between health and disease, as well as a discriminator between acute and convalescent stage of the disease. Native T1- was superior to T2-weighted imaging and late gadolinium enhancement with high diagnostic accuracy and positive and negative predictive values. Using pre-defined cutoff values for normal ranges, we demonstrated that acute myocarditis can be independently identified by native T1 of >5 SD above the mean of normal range, whereas convalescence is best defined by either abnormal native T1 (>2 SD) or presence of late gadolinium enhancement. We prospectively tested a new diagnostic algorithm in an independent dataset of patients with clinical diagnosis of myocarditis and achieved similar diagnostic performance. The new diagnostic algorithm using native T1 can reliably discriminate between health and disease and determine the clinical disease stage in patients with a clinical diagnosis of myocarditis.",
"Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.",
"The diagnosis of acute myocarditis is challenging. Nonspecific clinical presentation and an overlap with the diagnosis of acute myocardial infarction present a diagnostic dilemma. The purpose of this article is to describe the role of cardiac MRI and transthoracic echocardiography (TTE) in the diagnosis of acute myocarditis. Thirty-two sequential patients (all male; average age, 33 years) with clinically suspected myocarditis were included. All patients underwent cardiac MRI with sequences dedicated for the evaluation of myocardial delayed enhancement and TTE for the evaluation of wall motion abnormalities (WMAs). Nine patients were excluded because of diagnosis of acute myocardial infarction (n=2) or inadequate cardiac MRI technique (n=7). Retrospective analysis of the images of the remaining 23 patients was performed. An epicardial pattern of abnormal patchy myocardial delayed enhancement was seen on cardiac MRI in 21 of 23 (91%) patients. WMAs were seen on TTE in eight of 23 (35%) patients. Regional rather than global involvement was seen mainly in the inferolateral segments, with a predominance in the midventricular portion. Cardiac MRI might have a greater impact than TTE in confirming the presence of acute myocarditis and evaluating the extent of myocardial involvement. Cardiac MRI provides noninvasive imaging that may obviate invasive procedures such as coronary catheter angiography or endomyocardial biopsy.",
"This study sought to assess the prognostic impact of cardiac magnetic resonance (CMR) and conventional risk factors in patients with myocardial infarction with nonobstructed coronaries (MINOCA). Myocardial infarction with nonobstructed coronary arteries (MINOCA) represents a diagnostic dilemma, and the prognostic markers have not been clarified. A total of 388 consecutive patients with MINOCA undergoing CMR assessment were identified retrospectively from a registry database and prospectively followed for a primary clinical endpoint of all-cause mortality. A 1.5-T CMR was performed using a comprehensive protocol (cines, T2-weighted, and late gadolinium enhancement sequences). Patients were grouped into 4 categories based on their CMR findings: myocardial infarction (MI) (embolic/spontaneous recanalization), myocarditis, cardiomyopathy, and normal CMR. CMR (performed at a median of 37 days from presentation) was able to identify the cause for the troponin rise in 74% of the patients (25% myocarditis, 25% MI, and 25% cardiomyopathy), whereas a normal CMR was identified in 26%. Over a median follow-up of 1,262 days (3.5 years), 5.7% patients died. The cardiomyopathy group had the worst prognosis (mortality 15%; log-rank test: 19.9; p < 0.001), MI had 4% mortality, and 2% in both myocarditis and normal CMR. In a multivariable Cox regression model (including clinical and CMR parameters), CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation electrocardiogram (ECG) remained the only 2 significant predictors of mortality. Using presentation with ECG ST-segment elevation and CMR diagnosis of cardiomyopathy as risk markers, the mortality risk rates were 2%, 11%, and 21% for presence of 0, 1, and 2 factors, respectively (p < 0.0001). In a large cohort of patients with MINOCA, CMR (median 37 days from presentation) identified a final diagnosis in 74% of patients. Cardiomyopathy had the highest mortality, followed by MI. The strongest predictors of mortality were a CMR diagnosis of cardiomyopathy and ST-segment elevation on presentation ECG.",
"Cardiovascular magnetic resonance (CMR) has become the primary tool for noninvasive assessment of myocardial inflammation in patients with suspected myocarditis. The International Consensus Group on CMR Diagnosis of Myocarditis was founded in 2006 to achieve consensus among CMR experts and develop recommendations on the current state-of-the-art use of CMR for myocarditis. The recommendations include indications for CMR in patients with suspected myocarditis, CMR protocol standards, terminology for reporting CMR findings, and diagnostic CMR criteria for myocarditis (i.e., \"Lake Louise Criteria\").",
"Egger's regression test is often used to help detect publication bias in meta-analyses. However, the performance of this test and the usual funnel plot have been challenged particularly when the summary estimate is the natural log of the odds ratio (lnOR). To compare the performance of Egger's regression test with a regression test based on sample size (a modification of Macaskill's test) with lnOR as the summary estimate. Simulation of meta-analyses under a number of scenarios in the presence and absence of publication bias and between-study heterogeneity. Type I error rates (the proportion of false-positive results) for each regression test and their power to detect publication bias when it is present (the proportion of true-positive results). Type I error rates for Egger's regression test are higher than those for the alternative regression test. The alternative regression test has the appropriate type I error rates regardless of the size of the underlying OR, the number of primary studies in the meta-analysis, and the level of between-study heterogeneity. The alternative regression test has comparable power to Egger's regression test to detect publication bias under conditions of low between-study heterogeneity. Because of appropriate type I error rates and reduction in the correlation between the lnOR and its variance, the alternative regression test can be used in place of Egger's regression test when the summary estimates are lnORs.",
"The Lake Louise Criteria (LLC) were established in 2009 and are the recommended cardiac magnetic resonance imaging criterion for diagnosing patients with suspected myocarditis. Subsequently, newer parametric imaging techniques which can quantify T1, T2, and the extracellular volume (ECV) have been developed and may provide additional utility in the diagnosis of myocarditis. However, whether their diagnostic accuracy is superior to LLC remains unclear. In this meta-analysis, we compared the diagnostic performance of native T1, T2, ECV to LLC in diagnosing acute myocarditis. We searched PubMed for published studies of LLC, native T1, ECV, and T2 diagnostic criteria used to diagnose acute myocarditis. Seventeen studies were included, with a total of 867 myocarditis patients and 441 control subjects. Pooled sensitivity, specificity, and diagnostic odds ratio of all diagnostic tests were assessed by bivariate analysis. LLC had a pooled sensitivity of 74%, specificity of 86%, and diagnostic odds ratio of 17.7. Native T1 had a significantly higher sensitivity than LLC (85% versus 74%, P=0.025). Otherwise, there was no significant difference in sensitivity, specificity, and diagnostic odds ratio when comparing LLC to native T1, T2, or ECV. Native T1, T2, and ECV mapping provide comparable diagnostic performance to LLC. Although only native T1 had significantly better sensitivity than LLC, each technique offers distinct advantages for evaluating and characterizing myocarditis when compared with the LLC."
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Risks of gestational diabetes and pregnancy-induced hypertension in women with polycystic ovary syndrome
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To evaluate the risks of developing gestational diabetes (GDM) and pregnancy-induced hypertension (PIH) in women with polycystic ovary syndrome (PCOS) using data from Korea's National Health Insurance Service.
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"What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise and consumer preference? International evidence-based guidelines, including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial, and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis and translation experts. In total, 37 societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: (i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; (ii) reducing unnecessary testing; (iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and (iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREE-II criteria, and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC.",
"Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS.",
"Polycystic ovary syndrome (PCOS) affects 5-20% of women of reproductive age worldwide. The condition is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology (PCOM) - with excessive androgen production by the ovaries being a key feature of PCOS. Metabolic dysfunction characterized by insulin resistance and compensatory hyperinsulinaemia is evident in the vast majority of affected individuals. PCOS increases the risk for type 2 diabetes mellitus, gestational diabetes and other pregnancy-related complications, venous thromboembolism, cerebrovascular and cardiovascular events and endometrial cancer. PCOS is a diagnosis of exclusion, based primarily on the presence of hyperandrogenism, ovulatory dysfunction and PCOM. Treatment should be tailored to the complaints and needs of the patient and involves targeting metabolic abnormalities through lifestyle changes, medication and potentially surgery for the prevention and management of excess weight, androgen suppression and/or blockade, endometrial protection, reproductive therapy and the detection and treatment of psychological features. This Primer summarizes the current state of knowledge regarding the epidemiology, mechanisms and pathophysiology, diagnosis, screening and prevention, management and future investigational directions of the disorder.",
"The purpose of this study was to examine which maternal and neonatal complications are associated with polycystic ovary syndrome (PCOS) in pregnant women. The studies that were included compared pregnancy outcomes between women with PCOS and those without diagnosed PCOS. Our primary outcomes included gestational diabetes mellitus, pregnancy-induced hypertension, and preeclampsia. Secondary outcomes included cesarean delivery rates, operative vaginal delivery rates, preterm delivery, small-for-gestational-age (SGA) infants and large-for-gestational-age infants. We found that PCOS in pregnancy was associated with higher rates of gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, preterm delivery, cesarean delivery, operative vaginal delivery, SGA, and large-for-gestational age. Only gestational diabetes mellitus, pregnancy-induced hypertension, preeclampsia, preterm delivery, and SGA infants were found to be statistically significant. This metaanalysis confirms the higher association of pregnancy complications and PCOS compared with patients who do not have PCOS. Additionally, there may be a stronger association between PCOS and hypertensive disorders than has been shown previously.",
"To study oxidative stress (OS) markers on neonates. The specific aim was to evaluate advanced glycation end products (AGEs) and advanced oxidation protein products (AOPPs) serum levels along with the hormonal/metabolic profile and their possible relationship in a cohort of polycystic ovary syndrome PCOS(N) and gestational diabetes GDM(N) neonates and their mothers PCOS(M) and GDM(M). Prospective controlled study. Academic medical center. The study population comprised 151 mother/neonate pairs. Diet and/or insulin administration in GDM(M). Anthropometric, metabolic, hormonal parameters, and OS markers. The AGEs and AOPPs were higher in PCOS(M) and GDM(M) compared with controls (M). The same significant difference was observed in the corresponding groups of neonates. A strong relationship between mothers and neonates regarding AGEs (r = 0.605) and AOPPs levels (r = 0.735) was disclosed. Analogous findings were observed regarding androgens and insulin resistance in mothers and neonates, respectively. The present study demonstrated that in PCOS(N), the OS status was similar to that of GDM(N) and strongly associated with their mothers' oxidative status. These findings may have clinical implications, as exposure of PCOS(N) to high OS levels during pregnancy could affect several health issues of neonates."
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Non-Squamous Cell Carcinoma-Related Malignant Sinonasal Tract Tumors
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Non-squamous cell carcinoma-related malignant sinonasal tract tumors (non-SCC MSTT) are rare and diverse malignancies. In this study, we report our experience in the management of this group of patients. The treatment outcome has been presented, involving both primary treatment and salvage approaches. Data from 61 patients treated radically due to non-SCC MSTT between 2000 and 2016 at the National Cancer Research Institute, Gliwice branch, were analyzed. The group consisted of the following pathological subtypes of MSTT: adenoid cystic carcinoma (ACC), undifferentiated sinonasal carcinoma (USC), sarcoma, olfactory neuroblastoma (ONB), adenocarcinoma, small cell neuroendocrine carcinoma (SNC), mucoepidermic carcinoma (MEC), and acinic cell carcinoma, which were found in nineteen (31%), seventeen (28%), seven (11.5%), seven (11.5%), five (8%), three (5%), two (3%) and one (2%) of patients, respectively. There were 28 (46%) males and 33 (54%) females at the median age of 51 years. Maxilla was the primary tumor localization followed by the nasal cavity and ethmoid sinus in thirty-one (51%), twenty (32.5%), and seven (11.5%) patients, respectively. In 46 (74%) patients, an advanced tumor stage (T3 or T4) was diagnosed. Primary nodal involvement (N) was found in three (5%) cases, and all patients underwent radical treatment. The combined treatment consisted of surgery and radiotherapy (RT) and was given to 52 (85%) patients. The probabilities of overall survival (OS), locoregional control (LRC), metastases-free survival (MFS), and disease-free survival (DFS) were assessed in pathological subtypes and grouped together, along with the ratio and effectiveness of salvage. Locoregional treatment failure was seen in 21 (34%) patients. Salvage treatment was performed in fifteen (71%) patients and was effective in nine (60%) cases. There was a significant difference in OS between patients who underwent salvage and those who did not (median: 40 months vs. 7 months,
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"Sinonasal malignancies vary in behavior according to histology and anatomical location. Incidence, survival, and optimal treatment for these lesions are thus uncertain in various cases. Our objective was to utilize a national population-based registry to identify the most common sinonasal histopathologies by anatomical site, and subsequently analyze the data by incidence trends, survival rates, patient demographics, and treatment modalities. Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. The SEER database was examined for patients diagnosed with sinonasal malignancies between 1973 and 2011. Data were stratified according to anatomical site, incidence, survival, histology, staging, and patient demographics. Therapy-based outcomes were analyzed for cases from 1983 to 2011. A total of 13,295 patients were identified, with an incidence of 0.83 per 100,000 people. Males comprised 58.6% of cases. Whites represented 81.5% of cases, while blacks comprised 8.7%. Squamous cell carcinoma was the most common histology (41.9%) across all sites of the sinonasal tract. The most common anatomical site of malignancy was the nasal cavity (45.7%), and least common was the frontal sinus (1.2%). For single sites, 5-year disease-specific survival (DSS) was highest for nasal cavity tumors (67.1%) and lowest for overlapping sinus malignancies (37.6%). The overall 5-year DSS for all sinonasal malignancies was 53.7%. Sinonasal malignancies are rare entities with poor overall prognosis. By anatomical site, prognosis is best for nasal cavity cancers and worst for overlapping lesions. 4.",
"The sinuses, nasal cavity, and middle ear represent a rarer location of head and neck malignancy than more common sites such as the larynx and oral cavity. Population-based studies are a useful tool to study the demographic and treatment factors affecting survival in these malignancies. Population-based database search of the Survival, Epidemiology, and End Results (SEER) database from 1973 to 2015 for malignancies involving the nasal cavity, paranasal sinuses, and middle ear. Data were analyzed for demographics, treatment type, stage, primary site and histopathologic type. Kaplan-Meier analysis was used to assess and compare survival. A total of 13,992 cases of sinonasal or middle ear malignancy were identified and analyzed. The majority of patients were between ages 50 and 80 at the time of diagnosis. Overall 5-, 10-, and 20-year survival was 45.7%, 32.2%, and 16.4%, respectively. Lymph node metastasis was reported in 4.4% of patients, while distant metastasis was present in 1.5% of cases. On univariate analysis surgical vs. nonsurgical treatment, sex, race, age at diagnosis, T stage, N stage, M stage, AJCC overall stage, primary site, tumor grade, and histopathologic subtype significantly affected survival. On multivariate analysis age, race, sex, primary site, overall AJCC stage, surgical vs. nonsurgical treatment, and T, N, and M stage remained significant predictors of overall survival. Malignancies of the nasal cavity, paranasal sinuses, and middle ear account for a minority of overall head and neck cancers. The overall 5-, 10-, and 20-year survival for these malignancies is relatively low. Higher T, N, M, and overall stage and higher tumor grade is associated with lower survival. Patients treated with surgery as part of the treatment regimen had higher overall survival. Demographics and primary site also significantly affect survival. Certain histopathologic subtypes were associated with poorer survival.",
"Identify prognostic factors after salvage surgery for recurrent sinonasal malignancy (SNM). Case series with chart review. University of Pittsburgh Medical Center. Forty-two patients who underwent curative surgery for locally recurrent SNM ± adjuvant therapy from June 5, 2000, to December 19, 2012. Patients without follow-up were excluded. Chart review with established prognostic indicators for primary malignancies. Statistical analysis included Kaplan-Meier log-rank test, Fisher's exact test, Student's t test, and Cox regression. Forty-two patients met inclusion criteria: 38.5% developed a second recurrence, and 21.4% had metastases following treatment. The average disease-free interval (DFI) was 26.9 months (range, 2-90 months). DFI was significantly affected by ethmoid versus nonethmoid site (P = .049), histology (P = .012), carotid artery involvement (P = .008), perineural extension (P = .006), and clival invasion (P = .015). The overall survival rates at 6 months, 12 months, and 5 years following surgery were 83.3%, 69%, and 47.6%, respectively. Survival was affected by histology (P = .014), stratified grade (P = .042), tumor extension into the orbit (P = .019), carotid artery (P = .001), perineural space (P = .028), and clivus (P = .022). Complications occurred in 28.6% of patients and were associated with histology (P = .04). Length of hospital stay related to treatment was affected by histology (P = .009), grade (P = .013), and postoperative complication (P < .001). The median percentage of time hospitalized was 8%, and 43% of patients who died within 12 months spent >10% of their remaining days in the hospital. High-risk histologic subtype (melanoma, sinonasal undifferentiated carcinoma, adenocarcinoma, neuroendocrine cancer, sarcoma, and squamous cell carcinoma), grade, and orbital and skull base involvement negatively affect survival and/or DFI for patients with local recurrence of SNM. Improved stratification of patients can be used to guide decision making for patients with recurrent SNM and to avoid inappropriate surgery."
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Role of vascular cell adhesion molecule-1 on hepatic stellate cells in non-alcoholic steatohepatitis
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Non-alcoholic fatty liver disease (NAFLD) can progress to non-alcoholic steatohepatitis (NASH), characterized by inflammation and fibrosis. Fibrosis is mediated by hepatic stellate cells (HSC) and their differentiation into activated myofibroblasts; the latter process is also promoted by inflammation. Here we studied the role of the pro-inflammatory adhesion molecule vascular cell adhesion molecule-1 (VCAM-1) in HSCs in NASH. VCAM-1 expression was upregulated in the liver upon NASH induction, and VCAM-1 was found to be present on activated HSCs. We therefore utilized HSC-specific VCAM-1-deficient and appropriate control mice to explore the role of VCAM-1 on HSCs in NASH. However, HSC-specific VCAM-1-deficient mice, as compared to control mice, did not show a difference with regards to steatosis, inflammation and fibrosis in two different models of NASH. Hence, VCAM-1 on HSCs is dispensable for NASH development and progression in mice.
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"The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar. Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.",
"There has been a rise in the prevalence of nonalcoholic fatty liver disease (NAFLD), paralleling a worldwide increase in diabetes and metabolic syndrome. NAFLD, a continuum of liver abnormalities from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), has a variable course but can lead to cirrhosis and liver cancer. Here we review the pathogenic and clinical features of NAFLD, its major comorbidities, clinical progression and risk of complications and in vitro and animal models of NAFLD enabling refinement of therapeutic targets that can accelerate drug development. We also discuss evolving principles of clinical trial design to evaluate drug efficacy and the emerging targets for drug development that involve either single agents or combination therapies intended to arrest or reverse disease progression.",
"Although the majority of patients with non-alcoholic fatty liver disease (NAFLD) have only steatosis without progression, a sizeable fraction develop non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis and hepatocellular carcinoma (HCC). Many established diet-induced mouse models for NASH require 24-52 weeks, which makes testing for drug response costly and time consuming. We have sought to establish a murine NASH model with rapid progression of extensive fibrosis and HCC by using a western diet (WD), which is high-fat, high-fructose and high-cholesterol, combined with low weekly dose of intraperitoneal carbon tetrachloride (CCl4), which serves as an accelerator. C57BL/6J mice were fed a normal chow diet ± CCl4 or WD ± CCl4 for 12 and 24 weeks. Addition of CCl4 exacerbated histological features of NASH, fibrosis, and tumor development induced by WD, which resulted in stage 3 fibrosis at 12 weeks and HCC development at 24 weeks. Furthermore, whole liver transcriptomic analysis indicated that dysregulated molecular pathways in WD/CCl4 mice and immunologic features were similar to those of human NASH. Our mouse NASH model exhibits rapid progression of advanced fibrosis and HCC, and mimics histological, immunological and transcriptomic features of human NASH, suggesting that it will be a useful experimental tool for preclinical drug testing. A carefully characterized model has been developed in mice that recapitulates the progressive stages of human fatty liver disease, from simple steatosis, to inflammation, fibrosis and cancer. The functional pathways of gene expression and immune abnormalities in this model closely resemble human disease. The ease and reproducibility of this model make it ideal to study disease pathogenesis and test new treatments.",
"Hepatic fibrosis is a dynamic process characterized by the net accumulation of extracellular matrix resulting from chronic liver injury of any aetiology, including viral infection, alcoholic liver disease and NASH. Activation of hepatic stellate cells (HSCs) - transdifferentiation of quiescent, vitamin-A-storing cells into proliferative, fibrogenic myofibroblasts - is now well established as a central driver of fibrosis in experimental and human liver injury. Yet, the continued discovery of novel pathways and mediators, including autophagy, endoplasmic reticulum stress, oxidative stress, retinol and cholesterol metabolism, epigenetics and receptor-mediated signals, reveals the complexity of HSC activation. Extracellular signals from resident and inflammatory cells including macrophages, hepatocytes, liver sinusoidal endothelial cells, natural killer cells, natural killer T cells, platelets and B cells further modulate HSC activation. Finally, pathways of HSC clearance have been greatly clarified, and include apoptosis, senescence and reversion to an inactivated state. Collectively, these findings reinforce the remarkable complexity and plasticity of HSC activation, and underscore the value of clarifying its regulation in hopes of advancing the development of novel diagnostics and therapies for liver disease.",
"During liver injury, liver sinusoidal endothelial cells (LSECs) dysfunction and capillarization promote liver fibrosis. We have previously reported that the LSEC vascular cell adhesion molecule 1 (VCAM1) plays a key role in liver inflammation in nonalcoholic steatohepatitis (NASH) and we now aim to uncover its role in LSEC capillarization and liver fibrosis. Wild-type C57BL/6J mice were fed either chow or high fat, fructose and cholesterol diet to induce NASH and treated with either anti-VCAM1 neutralizing antibody or control isotype antibody. Inducible endothelial cell-specific Vcam1 deleted mice (Vcam1 ) and control mice (Vcam1 ) were fed choline-deficient high-fat diet (CD-HFD) to induce NASH or injected with carbon tetrachloride to induce liver fibrosis. LSECs isolated from Vcam1 or Vcam1 and hepatic stellate cells (HSCs) isolated from wild-type mice were cocultured in a 3-D system or a μ-Slide 2 well co-culture system. Immunostaining for Lyve1 (marker of differentiated LSECs) was reduced in Vcam1 mice and restored in Vcam1 mice in both NASH and liver fibrosis models. Co-immunostaining showed increased α-smooth muscle actin in the livers of Vcam1 mice in areas lacking Lyve1. Furthermore, scanning electron microscopy showed reduced LSEC fenestrae in the Vcam1 mice but not Vcam1 mice in both injury models, suggesting that VCAM1 promotes LSEC capillarization during liver injury. HSCs profibrogenic markers were reduced when cocultured with LSECs from CD-HFD fed Vcam1 mice compared to Vcam1 mice. Furthermore, recombinant VCAM1 activated the Yes-associated protein 1 pathway and induced a fibrogenic phenotype in HSCs in vitro, supporting the profibrogenic role of LSEC VCAM1. VCAM1 is not just a scaffold for leukocyte adhesion during liver injury, but also a modulator of LSEC capillarization and liver fibrosis.",
"Fibrogenesis is a progressive scarring event resulting from disrupted regular wound healing due to repeated tissue injury and can end in organ failure, like in liver cirrhosis. The protagonists in this process, either liver-resident cells or patrolling leukocytes attracted to the site of tissue damage, interact with each other by soluble factors but also by direct cell-cell contact mediated by cell adhesion molecules. Since cell adhesion molecules also support binding to the extracellular matrix, they represent excellent biosensors, which allow cells to modulate their behavior based on changes in the surrounding microenvironment. In this review, we focus on selectins, cadherins, integrins and members of the immunoglobulin superfamily of adhesion molecules as well as some non-classical cell adhesion molecules in the context of hepatic fibrosis. We describe their liver-specific contributions to leukocyte recruitment, cell differentiation and survival, matrix remodeling or angiogenesis and touch on their suitability as targets in antifibrotic therapies.",
"Neutrophils are specialized at killing bacteria and are recruited from the blood in a rapid and robust manner during infection. A cascade of adhesion events direct their attachment to the vascular endothelium and migration into the underlying tissue. A disintegrin and metalloproteinase 17 (ADAM17) functions in the cell membrane of neutrophils and endothelial cells by cleaving its substrates, typically in a cis manner, at an extracellular site proximal to the cell membrane. This process is referred to as ectodomain shedding and it results in the downregulation of various adhesion molecules and receptors, and the release of immune regulating factors. ADAM17 sheddase activity is induced upon cell activation and rapidly modulates intravascular adhesion events in response to diverse environmental stimuli. During sepsis, an excessive systemic inflammatory response against infection, neutrophil migration becomes severely impaired. This involves ADAM17 as indicated by increased levels of its cleaved substrates in the blood of septic patients, and that ADAM17 inactivation improves neutrophil recruitment and bacterial clearance in animal models of sepsis. Excessive ADAM17 sheddase activity during sepsis thus appears to undermine in a direct and indirect manner the necessary balance between intravascular adhesion and de-adhesion events that regulate neutrophil migration into sites of infection. This review provides an overview of ADAM17 function and regulation and its potential contribution to neutrophil dysfunction during sepsis."
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A novel multifunctional drug delivery system based on mesoporous silica particles
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Alendronate (ALN) is the most commonly prescribed oral nitrogen-containing bisphosphonate for osteoporosis therapy. However, its administration is associated with serious side effects. Therefore, the drug delivery systems (DDS) enabling local administration and localized action of that drug are still of great importance. Herein, a novel multifunctional DDS system based on the hydroxyapatite-decorated mesoporous silica particles (MSP-NH
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"In this paper we review the mathematical models used to determine the kinetics of drug release from drug delivery systems. The quantitative analysis of the values obtained in dissolution/release rates is easier when mathematical formulae are used to describe the process. The mathematical modeling can ultimately help to optimize the design of a therapeutic device to yield information on the efficacy of various release models.",
"Biomineral coatings have been extensively used to enhance the osteoconductivity of polymeric scaffolds. Numerous porous scaffolds have previously been coated with a bone-like apatite mineral through incubation in simulated body fluid (SBF). However, characterization of the mineral layer formed on scaffolds, including the amount of mineral within the scaffolds, often requires destructive methods. We have developed a method using micro-computed tomography (μ-CT) scanning to nondestructively quantify the amount of mineral in vitro and in vivo on biodegradable scaffolds made of poly (L-lactic acid) (PLLA) and poly (ε-caprolactone) (PCL). PLLA and PCL scaffolds were fabricated using an indirect solid freeform fabrication (SFF) technique to achieve orthogonally interconnected pore architectures. Biomineral coatings were formed on the fabricated PLLA and PCL scaffolds after incubation in modified SBF (mSBF). Scanning electron microscopy and X-ray diffraction confirmed the formation of an apatite-like mineral. The scaffolds were implanted into mouse ectopic sites for 3 and 10 weeks. The presence of a biomineral coating within the porous scaffolds was confirmed through plastic embedding and μ-CT techniques. Tissue mineral content (TMC) and volume of mineral on the scaffold surfaces detected by μ-CT had a strong correlation with the amount of calcium measured by the orthocresolphthalein complex-one (OCPC) method before and after implantation. There was a strong correlation between OCPC pre- and postimplantation and μ-CT measured TMC (R(2)=0.96 preimplant; R(2)=0.90 postimplant) and mineral volume (R(2)=0.96 preimplant; R(2)=0.89 postimplant). The μ-CT technique showed increases in mineral following implantation, suggesting that μ-CT can be used to nondestructively determine the amount of calcium on coated scaffolds.",
"A chitosan-based microsphere delivery system has been fabricated for controlled release of alendronate (AL). The present study aimed to incorporate the chitosan/hydroxyapatite microspheres-loaded with AL (CH/nHA-AL) into poly(L-lactic acid)/nanohydroxyapatite (PLLA/nHA) matrix to prepare a novel microspheres-scaffold hybrid system (CM-ALs) for drug delivery and bone tissue engineering application. The characteristics of CM-ALs scaffolds containing 10% and 20% CH/nHA-AL were evaluated in vitro, including surface morphology and porosity, mechanical properties, drug release, degradation, and osteogenic differentiation. The in vivo bone repair for large segmental radius defects (1.5 cm) in a rabbit model was evaluated by radiography and histology. In vitro study showed more sustained drug release of CM-AL-containing scaffolds than these of CM/nHA-AL and PLLA/nHA/AL scaffolds, and the mechanical and degradation properties of CM-ALs (10%) scaffolds were comparable to that of PLLA/nHA control. The osteogenic differentiation of adipose-derived stem cells (ASCs) was significantly enhanced as indicated by increased alkaline phosphates (ALP) activity and calcium deposition. In vivo study further showed better performance of CM-ALs (10%) scaffolds with complete repair of large-sized bone defects within 8 weeks. A microspheres-scaffold-based release system containing AL-encapsulated chitosan microspheres was successfully fabricated in this study. Our results suggested the promising application of CM-ALs (10%) scaffolds for drug delivery and bone tissue engineering.",
"The aim of this study was to investigate the effect of alendronate released from chitosan scaffolds on enhancement of osteoblast functions and inhibition of osteoclast differentiation in vitro. The surface and cell morphologies of chitosan scaffolds and alendronate-loaded chitosan scaffolds were characterized by variable pressure field emission scanning electron microscope (VP-FE-SEM). Alendronate was released in a sustained manner. For evaluating osteoblast functions in MG-63 cells, we investigated cell proliferation, alkaline phosphatase (ALP) activity, and calcium deposition. Furthermore, for evaluating inhibition of osteoclast differentiation in RAW 264.7 cells, we investigated tartrate-resistant acid phosphatase (TRAP) activity, TRAP staining, and gene expressions. The in vitro studies revealed that osteoblasts grown on alendronate-loaded chitosan scaffold showed a significant increment in cell proliferation, ALP activity, and calcium deposition as compared to those grown on chitosan scaffolds. In addition, the in vitro study showed that osteoclast differentiation in RAW 264.7 cells cultured on alendronate-loaded chitosan scaffolds was greatly inhibited as compared to those cultured on chitosan scaffolds by the results of TRAP activity, TRAP staining, and gene expressions. Taken together, alendronate-loaded chitosan scaffolds could achieve the dual functions of improvement in osteoblast functions and inhibition of osteoclast differentiation. Thus, alendronate-eluting chitosan substrates are promising materials for enhancing osteoblast functions and inhibiting osteoclast differentiation in orthopedic and dental fields.",
"To better mimic the mineral component and the microstructure of natural bone, novel nano-hydroxyapatite (NHAP)/polymer composite scaffolds with high porosity and well-controlled pore architectures were prepared using thermally induced phase separation (TIPS) techniques. The morphologies, mechanical properties and protein adsorption capacities of the composite scaffolds were investigated. The high porosity (90% and above) was easily achieved and the pore size was adjusted by varying phase separation parameters. The NHAP particles were dispersed in the pore walls of the scaffolds and bound to the polymer very well. NHAP/polymer scaffolds prepared using pure solvent system had a regular anisotropic but open 3D pore structure similar to plain polymer scaffolds while micro-hydroxyapatite (MHAP)/polymer scaffolds had a random irregular pore structure. The introduction of HAP greatly increased the mechanical properties and improved the protein adsorption capacity. In a dioxane/water mixture solvent system, NHAP-incorporated poly(L-lactic acid) (PLLA) scaffolds developed a fibrous morphology which in turn increased the protein adsorption three fold over non fibrous scaffolds. The results suggest that the newly developed NHAP/polymer composite scaffolds may serve as an excellent 3D substrate for cell attachment and migration in bone tissue engineering.",
"Recent advancements in drug delivery technologies utilizing a variety of carriers have resulted in a path-breaking revolution in the approach towards diagnosis and therapy alike in the current times. Need for materials with high thermal, chemical and mechanical properties have led to the development of mesoporous silica nanoparticles (MSNs). These ordered porous materials have garnered immense attention as drug carriers owing to their distinctive features over the others. They can be synthesized using a relatively simple process, thus making it cost effective. Moreover, by controlling the parameters during the synthesis; the morphology, pore size and volume and particle size can be transformed accordingly. Over the last few years, a rapid increase in research on MSNs as drug carriers for the treatment of various diseases has been observed indicating its potential benefits in drug delivery. Their widespread application for the loading of small molecules as well as macromolecules such as proteins, siRNA and so forth, has made it a versatile carrier. In the recent times, researchers have sorted to several modifications in the framework of MSNs to explore its potential in drug resistant chemotherapy, antimicrobial therapy. In this review, we have discussed the synthesis of these multitalented nanoparticles and the factors influencing the size and morphology of this wonder carrier. The second part of this review emphasizes on the applications and the advances made in the MSNs to broaden the spectrum of its use especially in the field of biomedicine. We have also touched upon the lacunae in the thorough understanding of its interaction with a biological system which poses a major hurdle in the passage of this carrier to the clinical level. In the final part of this review, we have discussed some of the major patents filed in the field of MSNs for therapeutic purpose.",
"α,α-Bisphosphonates (BPs) are well established in the treatment of bone diseases such as osteoporosis and Paget's disease. Their successful application originates from their high affinity to hydroxyapatite. While the initially appreciated features of BPs are already beneficial to many patients, recent developments have further expanded their pleiotropic applications. This review describes the background of the interactions of BPs with bone cells that form the basis of the classical treatment. A better understanding of the mechanism behind their interactions allows for the parallel application of BPs against bone cancer and metastases followed by palliative pain relief. Targeted therapy with bone-seeking BPs coupled with a diagnostic agent in one particle resulted in theranostics which is also described here. For example, in such a system, BP moieties are bound to contrast agents used in magnetic resonance imaging or radionuclides used in positron emission tomography. In addition, another example of the pleiotropic function of BPs which involves targeting the imaging agents to bone tissues accompanied by pain reduction is presented in this work."
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B-cell CLL/lymphoma 2 and the programmed cell death receptor 1 pathway
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Myelodysplastic syndromes (MDSs) belong to a group of clonal bone marrow malignancies. In light of the emergence of new molecules, a significant contribution to the understanding of the pathogenesis of the disease is the study of the B-cell CLL/lymphoma 2 (BCL-2) and the programmed cell death receptor 1 (PD-1) protein and its ligands. BCL-2-family proteins are involved in the regulation of the intrinsic apoptosis pathway. Disruptions in their interactions promote the progression and resistance of MDSs. They have become an important target for specific drugs. Bone marrow cytoarchitecture may prove to be a predictor of response to its use. The challenge is the observed resistance to venetoclax, for which the MCL-1 protein may be largely responsible. Molecules with the potential to break the associated resistance include S63845, S64315, chidamide and arsenic trioxide (ATO). Despite promising in vitro studies, the role of PD-1/PD-L1 pathway inhibitors has not yet been established. Knockdown of the PD-L1 gene in preclinical studies was associated with increased levels of BCL-2 and MCL-1 in lymphocytes T, which could increase their survival and promote tumor apoptosis. A trial (NCT03969446) is currently underway to combine inhibitors from both groups.
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[
"Therapy-related myeloid neoplasms (t-MN) are aggressive malignancies in need of effective therapies. The BCL-2 inhibitor venetoclax represents a paradigm shift in the treatment of acute myeloid leukemia. However, the effectiveness of venetoclax has not been studied in a large cohort of t-MN. We retrospectively analyzed 378 t-MN patients, of which 96 (25.4%, 47 therapy-related acute myeloid leukemia, 1 therapy-related chronic myelomonocytic leukemia, 48 therapy-related myelodysplastic syndrome) received venetoclax. Median interval from t-MN to venetoclax initiation was 2.9 (Interquartile range [IQR] 0.7-12) months, and patients received a median of 3 (IQR 1-4) cycles. The composite complete remission (CRc) rate, median progression-free survival (PFS), and overall survival (OS) were 39.1%, 4.9 months, and 7 months, respectively. The upfront use of venetoclax and achieving CRc were associated with improved survival, whereas the presence of Chromosome 7 abnormalities was associated with an inferior survival. Neither the TP53-status nor the percent bone marrow blast predicted the likelihood of CRc or survival. Paired genetic analysis performed at venetoclax initiation and failure did not show the evidence of the selection of the TP53-mutated clone. In a propensity-matched analysis, the use of venetoclax-based regimen as the first-line therapy was associated with a superior survival compared to hypomethylating agent (HMA)-based first-line therapy (9.4 vs. 6.1 months, p = .01). We conclude that the upfront use of venetoclax with HMA improved survival, though PFS and OS remain poor. As the phenotype at diagnosis or the percent blasts did not predict outcomes, venetoclax should be studied in all t-MN phenotypes.",
"Myelodysplastic and myeloproliferative disorders are rare in childhood and there is no widely accepted system for their diagnosis and classification. We propose minimal diagnostic criteria and a simple classification scheme which, while based on accepted morphological features and conforming with the recent suggestions of the WHO, allows for the special problems of myelodysplastic diseases in children. The classification recognizes three major diagnostic groups: (1) juvenile myelomonocytic leukemia (JMML), previously named chronic myelomonocytic leukemia (CMML) or juvenile chronic myeloid leukemia (JCML); (2) myeloid leukemia of Down syndrome, a disease with distinct clinical and biological features, encompassing both MDS and AML occurring in Down syndrome; and (3) MDS occurring both de novo and as a complication of previous therapy or pre-existing bone marrow disorder (secondary MDS). The main subtypes of MDS are refractory cytopenia (RC) and refractory anemia with excess of blasts (RAEB). It is suggested retaining the subtype of RAEB-T with 20-30% blasts in the marrow until more data are available. Cytogenetics and serial assessments of the patients are essential adjuncts to morphology both in diagnosis and classification.",
"The myelodysplastic syndromes (MDS) constitute a group of heterogeneous clonal haemopoietic stem cell disorders, characterized by ineffective and dysplastic haematopoiesis with varying degrees of peripheral cytopenia. Low-risk MDS is characterized by increased apoptosis in the bone marrow (BM) with autoimmune characteristics whereas the advanced or high-risk stages involve immune evasion and secondary DNA damage, giving cells growth potential to progress into acute myeloid leukaemia (AML). Nevertheless, the causes of MDS remain poorly defined and it is not clear how the disease progresses from an early stage to advanced MDS and AML. Although there are clear indications for a role of the immune system, the exact mechanism by which the immune response contributes to the progression is not yet clear. New insights into the pathophysiology of MDS with regard to the immune system will be instrumental for the development of novel patient-oriented therapies. This review is focused on the role of immune responses in MDS and the implications for the development of novel immune therapies.",
"Interferon (IFN)-γ is the major mediator of anti-tumor immune responses; nevertheless, cancer cells use intrigue strategies to alter IFN-γ signaling and avoid elimination. Understanding the immune regulatory mechanisms employed by acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) cells upon exposure to IFN-γ is critical for development of immunotherapy and checkpoint blockade therapy approaches. This study aims to explore the influence of myeloid maturation on IFN-γ-induced PD-L1 and PD-L2 expression and on pro-leukemogenic transcription factor STAT3 signaling in AML and MDS. Stimulation of myeloid blasts' maturation by all-trans retinoic acid (ATRA) or 1α,25-dihydroxyvitamin D3 (vitamin D) increased the CD11b+ fraction that expressed PD-1 ligands in response to IFN-γ. Intriguingly, STAT3 pathway was potently induced by IFN-γ and strengthened upon prolonged exposure. Nonetheless, STAT3-mediated atypical IFN-γ signaling appeared as a negligible factor for PD-L1 and PD-L2 expression. These negative influences of IFN-γ could be alleviated by a small-molecule inhibitor of STAT3, stattic, which also inhibited the upregulation of PD-L1. In conclusion, induction of myeloid maturation enhances the responsiveness of AML and MDS cells to IFN-γ. However, these malignant myeloid cells can exploit both STAT3 pathway and PD-1 ligands to survive IFN-γ-mediated immunity and maintain secondary immune resistance.",
"Little data are available for the expression of immune checkpoint (IC) molecules within myelodysplastic syndrome (MDS). Here, we report increased PD-L1+ CD34+ CD38- and PD-L1+ CD34+ CD38+ stem cell frequencies within MDS patients compared to stem cell recipients in remission. Additionally, we observed exceedingly similar PD1+ and Tim-3+ T-cell frequencies between acute myeloid leukaemia (AML) and MDS samples that were elevated compared to patients in remission. Furthermore, we found highly dynamic Tim-3+ and PD1+ T-cell frequencies within serial samples of relapsing MDS with excess blasts (MDS-EB II) patients, correlating with further disease markers. These findings support the idea of a potential successful implementation of IC inhibitor treatment in suitable MDS patients.",
"Intratumoral accumulation of CD4+CD25+Foxp3+ regulatory T (Treg) cells occurs in acute myeloid leukemia (AML), but little is known about the role of tumor cells themselves in this process. Here, we showed that an immune checkpoint PD-L1 expressed by AML cells promoted the conversion and expansion of Treg cells sustaining high expression of Foxp3 and PD-1 as well as a suppressive function. Furthermore, an AML cell line HEL overexpressed PD-L1 promoted the conversion and expansion of Treg cells and CD4+PD-1+Foxp3+ T (PD-1+Treg) cells from the conventional CD4+ T cells. CD4+CD25highPD-1+ T cells secreted more IL-10 production than CD4+CD25highPD-1- T cells. IL-35, another cytokine secreted by Treg cells, promoted the proliferation of HL-60 cells and enhanced chemoresistance to cytarabine. Blockade of PD-1 signaling using anti-PD-L1 antibody dramatically impaired the generation of Treg cells and sharply retarded the progression of a murine AML model injected with C1498 cells. The frequency of intratumoral PD-1+ Treg cells was capable of predicting patient survival in patients with AML. In conclusion, our data suggest that PD-L1 expression by AML cells may directly drive Treg cell expansion as a mechanism of immune evasion and the frequency of PD-1+ Treg cells is a potential prognostic predictor in patients with AML.",
"Patients who develop therapy-related myeloid neoplasm, either myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML), have a poor prognosis. An earlier Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 868 allogeneic hematopoietic cell transplantations (allo-HCTs) performed between 1990 and 2004 showed a 5-year overall survival (OS) and disease-free survival (DFS) of 22% and 21%, respectively. Modern supportive care, graft-versus-host disease prophylaxis, and reduced-intensity conditioning (RIC) regimens have led to improved outcomes. Therefore, the CIBMTR analyzed 1531 allo-HCTs performed in adults with t-MDS (n = 759) or t-AML (n = 772) between and 2000 and 2014. The median age was 59 years (range, 18 to 74 years) for the patients with t-MDS and 52 years (range, 18 to 77 years) for those with t-AML. Twenty-four percent of patients with t-MDS and 11% of those with t-AML had undergone a previous autologous (auto-) HCT. A myeloablative conditioning (MAC) regimen was used in 49% of patients with t-MDS and 61% of patients with t-AML. Nonrelapse mortality at 5 years was 34% (95% confidence interval [CI], 30% to 37%) for patients with t-MDS and 34% (95% CI, 30% to 37%) for those with t-AML. Relapse rates at 5 years in the 2 groups were 46% (95% CI, 43% to 50%) and 43% (95% CI, 40% to 47%). Five-year OS and DFS were 27% (95% CI, 23% to 31%) and 19% (95% CI, 16% to 23%), respectively, for patients with t-MDS and 25% (95% CI, 22% to 28%) and 23% (95% CI, 20% to 26%), respectively, for those with t-AML. In multivariate analysis, OS and DFS were significantly better in young patients with low-risk t-MDS and those with t-AML undergoing HCT with MAC while in first complete remission, but worse for those with previous auto-HCT, higher-risk cytogenetics or Revised International Prognostic Scoring System score, and a partially matched unrelated donor. Relapse remains the major cause of treatment failure, with little improvement seen over the past 2 decades. These data mandate caution when recommending allo-HCT in these conditions and indicate the need for more effective antineoplastic approaches before and after allo-HCT."
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Radiogenomic association map linking tumor morphology, shape, texture, and size with gene and miRNA signatures
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The heterogeneity of lung tumor nodules is reflected in their phenotypic characteristics in radiological images. The radiogenomics field employs quantitative image features combined with transcriptome expression levels to understand tumor heterogeneity molecularly. Due to the different data acquisition techniques for imaging traits and genomic data, establishing meaningful connections poses a challenge. We analyzed 86 image features describing tumor characteristics (such as shape and texture) with the underlying transcriptome and post-transcriptome profiles of 22 lung cancer patients (median age 67.5 years, from 42 to 80 years) to unravel the molecular mechanisms behind tumor phenotypes. As a result, we were able to construct a radiogenomic association map (RAM) linking tumor morphology, shape, texture, and size with gene and miRNA signatures, as well as biological correlates of GO terms and pathways. These indicated possible dependencies between gene and miRNA expression and the evaluated image phenotypes. In particular, the gene ontology processes "regulation of signaling" and "cellular response to organic substance" were shown to be reflected in CT image phenotypes, exhibiting a distinct radiomic signature. Moreover, the gene regulatory networks involving the TFs
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[
"The cell nucleus is a highly organized cellular organelle that contains the genetic material. The study of nuclear architecture has become an important field of cellular biology. Extracting quantitative data from 3D fluorescence imaging helps understand the functions of different nuclear compartments. However, such approaches are limited by the requirement for processing and analyzing large sets of images. Here, we describe Tools for Analysis of Nuclear Genome Organization (TANGO), an image analysis tool dedicated to the study of nuclear architecture. TANGO is a coherent framework allowing biologists to perform the complete analysis process of 3D fluorescence images by combining two environments: ImageJ (http://imagej.nih.gov/ij/) for image processing and quantitative analysis and R (http://cran.r-project.org) for statistical processing of measurement results. It includes an intuitive user interface providing the means to precisely build a segmentation procedure and set-up analyses, without possessing programming skills. TANGO is a versatile tool able to process large sets of images, allowing quantitative study of nuclear organization. TANGO is composed of two programs: (i) an ImageJ plug-in and (ii) a package (rtango) for R. They are both free and open source, available (http://biophysique.mnhn.fr/tango) for Linux, Microsoft Windows and Macintosh OSX. Distribution is under the GPL v.2 licence. thomas.boudier@snv.jussieu.fr Supplementary data are available at Bioinformatics online.",
"Molecular imaging is being hailed as the next great advance for imaging. This introductory article in the molecular imaging series to be published over the next several months in Radiology sets the stage for the subsequent set of articles by providing relevant definitions and background information and traces the evolution of molecular imaging to its current state of research and clinical practice. It discusses in detail the evolution of molecular imaging and the role that the National Cancer Institute and the National Institutes of Health have had in the funding and development of many of the important molecular imaging research programs that are in existence today. The article also provides basic information about the complex biology of the cell and details of the pathogenesis of cancer and how molecular imaging will be critical for earlier detection and management of cancer in the future. The article lays the foundation for the subsequent articles in the series and describes how and why molecular imaging will be critical and integral for clinical care of patients in the future. The introductory article also discusses the relevance of molecular imaging to clinical radiology practice and why it is critical for the practicing radiologist to understand these evolving techniques, as they will be the future of imaging.",
"Lung cancer is the highest cause of mortality among tumor pathologies worldwide. There are no validated techniques for an early detection of pulmonary cancer lesions other than low-dose helical computed tomography scan. Unfortunately, this method has some negative effects. Recent studies have laid the basis for development of exosomes-based techniques to screen/diagnose lung cancers. As the isolation of circulating exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostic applications. We used a first set of 30 plasma samples from as many patients, including 10 patients affected by lung adenocarcinomas, 10 with lung granulomas, and 10 healthy smokers matched for age and sex as negative controls. Wide-range microRNAs analysis (742 microRNAs) was performed by quantitative real time polymerase chain reaction. Data were compared on the basis of lesion characteristics, using WEKA software for statistics and modeling. Subsequently, selected microRNAs were evaluated on an independent larger group of samples (105 specimens: 50 lung adenocarcinomas, 30 lung granulomas, and 25 healthy smokers). This analysis led to the selection of four microRNAs to perform a screening test (miR-378a, miR-379, miR-139-5p, and miR-200b-5p), useful to divide population into two groups: nodule (lung adenocarcinomas + carcinomas) and non-nodule (healthy former smokers). Six microRNAs (miR-151a-5p, miR-30a-3p, miR-200b-5p, miR-629, miR-100, and miR-154-3p) were selected for a second test on the nodule population to discriminate between lung adenocarcinoma and granuloma. The screening test showed 97.5% sensitivity, 72.0% specificity, and area under the curve receiver operating characteristic of 90.8%. The diagnostic test had 96.0% sensitivity, 60.0% specificity, and area under the curve receiver operating characteristic of 76.0%. Further evaluation is needed to confirm the predictive power of these models on larger cohorts of samples.",
"Owing to novel therapy strategies in epidermal growth factor receptor (EGFR)-mutated patients, molecular analysis of the EGFR and KRAS genome has become crucial for routine diagnostics. Till date these data have been derived mostly from clinical trials, and thus collected in pre-selected populations. We therefore screened 'allcomers' with a newly diagnosed non-small cell lung carcinoma (NSCLC) for the frequencies of these mutations. A cohort study. Lung cancer centre in a tertiary care hospital. Within 15 months, a total of 552 cases with NSCLC were eligible for analysis. Frequency of scrutinising exons 18, 19 and 21 for the presence of activating EGFR mutation and secondary codon 12 and 13 for activating KRAS mutations. Of the 552 patients, 27 (4.9%) showed a mutation of EGFR. 19 of these patients (70%) had deletion E746-A750 in codon 19 or deletion L858R in codon 21. Adenocarcinoma (ACA) was the most frequent histology among patients with EGFR mutations (ACA, 22/254 (8.7%) vs non-ACA, 5/298 (1.7%); p<0.001). Regarding only ACA, the percentage of EGFR mutations was higher in women (16/116 (14%) women vs 6/138 (4.3%) men; p=0.008). Tumours with an activating EGFR mutation were more likely to be from non-smokers (18/27; 67%) rather than smoker (9/27; 33%). KRAS mutation was present in 85 (15%) of all cases. In 73 patients (86%), the mutation was found in exon 12 and in 12 cases (14%) in exon 13. Similarly, ACA had a higher frequency of KRAS mutations than non-ACA (67/254 (26%) vs 18/298 (6.0%); p<0.001). We found a lower frequency for EGFR and KRAS mutations in an unselected Caucasian patient cohort as previously published. Taking our results into account, clinical trials may overestimate the mutation frequency for EGFR and KRAS in NSCLC due to important selection biases.",
"In the past decade, the characterization of non-small-cell lung cancer (NSCLC) into subtypes based on genotype and histology has resulted in dramatic improvements in disease outcome in select patient subgroups. In particular, molecularly targeted agents that inhibit EGFR or ALK are approved for the treatment of NSCLC harbouring genetic alterations in the genes encoding these proteins. Although acquired resistance usually limits the duration of response to these therapies, a number of new agents have proven effective at tackling specific resistance mechanisms to first-generation inhibitors. Large initiatives are starting to address the role of biomarker-driven targeted therapy in squamous lung cancers, and in the adjuvant setting. Immunotherapy undeniably holds great promise and our understanding of subsets of NSCLC based on patterns of immune response is continuing to evolve. In addition, efforts are underway to identify rare genomic subsets through genomic screening, functional studies, and molecular characterization of exceptional responders. This Review provides an overview of the key developments in the treatment of NSCLC, and discusses potential strategies to further optimize therapy by targeting disease subtypes.",
"Early identification of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations is crucial for selecting a therapeutic strategy for patients with non-small-cell lung cancer (NSCLC). We proposed a machine learning-based model for feature selection and prediction of EGFR and KRAS mutations in patients with NSCLC by including the least number of the most semantic radiomics features. We included a cohort of 161 patients from 211 patients with NSCLC from The Cancer Imaging Archive (TCIA) and analyzed 161 low-dose computed tomography (LDCT) images for detecting EGFR and KRAS mutations. A total of 851 radiomics features, which were classified into 9 categories, were obtained through manual segmentation and radiomics feature extraction from LDCT. We evaluated our models using a validation set consisting of 18 patients derived from the same TCIA dataset. The results showed that the genetic algorithm plus XGBoost classifier exhibited the most favorable performance, with an accuracy of 0.836 and 0.86 for detecting EGFR and KRAS mutations, respectively. We demonstrated that a noninvasive machine learning-based model including the least number of the most semantic radiomics signatures could robustly predict EGFR and KRAS mutations in patients with NSCLC.",
"Recent diagnostic procedure advances have considerably improved early lung cancer detection. However, the invasive, unpleasant, and inconvenient nature of current diagnostic procedures limits their application. There is a great need for novel noninvasive biomarkers for early lung cancer diagnosis. In the present study, we aimed to determine whether microRNA (miRNA) blood signatures are suitable for early detection of lung cancer. Using quantitative reverse transcriptase PCR analysis, we first selected and identified three aberrant plasma expression miRNAs (miR-21, miR-145, and miR-155) in a training set of 62 patients and 60 healthy smokers to define a panel that had high diagnostic efficiency for lung cancer. Then, we validated the detective ability of this miRNA panel in a testing set of 34 malignant tumor patients, 30 patients with benign pulmonary nodules and 32 healthy smokers. In the training set, miR-21 and miR-155 showed higher plasma expression levels, whereas miR-145 showed a lower expression level in patients with malignant cancer, compared with healthy controls (P ≤ 0.001). The three miRNAs used in combination produced the area under receiver operating characteristic curve at 0.847, which helped distinguish lung cancer from healthy smokers with 69.4% sensitivity and 78.3% specificity. A logistic regression model with the best prediction was constructed on the basis of miR-21, miR-145, and miR-155. Validation of the miRNA panel in the testing set confirmed their diagnostic value, which yields a significant improvement over any single one. Plasma miR-21, miR-145, and miR-155 have strong potential as novel noninvasive biomarkers for early detection of lung cancer.",
"The National Institutes of Health have placed significant emphasis on sharing of research data to support secondary research. Investigators have been encouraged to publish their clinical and imaging data as part of fulfilling their grant obligations. Realizing it was not sufficient to merely ask investigators to publish their collection of imaging and clinical data, the National Cancer Institute (NCI) created the open source National Biomedical Image Archive software package as a mechanism for centralized hosting of cancer related imaging. NCI has contracted with Washington University in Saint Louis to create The Cancer Imaging Archive (TCIA)-an open-source, open-access information resource to support research, development, and educational initiatives utilizing advanced medical imaging of cancer. In its first year of operation, TCIA accumulated 23 collections (3.3 million images). Operating and maintaining a high-availability image archive is a complex challenge involving varied archive-specific resources and driven by the needs of both image submitters and image consumers. Quality archives of any type (traditional library, PubMed, refereed journals) require management and customer service. This paper describes the management tasks and user support model for TCIA.",
"In the field of glioma, transcriptome subtypes have been considered as an important diagnostic and prognostic biomarker that may help improve the treatment efficacy. However, existing identification methods of transcriptome subtypes are limited due to the relatively long detection period, the unattainability of tumor specimens via biopsy or surgery, and the fleeting nature of intralesional heterogeneity. In search of a superior model over previous ones, this study evaluated the efficiency of eXtreme Gradient Boosting (XGBoost)-based radiomics model to classify transcriptome subtypes in glioblastoma patients. This retrospective study retrieved patients from TCGA-GBM and IvyGAP cohorts with pathologically diagnosed glioblastoma, and separated them into different transcriptome subtypes groups. GBM patients were then segmented into three different regions of MRI: enhancement of the tumor core (ET), non-enhancing portion of the tumor core (NET), and peritumoral edema (ED). We subsequently used handcrafted radiomics features (n = 704) from multimodality MRI and two-level feature selection techniques (Spearman correlation and F-score tests) in order to find the features that could be relevant. After the feature selection approach, we identified 13 radiomics features that were the most meaningful ones that can be used to reach the optimal results. With these features, our XGBoost model reached the predictive accuracies of 70.9%, 73.3%, 88.4%, and 88.4% for classical, mesenchymal, neural, and proneural subtypes, respectively. Our model performance has been improved in comparison with the other models as well as previous works on the same dataset. The use of XGBoost and two-level feature selection analysis (Spearman correlation and F-score) could be expected as a potential combination for classifying transcriptome subtypes with high performance and might raise public attention for further research on radiomics-based GBM models.",
"Two major treatment strategies employed in non-small cell lung cancer, NSCLC, are tyrosine kinase inhibitors, TKIs, and immune checkpoint inhibitors, ICIs. The choice of strategy is based on heterogeneous biomarkers that can dynamically change during therapy. Thus, there is a compelling need to identify comprehensive biomarkers that can be used longitudinally to help guide therapy choice. Herein, we report a 18F-FDG-PET/CT-based deep learning model, which demonstrates high accuracy in EGFR mutation status prediction across patient cohorts from different institutions. A deep learning score (EGFR-DLS) was significantly and positively associated with longer progression free survival (PFS) in patients treated with EGFR-TKIs, while EGFR-DLS is significantly and negatively associated with higher durable clinical benefit, reduced hyperprogression, and longer PFS among patients treated with ICIs. Thus, the EGFR-DLS provides a non-invasive method for precise quantification of EGFR mutation status in NSCLC patients, which is promising to identify NSCLC patients sensitive to EGFR-TKI or ICI-treatments."
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PROTRAIT: A Deep Learning Framework for Single-Cell Chromatin Accessibility Analysis
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Recent advances in single-cell sequencing assays for the transposase-accessibility chromatin (scATAC-seq) technique have provided cell-specific chromatin accessibility landscapes of cis-regulatory elements, providing deeper insights into cellular states and dynamics. However, few research efforts have been dedicated to modeling the relationship between regulatory grammars and single-cell chromatin accessibility and incorporating different analysis scenarios of scATAC-seq data into the general framework. To this end, we propose a unified deep learning framework based on the ProdDep Transformer Encoder, dubbed PROTRAIT, for scATAC-seq data analysis. Specifically motivated by the deep language model, PROTRAIT leverages the ProdDep Transformer Encoder to capture the syntax of transcription factor (TF)-DNA binding motifs from scATAC-seq peaks for predicting single-cell chromatin accessibility and learning single-cell embedding. Based on cell embedding, PROTRAIT annotates cell types using the Louvain algorithm. Furthermore, according to the identified likely noises of raw scATAC-seq data, PROTRAIT denoises these values based on predated chromatin accessibility. In addition, PROTRAIT employs differential accessibility analysis to infer TF activity at single-cell and single-nucleotide resolution. Extensive experiments based on the Buenrostro2018 dataset validate the effeteness of PROTRAIT for chromatin accessibility prediction, cell type annotation, and scATAC-seq data denoising, therein outperforming current approaches in terms of different evaluation metrics. Besides, we confirm the consistency between the inferred TF activity and the literature review. We also demonstrate the scalability of PROTRAIT to analyze datasets containing over one million cells.
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[
"It is a challenging task to integrate scRNA-seq and scATAC-seq data obtained from different batches. Existing methods tend to use a pre-defined gene activity matrix to convert the scATAC-seq data into scRNA-seq data. The pre-defined gene activity matrix is often of low quality and does not reflect the dataset-specific relationship between the two data modalities. We propose scDART, a deep learning framework that integrates scRNA-seq and scATAC-seq data and learns cross-modalities relationships simultaneously. Specifically, the design of scDART allows it to preserve cell trajectories in continuous cell populations and can be applied to trajectory inference on integrated data.",
"The development of high-throughput RNA sequencing (RNA-seq) at the single-cell level has already led to profound new discoveries in biology, ranging from the identification of novel cell types to the study of global patterns of stochastic gene expression. Alongside the technological breakthroughs that have facilitated the large-scale generation of single-cell transcriptomic data, it is important to consider the specific computational and analytical challenges that still have to be overcome. Although some tools for analysing RNA-seq data from bulk cell populations can be readily applied to single-cell RNA-seq data, many new computational strategies are required to fully exploit this data type and to enable a comprehensive yet detailed study of gene expression at the single-cell level.",
"Single-cell RNA sequencing technologies suffer from many sources of technical noise, including under-sampling of mRNA molecules, often termed \"dropout,\" which can severely obscure important gene-gene relationships. To address this, we developed MAGIC (Markov affinity-based graph imputation of cells), a method that shares information across similar cells, via data diffusion, to denoise the cell count matrix and fill in missing transcripts. We validate MAGIC on several biological systems and find it effective at recovering gene-gene relationships and additional structures. Applied to the epithilial to mesenchymal transition, MAGIC reveals a phenotypic continuum, with the majority of cells residing in intermediate states that display stem-like signatures, and infers known and previously uncharacterized regulatory interactions, demonstrating that our approach can successfully uncover regulatory relations without perturbations.",
"We present cisTopic, a probabilistic framework used to simultaneously discover coaccessible enhancers and stable cell states from sparse single-cell epigenomics data ( http://github.com/aertslab/cistopic ). Using a compendium of single-cell ATAC-seq datasets from differentiating hematopoietic cells, brain and transcription factor perturbations, we demonstrate that topic modeling can be exploited for robust identification of cell types, enhancers and relevant transcription factors. cisTopic provides insight into the mechanisms underlying regulatory heterogeneity in cell populations."
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The Mediating Effect of Challenges on Demographic Characteristics and Coping Strategies of Healthcare Workers
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Healthcare workers (HCWs) including doctors, nurses and allied workers struggled to cope up with the stressful situation as the COVID-19 pandemic unsettled healthcare systems, including India's. Many factors (commonly called as stressors) acted as major sources of stress and resulted in poor mental health of HCWs. Therefore, this study predicted and explained the mediating effect of challenges on demographic characteristics and coping strategies of HCWs. Data from a cross-sectional study was collected from the district hospital of Rajasthan, India, during the period of August 2022-October 2022. HCW's experience level, shift type and distance of greenspaces from their accommodation were significantly correlated with the challenges they faced at work, specifically societal challenges. Thus, HCWs were more inclined to adopt a meaning-focused coping strategy to retain good mental health during the pandemic. Therefore, these findings call for interventions requiring a layered response, comprising strategies and actions that are structural. At the organizational level, these actions may provide supportive workplace environments.
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[
"The purpose of this study was to analyze the mediating effect of self-efficacy and coping strategy in the relationship between job stress and the psychological well-being of care workers. The subjects were 112 home-visiting care workers, and data were collected at four home-visiting nursing centers in a metropolitan city and a small and medium-sized city from July to August 2022. The collected data were analyzed by descriptive statistics, t-test, ANOVA, Pearson's correlation co-efficient, multiple linear regression, and Sobel test. The mean score of psychological well-being was 3.33 ± 0.46 out of a possible 5. The subject's psychological well-being was correlated with self-efficacy (r = 0.64, p < 0.001), problem-solving-focused coping (r = 0.58, p < 0.001), social-support-seeking coping (r = 0.34, p < 0.001), job stress (r = -0.31, p = 0.001), avoidance-focused coping (r = -0.37, p < 0.001). Self-efficacy (Z = -4.92, p < 0.001), problem-solving-focused coping (Z = -2.56, p = 0.010), and avoidance-focused coping (Z = -3.07, p = 0.002) had a mediating effect in the relationship between job stress and psychological well-being of the subjects during the COVID-19 pandemic. Based on these results, the psychological well-being nursing intervention program for home-visiting care workers need to include job stress, problem-solving-focused coping, and avoidance-focused coping.",
"Although a large body of research supports the theory that exposure to nature results in mental health benefits, research evidence on the effects of having a view of green space from home is still scarce. The aim of the present study is to assess the impact that access to a green space view from home has on anxiety and depression. This is a cross-sectional study extracting data from the \"2018 Green Spaces, Daily Habits and Urban Health Survey\" conducted in Carmona (Spain). The study included variables on sociodemographic and lifestyle, view of green spaces from home, self-perceived health status, and risk of anxiety and depression measured using the Hospital Anxiety and Depression Scale (HADS). Chi-square tests were used to assess variable's associations and a multiple linear regression models used to identify the variables explaining the risk of anxiety and depression, taking into account sociodemographic characteristics, frequency of visits and view of green spaces from home. According to our results, adults who enjoy a view of green spaces from home have a lower risk of anxiety and depression.",
"We developed a multidimensional coping inventory to assess the different ways in which people respond to stress. Five scales (of four items each) measure conceptually distinct aspects of problem-focused coping (active coping, planning, suppression of competing activities, restraint coping, seeking of instrumental social support); five scales measure aspects of what might be viewed as emotional-focused coping (seeking of emotional social support, positive reinterpretation, acceptance, denial, turning to religion); and three scales measure coping responses that arguably are less useful (focus on and venting of emotions, behavioral disengagement, mental disengagement). Study 1 reports the development of scale items. Study 2 reports correlations between the various coping scales and several theoretically relevant personality measures in an effort to provide preliminary information about the inventory's convergent and discriminant validity. Study 3 uses the inventory to assess coping responses among a group of undergraduates who were attempting to cope with a specific stressful episode. This study also allowed an initial examination of associations between dispositional and situational coping tendencies.",
"Urbanization, resource exploitation, and lifestyle changes have diminished possibilities for human contact with nature in urbanized societies. Concern about the loss has helped motivate research on the health benefits of contact with nature. Reviewing that research here, we focus on nature as represented by aspects of the physical environment relevant to planning, design, and policy measures that serve broad segments of urbanized societies. We discuss difficulties in defining \"nature\" and reasons for the current expansion of the research field, and we assess available reviews. We then consider research on pathways between nature and health involving air quality, physical activity, social cohesion, and stress reduction. Finally, we discuss methodological issues and priorities for future research. The extant research does describe an array of benefits of contact with nature, and evidence regarding some benefits is strong; however, some findings indicate caution is needed in applying beliefs about those benefits, and substantial gaps in knowledge remain."
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Behavioral, clinical, and vascular variables associated with cognitive impairment in hemodialysis patients
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(1) Background: Cognitive impairment (CI) is more prevalent in hemodialysis (HD) patients than in the general population. The purpose of this study was to examine if behavioral, clinical, and vascular variables are linked with CI in individuals with HD. (2) Methods: Initially, 47 individuals with chronic HD volunteered to participate in the trial, but only 27 patients ultimately completed the Montreal Cognitive Assessment (MoCA) and the Computerized Cognitive Assessment Tool (CompBased-CAT). We collected information on smoking, mental activities, physical activity (Rapid Assessment of Physical Activity, RAPA), and comorbidity. The oxygen saturation (rSO2) and pulse wave velocity (PWV; IEM Mobil-O-Graph) of the frontal lobes were measured. (3) Results: Significant associations were discovered between MoCA and rSO2 (r = 0.44, p = 0.02 and r = 0.62,
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"Patients with chronic kidney disease treated with hemodialysis (HD) have lower cognitive abilities compared to the age-matched healthy population. Recently, physical exercise and cognitive training have been presented as possible interventions to improve cognitive abilities both in the general population and in patients with chronic diseases. To date, there is no general overview of the current knowledge on how these interventions affect cognitive abilities in HD patients and what tests are used to measure these effects. Three electronic databases were searched for randomized controlled studies of physical exercise or cognitive training interventions that examined effects on cognitive abilities/performance in HD patients. Six articles were included. All included studies used physical exercise as an intervention, with one study also including tablet-based cognitive training. Four studies included an intradialytic approach and two included a home-based intervention. Intervention lasted. A significant intervention effect was observed in three studies compared with the control condition. The present review suggests that physical exercise might improve or at least not worsen cognitive performance in HD patients, whereas the effect of cognitive training has not yet been adequately studied. There is a need for more sensitive and specific cognitive tests to adequately measure the effects of interventions in the HD population.",
"Cognitive impairment is common in hemodialysis patients and is associated with significant morbidity. Limited information exists about whether cognitive impairment is associated with survival and whether the type of cognitive impairment is important. Longitudinal cohort. Cognitive function was assessed at baseline and yearly using a comprehensive battery of cognitive tests in 292 prevalent hemodialysis patients. Using principal component analysis, individual test results were reduced into 2 domain scores, representing memory and executive function. By definition, each score carried a mean of 0 and SD of 1. Association of each score with all-cause mortality was assessed using Cox proportional hazards models adjusted for demographics and dialysis and cardiovascular (CV) risk factors. Mean age of participants was 63 years, 53% were men, 23% were African American, and 90% had at least a high school education. During a median follow-up of 2.1 (IQR, 1.1-3.7) years, 145 deaths occurred. Each 1-SD better executive function score was associated with a 35% lower hazard of mortality (HR, 0.65; 95% CI, 0.55-0.76). In models adjusting for demographics and dialysis-related factors, this relationship was partially attenuated but remained significant (HR, 0.81; 95% CI, 0.67-0.98), whereas adjustment for CV disease and heart failure resulted in further attenuation (HR, 0.87; 95% CI, 0.72-1.06). Use of time-dependent models showed a similar unadjusted association (HR, 0.62; 95% CI, 0.54-0.72), with the relationship remaining significant after adjustment for demographics and dialysis and CV risk factors (HR, 0.79; 95% CI, 0.66-0.94). Better memory was associated with lower mortality in univariate analysis (HR per 1 SD, 0.82; 95% CI, 0.69-0.96), but not when adjusting for demographics (HR, 1.00; 95% CI, 0.83-1.19). Patients with dementia were excluded from the full battery, perhaps underestimating the strength of the association. Worse executive function and memory are associated with increased risk of mortality. For memory, this association is explained by patient demographics, whereas for executive function, this relationship may be explained in part by CV disease burden.",
"Physical activity has been associated with better health status in diverse populations, but the association in patients on maintenance hemodialysis is less established. Patient-reported physical activities and associations with mortality, health-related quality of life, and depression symptoms in patients on maintenance hemodialysis in 12 countries were examined. In total, 5763 patients enrolled in phase 4 of the Dialysis Outcomes and Practice Patterns Study (2009-2011) were classified into five aerobic physical activity categories (never/rarely active to very active) and by muscle strength/flexibility activity using the Rapid Assessment of Physical Activity questionnaire. The Kidney Disease Quality of Life scale was used for health-related quality of life. The Center for Epidemiologic Studies Depression scale was used for depression symptoms. Linear regression was used for associations of physical activity with health-related quality of life and depression symptoms scores. Cox regression was used for association of physical activity with mortality. The median (interquartile range) of follow-up was 1.6 (0.9-2.5) years; 29% of patients were classified as never/rarely active, 20% of patients were classified as very active, and 20.5% of patients reported strength/flexibility activities. Percentages of very active patients were greater in clinics offering exercise programs. Aerobic activity, but not strength/flexibility activity, was associated positively with health-related quality of life and inversely with depression symptoms and mortality (adjusted hazard ratio of death for very active versus never/rarely active, 0.60; 95% confidence interval, 0.47 to 0.77). Similar associations with aerobic activity were observed in strata of age, sex, time on dialysis, and diabetes status. The findings are consistent with the health benefits of aerobic physical activity for patients on maintenance hemodialysis. Greater physical activity was observed in facilities providing exercise programs, suggesting a possible opportunity for improving patient outcomes.",
"Hemodialysis (HD) patients are educated and counseled during the HD procedure. There are few studies assessing whether cognitive performance varies with dialysis. Using a randomized cross-over design, 40 patients were assigned to one of two sequences: testing 1 h before dialysis followed 1 month later by testing during the first hour of dialysis (n = 21) versus testing during the first hour of dialysis followed 1 month later by 1 h before dialysis (n = 19). Cognitive tests were administered at each testing period. Mixed regression models evaluated for a dialysis effect (difference between test performance before vs. during dialysis) while adjusting for potential learning (difference between first and second tests). In models accounting for period of testing, there was no difference in test performance between 1 h before versus during the first hour of HD for all administered cognitive tests (p > 0.05). A learning effect was detected between first and second test administration in two tests, specifically, the Word List Learning and the Digit Symbol Substitution Test. We found no difference in cognitive performance depending on the time of testing, suggesting that cognitive tests performed during the first hour of dialysis are a valid assessment of cognitive performance.",
"Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) therapy have an increased risk of developing cognitive impairment and dementia, which are known relevant factors in disease prognosis and therapeutic success, but still lack adequate screening in clinical routine. We evaluated the Montreal Cognitive Assessment (MoCA) for suitability in assessing cognitive performance in HD patients in comparison to the commonly used Mini-Mental State Examination (MMSE) and a detailed neuropsychological test battery, used as gold standard. 43 HD patients and 42 healthy controls with an average age of 58 years, were assessed with the MoCA, the MMSE and a detailed neuropsychological test battery, covering the domains of memory, attention, language, visuospatial and executive functions. Composite scores were created for comparison of cognitive domains and test results were analyzed using Spearman's correlation and linear regression. Cognitive dysfunction was defined using z-score values and predictive values were calculated. Sensitivity and specificity of the MoCA were determined using receiver operating characteristic (ROC) analysis. HD patients performed worse in all cognitive domains, especially in memory recall and executive functions. The MoCA correlated well with the detailed test battery and identified patients with cognitive impairment with a sensitivity of 76.7% and specificity of 78.6% for a cut-off value of ≤24 out of 30 points. In the detailed assessment executive functions accounted significantly for performance in the MoCA. The MMSE only discriminated weakly between groups. The MoCA represents a suitable cognitive screening tool for hemodialysis patients, demonstrating good sensitivity and specificity levels, and covering executive functions, which appear to play an important role in cognitive performance of HD patients.",
"Older patients with ESKD experience rapid declines in executive function after initiating hemodialysis; these impairments might lead to high rates of dementia and Alzheimer's disease in this population. We estimated incidence, risk factors, and sequelae of diagnosis with dementia and Alzheimer's disease among older patients with ESKD initiating hemodialysis. We studied 356,668 older (age ≥66 years old) patients on hemodialysis (January 1, 2001 to December 31, 2013) from national registry data (US Renal Data System) linked to Medicare. We estimated the risk (cumulative incidence) of diagnosis of dementia and Alzheimer's disease and studied factors associated with these disorders using competing risks models to account for death, change in dialysis modality, and kidney transplant. We estimated the risk of subsequent mortality using Cox proportional hazards models. The 1- and 5-year risks of diagnosed dementia accounting for competing risks were 4.6% and 16% for women, respectively, and 3.7% and 13% for men, respectively. The corresponding Alzheimer's disease diagnosis risks were 0.6% and 2.6% for women, respectively, and 0.4% and 2.0% for men, respectively. The strongest independent risk factors for diagnosis of dementia and Alzheimer's disease were age ≥86 years old (dementia: hazard ratio, 2.11; 95% confidence interval, 2.04 to 2.18; Alzheimer's disease: hazard ratio, 2.11; 95% confidence interval, 1.97 to 2.25), black race (dementia: hazard ratio, 1.70; 95% confidence interval, 1.67 to 1.73; Alzheimer's disease: hazard ratio, 1.78; 95% confidence interval, 1.71 to 1.85), women (dementia: hazard ratio, 1.10; 95% confidence interval, 1.08 to 1.12; Alzheimer's disease: hazard ratio, 1.12; 95% confidence interval, 1.08 to 1.16), and institutionalization (dementia: hazard ratio, 1.36; 95% confidence interval, 1.33 to 1.39; Alzheimer's disease: hazard ratio, 1.10; 95% confidence interval, 1.05 to 1.15). Older patients on hemodialysis with a diagnosis of dementia were at 2.14-fold (95% confidence interval, 2.07 to 2.22) higher risk of subsequent mortality; those with a diagnosis of Alzheimer's disease were at 2.01-fold (95% confidence interval, 1.89 to 2.15) higher mortality risk. Older patients on hemodialysis are at substantial risk of diagnosis with dementia and Alzheimer's disease, and carrying these diagnoses is associated with a twofold higher mortality.",
"Physical functioning in patients with end-stage renal disease treated with dialysis is low, whether measured using objective laboratory measures, physical performance testing, or self-reported measures. Peak oxygen uptake (VO2peak), self-reported functioning measures, and physical activity levels are independent predictors of mortality in these patients. Cardiovascular exercise training studies result in improvements in VO2peak, physical performance tests, and self-reported functioning. Resistance exercise training improves muscle strength. Exercise training may have positive benefits on other factors that are important clinical issues in dialysis patients, including cardiovascular risk profile, oxidative stress, and inflammation. Endothelial function, a surrogate marker of atherosclerosis, has been shown to improve with exercise training in dialysis patients. Although there have been numerous recent studies on benefits of exercise, few dialysis clinics or nephrologists provide encouragement or programs as a part of their routine care of their patients. There are many national guidelines that include exercise or increasing physical activity as a part of the treatment of many conditions that are relevant in dialysis patients, including hypertension, hyperlipidemia, and high cardiovascular disease risk. The nephrology community continues to state concern for outcomes; however, a simple, low-tech intervention that has many benefits to their patients (i.e., encouragement, recommendations, and opportunity for increasing physical activity) has not been adopted as part of the standard care. Adoption of routine counseling and encouragement for physical activity has the potential to improve outcomes, improve physical functioning, and optimize quality of life and overall health of dialysis patients."
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Effect of topical diacerein on imiquimod-induced psoriasis
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Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c
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"Psoriasis is a type I-deviated disease characterized by the presence of interferon (IFN)-gamma and multiple IFN-related inflammatory genes in lesions. Because interleukin (IL)-23 is now recognized to play a role in the recruitment of inflammatory cells in a T helper cell (Th)1-mediated disease, we examined psoriasis skin lesions for production of this newly described cytokine. IL-23 is composed of two subunits: a unique p19 subunit and a p40 subunit shared with IL-12. We found a reliable increase in p19 mRNA by quantitative reverse transcription polymerase chain reaction in lesional skin compared with nonlesional skin (22.3-fold increase; P = 0.001). The p40 subunit, shared by IL-12 and IL-23, increased by 11.6-fold compared with nonlesional skin (P = 0.003), but the IL-12 p35 subunit was not increased in lesional skin. IL-23 was expressed mainly by dermal cells and increased p40 immunoreactivity was visualized in large dermal cells in the lesions. Cell isolation experiments from psoriatic tissue showed strong expression of p19 mRNA in cells expressing monocyte (CD14+ CD11c+ CD83-) and mature dendritic cell (DC) markers (CD14- CD11c+ CD83+), whereas in culture, the mRNAs for p40 and p19 were strongly up-regulated in stimulated monocytes and monocyte-derived DCs, persisting in the latter for much longer periods than IL-12. Our data suggest that IL-23 is playing a more dominant role than IL-12 in psoriasis, a Th1 type of human inflammatory disease.",
"Psoriasis is a chronic inflammatory skin disease that is thought to be related to oxidative stress. Much progress has been made in understanding the pathophysiology of psoriasis in relation to the immunologic and antioxidant systems. However, this progress has been hindered by the lack of an appropriate animal model for psoriasis. Recently, imiquimod (IQM)-induced psoriasis-like cutaneous inflammation has been reported in mice and humans. We verified the usefulness of an IQM-induced mouse model in relation to the antioxidant system. BALB/C female mice at 8-10 weeks of age were treated with IQM cream in this study. We analyzed clinical and histopathological changes. Increased reactive oxygen species production was measured by glutathione assay. Levels of myeloperoxidase (MPO) and superoxide dismutase-1 (SOD1) were determined by western blotting and immunohistochemical analyses. The activity of SOD was measured by a SOD activity assay kit. Application of IQM-induced skin inflammation similar to psoriasis in clinical and histopathological aspects. Accumulation of immune cells was confirmed. Oxidative stress was increased, the antioxidant enzyme MPO levels were increased, and both SOD levels and activity were decreased. In conclusion, the IQM-induced mouse model showed an aberrant antioxidant system. Levels of MPO and oxidative stress were increased, and the level and activity of SOD were decreased. Since this model seemed to be an appropriate model for psoriasis, it can be used to further study the pathogenic role of redox imbalance in psoriasis.",
"In osteoarthritis (OA), the alterations in joint tissues are numerous and involve morphological, biochemical and metabolic changes and an upregulation of the inflammatory pathways. The focus of this article is a brief narrative review of the effects of diacerein, an antirheumatic drug from the anthraquinone chemical class, and its active metabolite, rhein, on the factors that participate in the complex interaction between OA tissues and cells leading to the progression of joint structural changes.",
"Psoriasis is associated with atherosclerotic cardiovascular disease (CVD) with significant overlap of inflammatory pathways. A link between vascular inflammation and inflammation in multiple adipose tissue types, spleen, and bone marrow may exist. Therefore, we investigated these associations using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) in patients with psoriasis (n = 83) where half had established CVD. Carotid ultrasound imaging was also performed. Inflammation was measured by FDG uptake in the aorta, visceral- (VAT), subcutaneous- (SAT), and pericardial (PAT) adipose tissues, and spleen and bone marrow, respectively. Vascular inflammation was associated with FDG uptakes in all adipose tissues, including VAT (β = 0.26; p < 0.001), SAT (β = 0.28; p < 0.001), PAT (β = 0.24; p < 0.001), spleen (β = 1.35; p = 0.001), and bone marrow (β = 1.14; p < 0.001). Adjustments for age, sex, body mass index, and high sensitivity C-reactive protein did not change the results. These associations were generally preserved in the patients without prior CVD. No associations were observed between vascular inflammation and carotid intima-media thickness or presence of carotid plaques, respectively. The results suggest an inflammatory link between vascular and adipose tissues, spleen, and bone marrow in patients with psoriasis."
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Acetaminophen and non-steroidal anti-inflammatory drugs in patients with serious acute respiratory syndrome coronavirus 2 infection
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Acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) have been widely prescribed to infected patients; however, the safety of them has not been investigated in patients with serious acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Our objective was to evaluate the association between the previous use of acetaminophen or NSAIDs and the clinical outcomes of SARS-CoV-2 infection. A nationwide population-based cohort study was conducted using the Korean Health Insurance Review and Assessment Database through propensity score matching (PSM). A total of 25,739 patients aged 20 years and older who tested for SARS-CoV-2 were included from 1 January 2015 to 15 May 2020. The primary endpoint was a positive result for a SARS-CoV-2 test, and the secondary endpoint was serious clinical outcomes of SARS-CoV-2 infection, such as conventional oxygen therapy, admission to the intensive care unit, need for invasive ventilation care, or death. Of 1058 patients, after propensity score matching, 176 acetaminophen users and 162 NSAIDs users were diagnosed with coronavirus disease 2019. After PSM, 162 paired data sets were generated, and the clinical outcomes of the acetaminophen group were not significantly different from those of the NSAIDs group. This suggests that acetaminophen and NSAIDs can be used safely to control symptoms in patients suspected of having SARS-CoV-2.
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"Concerns have been expressed that some drugs may increase susceptibility to SARS-CoV-2 infection. In contrast, other drugs have generated interest as potential therapeutic agents. All adults aged ≥18 years who were tested for COVID-19 were included. Exposure was defined as a prescription of study drugs which would have been continued until 7 days prior to test for COVID-19 or later. The outcome measures were the diagnosis of COVID-19 and severe COVID-19. Disease risk score matching and multiple logistic regression was used. Matched claims and testing results were available for 219,961 subjects, of whom 7,341 (3.34%) were diagnosed with COVID-19. Patients were matched to 36,705 controls, and the subset of 878 patients of severe COVID-19 also matched with 1,927 mild-to-moderate patients. Angiotensin receptor blockers were not associated with either the diagnosis of COVID-19 (adjusted OR [aOR], 1.02; 95% confidence interval [CI], 0.90-1.15) or severe disease (aOR, 1.11; 95% CI, 0.87-1.42). The use of hydroxychloroquine was not associated with a lower risk for COVID-19 (aOR, 0.94; 95% CI, 0.53-1.66) or severe disease (aOR, 3.51; 95% CI, 0.76-16.22). In this national claims data-based case-control study, no commonly prescribed medications were associated with risk of COVID-19 infection or COVID-19 severity.",
"Due to the fact that coronavirus disease 2019 (COVID-19) is still prevalent, and current reports show that some parts of the world have seen increase in incidence, it is relevant that health professionals and scientists know about recent or novel trends, especially drug treatments. Additionally, the safety profiles of these drug treatments need to be documented and shared with the public. Some studies have demonstrated the clinical benefits of non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids in COVID-19 treatment. On the contrary, others have also reported that NSAIDs and corticosteroids may worsen symptoms associated with COVID-19. While some researchers have suggested that corticosteroids may be helpful if used in the early stages of COVID-19, there are still some conflicting findings regarding the use of corticosteroids in certain viral infections. Our review suggests that methylprednisolone, dexamethasone, and ibuprofen have therapeutic potential in reducing mortality due to COVID-19 among hospitalized patients. This review also highlights the fact that the use of NSAIDs is not associated with adverse outcomes of COVID-19. In reality, evidence suggests that NSAIDs do not increase the risk of COVID-19 infections. Also, the literature reviewed suggests that corticosteroid treatment in COVID-19 was linked with a decrease in all-cause mortality and disease progression, without increase in adverse events when compared to no corticosteroid treatment.",
"There is limited information describing the presenting characteristics and outcomes of US patients requiring hospitalization for coronavirus disease 2019 (COVID-19). To describe the clinical characteristics and outcomes of patients with COVID-19 hospitalized in a US health care system. Case series of patients with COVID-19 admitted to 12 hospitals in New York City, Long Island, and Westchester County, New York, within the Northwell Health system. The study included all sequentially hospitalized patients between March 1, 2020, and April 4, 2020, inclusive of these dates. Confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by positive result on polymerase chain reaction testing of a nasopharyngeal sample among patients requiring admission. Clinical outcomes during hospitalization, such as invasive mechanical ventilation, kidney replacement therapy, and death. Demographics, baseline comorbidities, presenting vital signs, and test results were also collected. A total of 5700 patients were included (median age, 63 years [interquartile range {IQR}, 52-75; range, 0-107 years]; 39.7% female). The most common comorbidities were hypertension (3026; 56.6%), obesity (1737; 41.7%), and diabetes (1808; 33.8%). At triage, 30.7% of patients were febrile, 17.3% had a respiratory rate greater than 24 breaths/min, and 27.8% received supplemental oxygen. The rate of respiratory virus co-infection was 2.1%. Outcomes were assessed for 2634 patients who were discharged or had died at the study end point. During hospitalization, 373 patients (14.2%) (median age, 68 years [IQR, 56-78]; 33.5% female) were treated in the intensive care unit care, 320 (12.2%) received invasive mechanical ventilation, 81 (3.2%) were treated with kidney replacement therapy, and 553 (21%) died. As of April 4, 2020, for patients requiring mechanical ventilation (n = 1151, 20.2%), 38 (3.3%) were discharged alive, 282 (24.5%) died, and 831 (72.2%) remained in hospital. The median postdischarge follow-up time was 4.4 days (IQR, 2.2-9.3). A total of 45 patients (2.2%) were readmitted during the study period. The median time to readmission was 3 days (IQR, 1.0-4.5) for readmitted patients. Among the 3066 patients who remained hospitalized at the final study follow-up date (median age, 65 years [IQR, 54-75]), the median follow-up at time of censoring was 4.5 days (IQR, 2.4-8.1). This case series provides characteristics and early outcomes of sequentially hospitalized patients with confirmed COVID-19 in the New York City area.",
"The role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB) in the setting of the coronavirus disease 2019 (COVID-19) pandemic is hotly debated. There have been recommendations to discontinue these medications, which are essential in the treatment of several chronic disease conditions, while, in the absence of clinical evidence, professional societies have advocated their continued use. To study the association between use of ACEIs/ARBs with the likelihood of testing positive for COVID-19 and to study outcome data in subsets of patients taking ACEIs/ARBs who tested positive with severity of clinical outcomes of COVID-19 (eg, hospitalization, intensive care unit admission, and requirement for mechanical ventilation). Retrospective cohort study with overlap propensity score weighting was conducted at the Cleveland Clinic Health System in Ohio and Florida. All patients tested for COVID-19 between March 8 and April 12, 2020, were included. History of taking ACEIs or ARBs at the time of COVID-19 testing. Results of COVID-19 testing in the entire cohort, number of patients requiring hospitalizations, intensive care unit admissions, and mechanical ventilation among those who tested positive. A total of 18 472 patients tested for COVID-19. The mean (SD) age was 49 (21) years, 7384 (40%) were male, and 12 725 (69%) were white. Of 18 472 patients who underwent COVID-19 testing, 2285 (12.4%) were taking either ACEIs or ARBs. A positive COVID-19 test result was observed in 1735 of 18 472 patients (9.4%). Among patients who tested positive, 421 (24.3%) were admitted to the hospital, 161 (9.3%) were admitted to an intensive care unit, and 111 (6.4%) required mechanical ventilation. Overlap propensity score weighting showed no significant association of ACEI and/or ARB use with COVID-19 test positivity (overlap propensity score-weighted odds ratio, 0.97; 95% CI, 0.81-1.15). This study found no association between ACEI or ARB use and COVID-19 test positivity. These clinical data support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic. However, further study in larger numbers of hospitalized patients receiving ACEI and ARB therapy is needed to determine the association with clinical measures of COVID-19 severity.",
"Angiotensin-converting enzyme 2 (ACE2) has emerged as a novel regulator of cardiac function and arterial pressure by converting angiotensin II (Ang II) into the vasodilator and antitrophic heptapeptide, angiotensin-(1-7) [Ang-(1-7)]. As the only known human homolog of ACE, the demonstration that ACE2 is insensitive to blockade by ACE inhibitors prompted us to define the effect of ACE inhibition on the ACE2 gene. Blood pressure, cardiac rate, and plasma and cardiac tissue levels of Ang II and Ang-(1-7), together with cardiac ACE2, neprilysin, Ang II type 1 receptor (AT1), and mas receptor mRNAs, were measured in Lewis rats 12 days after continuous administration of vehicle, lisinopril, losartan, or both drugs combined in their drinking water. Equivalent decreases in blood pressure were obtained in rats given lisinopril or losartan alone or in combination. ACE inhibitor therapy caused a 1.8-fold increase in plasma Ang-(1-7), decreased plasma Ang II, and increased cardiac ACE2 mRNA but not cardiac ACE2 activity. Losartan increased plasma levels of both Ang II and Ang-(1-7), as well as cardiac ACE2 mRNA and cardiac ACE2 activity. Combination therapy duplicated the effects found in rats medicated with lisinopril, except that cardiac ACE2 mRNA fell to values found in vehicle-treated rats. Losartan treatment but not lisinopril increased cardiac tissue levels of Ang II and Ang-(1-7), whereas none of the treatments had an effect on cardiac neprilysin mRNA. Selective blockade of either Ang II synthesis or activity induced increases in cardiac ACE2 gene expression and cardiac ACE2 activity, whereas the combination of losartan and lisinopril was associated with elevated cardiac ACE2 activity but not cardiac ACE2 mRNA. Although the predominant effect of ACE inhibition may result from the combined effect of reduced Ang II formation and Ang-(1-7) metabolism, the antihypertensive action of AT1 antagonists may in part be due to increased Ang II metabolism by ACE2.",
"The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virus-induced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic."
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Peer Relationship Profiles among Early Adolescents from Low-Income Families
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Using research data gathered from multiple sources, the current study explored positive aspects of peer relationship profiles (indexed by peer-nominated acceptance and self-reported friendships) in a person-centered approach among early adolescents from low-income families. Moreover, this study investigated the unique and combined associations of adolescents' attachment to mothers and parent-rated conscientiousness with emerging peer relationship profiles. A total of 295 early adolescents (42.7% girls;
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"The present study concerns an overlooked trait indicator of childhood peer status: Being fun. The study is designed to identify the degree to which being fun is uniquely associated with the peer status variables of likeability and popularity. Two studies of children in grades 4 to 6 (ages 9 to 12) are reported. The first involved 306 girls and 305 boys attending school in northern Colombia. The second involved 363 girls and 299 boys attending school in southern Florida. Students completed similar peer nomination inventories, once in the first study and twice (8 weeks apart) in the second. In both studies, being fun was positively correlated with likeability and popularity. In the second study, being fun predicted subsequent changes in likeability and popularity, after controlling for factors known to be related to each. Initial likeability and popularity also predicted subsequent changes in perceptions of being fun. Anecdotal evidence suggests that children are intensely focused on having fun. The findings indicate that this focus extends beyond the immediate rewards that fun experiences provide; some portion of peer status is uniquely derived from the perception that one is fun to be around.",
"Two studies examine the convergence between measures of friendship and measures of liking in the assessment of friendship and peer acceptance. In the first study, 551 (301 boys and 250 girls) Canadian primary school children (ages 8 to 11) nominated friends and liked-most classmates. In the second study, 282 (127 boys and 155 girls) U.S. primary school children (ages 9 to 11) nominated friends and rated classmates on a sociometric preference scale. The results revealed considerable convergence in the assessment of friendship. Most 1st, 2nd, and 3rd ranked friends were also nominated and rated as liked-peers, suggesting that when measures of liking are used to identify friends, few top-ranked friendships are overlooked. There was less convergence in assessments of peer acceptance. Peer acceptance scores derived from friend nominations were more strongly correlated with peer acceptance scores derived from liking nominations than with those derived from sociometric preference ratings. We conclude that liking nominations accurately capture friendships, particularly best friendships. Friend nominations may be a suitable substitute for assessments of liking, but they are a poor substitute for assessments of sociometric preference.",
"The potential role that children's classroom peer relations play in their school adjustment was investigated during the first 2 months of kindergarten and the remainder of the school year. Measures of 125 children's classroom peer relationships were obtained on 3 occasions: at school entrance, after 2 months of school, and at the end of the school year. Measures of school adjustment, including children's school perceptions, anxiety, avoidance, and performance, were obtained during the second and third assessment occasions. After controlling mental age, sex, and preschool experience, measures of children's classroom peer relationships were used to forecast later school adjustment. Results indicated that children with a larger number of classroom friends during school entrance developed more favorable school perceptions by the second month, and those who maintained these relationships liked school better as the year progressed. Making new friends in the classroom was associated with gains in school performance, and early peer rejection forecasted less favorable school perceptions, higher levels of school avoidance, and lower performance levels over the school year.",
"A systematic meta-analysis was conducted of the association between preference and popularity across childhood and adolescence. The role of development, sex, and region of the world were examined. The analysis was conducted on 135 samples including 136,014 participants. The samples were divided by age (upper grades primary school, k = 41; lower grades secondary school, k = 72; upper grades secondary school, k = 22) and region (North America, k = 54; Europe, k = 66; China, k = 10). Across all samples, a moderate positive association between preference and popularity was found (r = 0.45). The association was significantly weaker in the upper grades of secondary school (r = 0.37) than in the lower grades of secondary school (r = 0.47) or the upper grades of primary school (r = 0.47). The association was weaker for girls (r = 0.26) than for boys (r = 0.38) in the upper grades of secondary school. The association was weaker in European samples (r = 0.41) than in those from North America (r = 0.50) and China (r = 0.57). The results confirmed that preference and popularity are related but distinct dimensions of adolescent peer status. The association differed significantly by age, sex, and region of the world. Further research should examine additional factors that explain the variability in the association between preference and popularity.",
"Conscientiousness, the propensity to be organized, responsible, self-controlled, industrious, and rule-following, is related to numerous important outcomes including many forms of psychopathology. Given the increasing awareness of the importance of conscientiousness, it is becoming common to want to understand how to foster it. In this paper we first describe and update a recent model that was put forward as a theoretically informed intervention to change conscientiousness. We then consider recent life span theories focused on conscientiousness that might inform how best to use existing interventions as well as identify potential moderators of the effectiveness of intervention. Finally, we integrate these perspectives into a framework for how to foster conscientiousness that we label the Sociogenomic Trait Intervention Model (STIM). (PsycINFO Database Record",
"This research examined how conscientiousness contributes to adolescents' positive peer relationships and vulnerability to poorer ones. Given its temperamental origins in effortful control, conscientiousness was expected to be particularly important. A total of 256 fifth to eighth graders completed personality, peer-relationship, and victimization measures. Peers, parents, and teachers also completed assessments. Adolescents higher on conscientiousness experienced less victimization, better quality friendships, and higher peer acceptance even after controlling for the other Big Five dimensions. Externalizing and/or attention problems mediated the link between conscientiousness and peer relations. Conscientiousness moderated the relation between internalizing problems and poor interpersonal functioning. Results suggest that self-control processes associated with conscientiousness are important in developing and maintaining relationships in adolescence."
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The extent of practice variation in emergency medicine in The Netherlands.
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Structural insights in the use of protocols and the extent of practice variation in EDs are lacking. The objective is to determine the extent of practice variation in EDs in The Netherlands, based on specified common practices. We performed a comparative study on Dutch EDs that employed emergency physicians to determine practice variation. Data on practices were collected via a questionnaire. Fifty-two EDs across The Netherlands were included. Thrombosis prophylaxis was prescribed for below-knee plaster immobilization in 27% of EDs. Vitamin C was prescribed in 50% of EDs after a wrist fracture. Splitting of applied casts to the upper or lower limb was performed in one-third of the EDs. Analysis of the cervical spine after trauma was performed by the NEXUS criteria (69%), the Canadian C-spine Rule (17%) or otherwise. The imaging modality for cervical spine trauma in adults was a CT scan (98%). The cast used for scaphoid fractures was divided between the short arm cast (46%) and the navicular cast (54%). Locoregional anaesthesia for femoral fractures was applied in 54% of the EDs. EDs in The Netherlands showed considerable practice variation in treatments among the subjects studied. Further research is warranted to gain a full understanding of the variation in practice in EDs and the potential to improve quality and efficiency.
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[
"Feedback is essential to learning and practice improvement, yet challenging both to provide and receive. The purpose of this paper was to explore reflective processes which physicians described as they considered their assessment feedback and the perceived utility of that reflective process. This is a qualitative study using principles of grounded theory. We conducted interviews with 28 family physicians participating in a multi-source feedback program and receiving scores across the spectrum from high to low. Feedback, especially negative feedback, evoked reflective responses. Reflection seemed to be the process through which feedback was or was not assimilated and appeared integral to decisions to accept and use the feedback. Facilitated reflection upon feedback was viewed as a positive influence for assimilation and acceptance. Receiving feedback inconsistent with self-perceptions stimulated physicians' reflective processes. The process of reflection appeared instrumental to feedback acceptance and use, suggesting that reflection may be an important educational focus in the formative assessment and feedback process.",
"Implantable cardioverter defibrillator (ICD) therapy is used for primary prevention of death among people with heart failure, and new evidence in 2005 on its effectiveness changed practice guidelines in the United States. The objective of this study is to examine how the connectedness of physicians and hospitals, measured using network analysis, relates to guideline-consistent ICD implantation. We constructed physician and hospital networks for cardiovascular disease. Physicians were linked if they shared cardiovascular disease patients; these links were aggregated by hospital affiliation to construct a hospital network. Medicare beneficiaries who underwent ICD therapy for primary prevention from 2007 to 2011. The clinical outcome of interest was guideline-consistent ICD implantation, calculated using the National Cardiovascular Data Registry. The exposure variables of interest were the network measures of the ICD surgeon, the referring hospital, and the hospital where the ICD surgery occurred. We focused on patients who were referred between hospitals for ICD implantation because they were more likely influenced by the hospital network (n=28,179). Patients were less likely to meet guidelines if their referring hospital had more connections to other hospitals (OR, 0.49; 95% confidence interval, 0.25-0.96) and more likely to meet guidelines if their ICD surgery hospital had more connections (OR, 1.61; 95% confidence interval, 0.98-2.64). The ICD surgeon's network measures were not associated with guideline-consistent implantation. Associations between the hospital network measures and guideline adherence suggests new approaches to better disseminate clinical guidelines across health systems.",
"In the past decades, extensive research has been performed on the phenomenon of unwarranted clinical variation in clinical practice. Many studies have been performed on signaling, describing and visualizing clinical variation. We argue that it is time for next steps in practice variation research. In addition to describing and signaling variation patterns, we argue that a better understanding of causes of variation should be gained. Moreover, target points for improving and decreasing clinical variation should be created. Key elements in this new focus should be research on the complex interaction of networks, reflective medicine, patient beliefs and objective criteria for treatment choices. By combining these different concepts, alternative research objectives and new targets for improving and reducing unwarranted variation may be defined. In this perspective, we reflect on these concepts and propose target points for future research.",
"From previous work, we know that medical practice varies widely, and that unwarranted variation signals low value for patients and society. We also know that public reporting helps to create awareness of the need for quality improvement. Despite the availability of rich data, most Western countries have no routine surveillance of the geographic distribution of utilization, costs, and outcomes of healthcare, including trends in variation over time. This paper highlights the role of transparent public reporting as a necessary first step to spark change and reduce unwarranted variation. Two recent examples of public reporting are presented to illustrate possible ways to reduce unwarranted variation and improve care. We conclude by introducing the Value Improvement Cycle, which underscores that reporting is only a necessary first step, and suggests a path toward developing a multi-stakeholder approach to change.",
"Whether one examines the average length of hospital stay at the level of geographic areas, at the level of hospitals, or at the level of doctors, length-of-stay figures are known to vary widely. Even for hospital admissions for comparable surgical procedures among comparable groups of patients, significant length-of-stay variations have been reported. As is the case for variations in the occurrence of common surgical procedures, the overall conclusion is that large variations in duration of hospital stay associated with these common surgical procedures are the rule rather than the exception. The objective of the study is to examine whether variations in hospital medical practice, indicated by the duration of hospital stay in this study, can be reduced to differences in practice style between individual doctors within the same institutional setting or to differences in practice style between groups of doctors within the same institutional setting. The latter is assumed to be the combined effect of restrictions on the (hospital) supply side and the predilection of doctors to conform to the practice of immediate colleagues. It was found out that the variation in length of hospital stay, adjusted for patient case-mix, within hospitals is much smaller than the length-of-stay variation between different hospitals. The within hospital variation between (partnership of) doctors is in most of the cases statistically insignificant. Doctors working in more than one hospital on average choose a length of stay close to the average length of stay prevailing in the different hospitals.",
"Plaster casts are often split to accommodate swelling following injury. This is not influenced by the axis of the split. The aim of this study was to compare the mechanical properties of plasters split along different axes. Full plasters were applied to mannequin forearms, and then split along dorsal, volar, radial or ulnar sides. Following this the plasters were loaded in a dorsal direction. We found that of all the axes tested, the dorsal split was the best for maintaining fracture reduction (p = 0.001)."
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How do I get a list of all the fruits of a tree?
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The fruits of
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[
"The aim of the present study was to investigate and compare the anti-platelet action of extracts from three different plants: bark of Yucca schidigera, seeds of grape and berries of Aronia melanocarpa (chokeberry). Anti-platelet action of tested extracts was compared with action of well characterized antioxidative and anti-platelet commercial monomeric polyphenol-resveratrol. The effects of extracts on platelet adhesion to collagen, collagen-induced platelet aggregation and on the production of O2-* in resting platelets and platelets stimulated by a strong platelet agonist-thrombin were studied. The in vitro experiments have shown that all three tested extracts (5-50 microg/ml) rich in polyphenols reduce platelet adhesion, aggregation and generation of O2-* in blood platelets. Comparative studies indicate that all three plant extracts were found to be more reactive in reduction of platelet processes than the solution of pure resveratrol. The tested extracts due to their anti-platelet effects may play an important role as components of human diet in prevention of cardiovascular or inflammatory diseases, where blood platelets are involved.",
"Reactive oxygen species (ROS) are produced by living organisms as a result of normal cellular metabolism and environmental factors, such as air pollutants or cigarette smoke. ROS are highly reactive molecules and can damage cell structures such as carbohydrates, nucleic acids, lipids, and proteins and alter their functions. The shift in the balance between oxidants and antioxidants in favor of oxidants is termed \"oxidative stress.\" Regulation of reducing and oxidizing (redox) state is critical for cell viability, activation, proliferation, and organ function. Aerobic organisms have integrated antioxidant systems, which include enzymatic and nonenzymatic antioxidants that are usually effective in blocking harmful effects of ROS. However, in pathological conditions, the antioxidant systems can be overwhelmed. Oxidative stress contributes to many pathological conditions and diseases, including cancer, neurological disorders, atherosclerosis, hypertension, ischemia/perfusion, diabetes, acute respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, and asthma. In this review, we summarize the cellular oxidant and antioxidant systems and discuss the cellular effects and mechanisms of the oxidative stress.",
"Most reactive oxygen species (ROS) can oxidize methionine (Met) residues of proteins to methionine sulfoxide (MetO). However, unlike the ROS-dependent oxidation of other amino acid residues of proteins (except cysteine residues), the oxidation of Met residues is readily reversed by the action of methionine sulfoxide reductase (Msr) that catalyzes the thioredoxin-dependent reduction of MetO residues of proteins back to Met. We summarize here results of studies showing that the cyclic interconversion of Met and MetO residues of proteins is involved in several different biological processes: (a) It is the basis of an important antioxidant mechanism for the scavenging of ROS. (b) It is likely involved in the regulation of enzyme activities. (c) It is involved in cell signaling. (d) It can target proteins for proteolytic degradation. Furthermore, a loss in the ability to catalyze the reduction of protein MetO to Met residues leads to a decrease in the maximum life span, whereas overexpression of this activity leads to an increase in the life span of animals. In addition, a decrease in Msr activities in brain tissues is associated with the development of Alzheimer's disease.",
"We previously reported that dimethylarsinic acid (DMAA), a major metabolite of inorganic arsenics, induced DNA single-strand breaks (ssb) both in vivo and in cultured alveolar type II (L-132) cells in vitro, possibly via the production of dimethylarsenic peroxyl radicals. Here, the interaction of superoxide anion radicals (O2-) in the induction of ssb in L-132 cells was investigated using paraquat, an O2(-)-producing agent. A significant enhancement of ssb formation was observed in the DMAA-exposed cells when coexposed to paraquat. This enhancement occurred even when post-exposed to DMAA after washing, suggesting that the DMAA exposure caused some modification of DNA such as DNA-adducts, which was recognized by active oxygens to form ssb. An experiment with UV-irradiation, which was likely to induce ssb at the modified region, supported the possibility of DNA modification by DMAA exposure. An ESR study indicated that O2- produced by paraquat in DMAA-exposed cells was more consumed than in non-exposed cells, assumingly through the reaction with the dimethylarsenic-modified region of DNA. The species of active oxygens were estimated by using diethyldithiocarbamate, aminotriazole, diethylmaleate, hydrogen peroxide (H2O2), gamma-irradiation and ethanol. O2- but neither H2O2 nor hydroxyl radicals was very likely to contribute to the ssb-enhancing action of paraquat."
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Gut microbiota in chronic kidney disease
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A bidirectional kidney-gut axis was described in patients with chronic kidney disease (CKD). On the one hand, gut dysbiosis could promote CKD progression, but on the other hand, studies reported specific gut microbiota alterations linked to CKD. Therefore, we aimed to systematically review the literature on gut microbiota composition in CKD patients, including those with advanced CKD stages and end-stage kidney disease (ESKD), possibilities to shift gut microbiota, and its impact on clinical outcomes.
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[
"The human gut microbiota has been identified as a possible novel risk factor for cardiovascular disease. The intestinal microbiome plays a role in the pathogenesis of atherosclerosis and heart failure. Even though studies in rodents suggested that gut microbes may affect the risk of heart disease, this link has not been shown in humans. In the present study, we review several potential mechanisms by which the gut microbiome and bacterial translocation are associated with the development of cardiac disorders making them potential targets for novel therapeutic measures for these conditions. Modulation of the gut microbiota as a mechanism for altering the pathogenesis of disorders is an area of growing interest. Alteration in the gut microbiota is being explored as a method of reducing risk factors associated with cardiac diseases.",
"To investigate alteration of intestinal microflora in uremia patients with or without blood purification treatments. The present study included a total of 109 adult patients who were administered in our hospital during 2014 August to 2015 December, 85 cases had already received hemodialysis treatment and 24 cases had not received any renal transplantation treatments. Serum levels of hemoglobin, albumin, creatinine, hypersensitive C reactive protein, and cystatin C, as well as blood urea nitrogen and estimated glomerular filtration rate were determined. 16S rRNA sequencing was conducted to determine the levels of Bifidobacterium, Lactobacillus acidophilus, Escherichia coli, and Enterococcus faecalis. The hemoglobin level in the hemodialysis group was significantly higher than that of the non-hemodialysis patients. The levels of Bifidobacterium and Lactobacillus acidophilus were significantly lower while the levels of Escherichia coli and Enterococcus faecalis were significantly higher in both of the patient groups compared with the healthy control. In all treatment groups, levels of Bifidobacterium and Lactobacillus acidophilus were significantly higher and levels of Escherichia coli and Enterococcus faecalis were significantly lower compared with the non-blood purification treatment group. The intestinal microflora might be influenced by uremia and might also be affected by blood purification treatments.",
"The interplay of the gut microbes with gut-producing nephrotoxins and the renal progression remains unclear in large human cohort. Significant compositional and functional differences in the intestinal microbiota (by 16S rRNA gene sequencing) were noted among 30 controls and 92 (31 mild, 30 moderate and 31 advanced) patients at different chronic kidney disease (CKD) stages (discovery cohort). A core CKD-associated microbiota consisted of 7 genera (Escherichia_Shigella, Dialister, Lachnospiraceae_ND3007_group, Pseudobutyrivibrio, Roseburia, Paraprevotella and Ruminiclostridium) and 2 species (Collinsella stercoris and Bacteroides eggerthii) were identified to be highly correlated with the stages of CKD. Paraprevotella, Pseudobutyrivibrio and Collinsella stercoris were superior in discriminating CKD from the controls than the use of urine protein/creatinine ratio, even at early-stage of disease. The performance was further confirmed in a validation cohort comprising 22 controls and 76 peritoneal dialysis patients. Bacterial genera highly correlated with indoxyl sulfate and p-cresyl sulfate levels were identified. Prediction of the functional capabilities of microbial communities showed that microbial genes related to the metabolism of aromatic amino acids (phenylalanine, tyrosine, and tryptophan) were differentially enriched among the control and different CKD stages. Collectively, our results provide solid human evidence of the impact of gut-metabolite-kidney axis on the severity of chronic kidney disease and highlight a usefulness of specific gut microorganisms as possible disease differentiate marker of this global health burden.",
"Gut dysbiosis is associated with chronic kidney disease (CKD), and serum free immunoglobulin light chains (FLCs) are biomarkers for CKD. This study aims to assess the CKD gut microbiome and to determine its impact on serum FLC levels. To control for confounders, 100 patients and sex- and age-matched healthy controls (HCs) were recruited. The gut microbiome was assessed by sequencing 16S rRNA gene V3-V4 hypervariable regions. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States was applied to infer functional metabolic pathways. When observing group differences in the microbiome and predicted metabolic pathways, demographic confounders were adjusted using binary logistic regression; when examining impacts of the gut microbiome and metabolic pathways on serum FLCs, factors influencing FLC levels were adjusted using multiple regression. Principal coordinate analysis revealed a significantly different bacterial community between the CKD and HC groups (P < 0.05). After adjusting for confounders, lower Chao 1, observed species and Shannon indices based on binary logistic regression predicted CKD prevalence. Actinobacteria, Alistipes, Bifidobacterium and Bifidobacterium longum enrichment, upregulation of metabolic pathways of bacterial toxin, chloroalkane and chloroalkene degradation, and Staphylococcus aureus infection also predicted CKD prevalence (P < 0.05). Furthermore, depletion of Actinobacteria and Bifidobacterium and reduced chloroalkane and chloroalkene degradation predicted high levels of FLC λ (P < 0.05). Gut dysbiosis in CKD patients was confirmed by controlling for confounders in the present study. Additionally, the association between gut dysbiosis and FLC λ levels demonstrates the existence of crosstalk between the microbiome and immune response in CKD.",
"The gut microbiota can affect human metabolism, immunity, and other biologic pathways through the complex gut-kidney axis (GKA), and in turn participate in the occurrence and development of kidney disease. In this study, 39 patients with stage 4-5 chronic kidney disease (CKD) and 40 healthy individuals were recruited and 16S rDNA sequencing was performed to analyze the V3-V4 conserved regions of their microbiota. A total of 795 operational taxonomic units (OTUs) shared between groups or specific to each group were obtained, among which 255 OTUs with significant differences between the two groups were identified (P<0.05). Adonis differential analysis showed that the diversity of gut microbiota was highly correlated with CKD stages 4-5. Additionally, 61 genera with differences in the two groups were identified (P<0.05) and 111 species with significant differences in the phyla, classes, orders, families, and genera between the two groups were identified (P<0.05). The differential bacterial genera with the greatest contribution were, in descending order: c_Bacteroidia, o_Bacteroidales, p_Bacteroidetes, c_Clostridia, o_Clostridiales, etc. Those with the greatest contribution in stages 4-5 CKD were, in descending order: p_Proteobacteria, f_Enterobacteriaceae, o_Enterobacteriales, c_Gammaproteobacteria, c_Bacilli, etc. The results suggest that the diversity of the microbiota may affect the occurrence, development, and outcome of the terminal stages of CKD.",
"Recent studies have shown that gut microbiota is associated with immunomodulation in transplant recipients, but the composition and function of gut microbiota in renal transplant recipients have not been understood. We analyzed the composition and function of gut microbiota in the fecal samples from 16 renal transplant (RT) recipients by deep sequencing of the 16S rRNA V3 variable region. The gut microbiota of RT recipients was compared to that of 84 patients with chronic kidney disease (CKD) and 53 healthy subjects. The overall microbial structure of RT recipients was similar to that of CKD. The abundance of Firmicutes, Lachnospiraceae, Ruminococcaceae and Faecalibacterium was decreased and that of Bacteroidetes, Proteobacteria, Clostridiales, and Enterobacteriaceae was increased significantly in RT recipients and CKD patients compared with the healthy control subjects. Functional comparison revealed significantly enhanced carbohydrate metabolism and decreased metabolism of cofactors, vitamins, cell motility and genetic information processing in RT recipients and CKD patients. RT recipients and CKD patients also showed slight differences in that the abundance of Proteobacteria and Enterobacteriaceae and the pathways involving transport system members and carbohydrate metabolism were much greater in the former. We found that several beneficial genera in the Lachnospiraceae and Veillonellaceae were negatively correlated with such clinical markers as serum creatinine and blood urea nitrogen. Our results suggested that alterations in the composition and function of gut microbiota are significantly correlated with the clinical conditions of in RT recipients, and future prospective studies of these correlations may provide evidence for predicting the clinical outcomes of RT recipients.",
"Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light-dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4-week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques, a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii, a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances."
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Experiences of NBGQ youth with microaggressions
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This study explores the experiences of NBGQ youth with microaggressions. It investigates the types of microaggressions they face and their subsequent needs and coping mechanisms and the impacts on their lives. Semi-structured interviews with ten NBGQ youth in Belgium were conducted and analyzed using a thematic approach. The results showed that experiences of microaggressions were centered around denial. The most common ways to cope were finding acceptance from (queer) friends and therapists, engaging in a conversation with the aggressor, and rationalizing and empathizing with the aggressor, leading to self-blame and normalization of the experiences. Microaggressions were experienced as exhausting, which influenced the extent to which the NBGQ individuals wanted to explain themselves to others. Furthermore, the study shows an interaction between microaggressions and gender expression, in which gender expression is seen as a motive for microaggressions and microaggressions have an impact on the gender expression of NBGQ youth.
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[
"It is vital that the treatment offered at transgender health services can be evaluated to ensure a high quality of care. However, the tools currently used to evaluate treatment at transgender health services are limited by mainly focusing on mental health or because they have been developed for binary transgender people only. This study therefore aimed to develop and validate a tool that addresses these limitations. The Gender Congruence and Life Satisfaction Scale (GCLS) was developed through reviewing the literature, conducting interviews with transgender people, and holding discussions with experts working in transgender healthcare. An initial pool of items was developed and feedback on these was obtained. The tool was then validated. For the validation of the tool, a total of 789 participants (451 transgender [171 transgender females, 147 transgender males, 133 people identifying as non-binary], and 338 cisgender [254 females, 84 males]) were recruited from the United Kingdom to test the factor structure and validity of the GCLS. Exploratory factor analysis retained 38 items which formed seven subscales (psychological functioning; genitalia; social gender role recognition; physical and emotional intimacy; chest; other secondary sex characteristics; and life satisfaction). These seven subscales were found to have good internal consistency and convergent validity. The GCLS was also found to be capable of discriminating between groups (e.g., people who have and have not undergone gender affirming medical interventions). Transgender and cisgender subscale norms are provided for the GCLS. The GCLS is a suitable tool to use with the transgender population to measure health-related outcomes for both clinical and research purposes.",
"Although literature documents the experiences of socially assigned gender nonconformity (SAGNC) by minority sexual orientation (i.e., lesbian, gay, and bisexual [LGB]), examination of the role of gender expression on school violence outcomes in the presence of sexual orientation and gender identity is not well understood. This study describes SAGNC among a representative sample of adolescents, accounting for sexual orientation and gender identity (e.g., transgender). A secondary data analysis was conducted using Youth Risk Behavior Survey data from Los Angeles Unified School District high schools in 2013 (N = 1,496). The prevalence of school violence by self-reported SAGNC and gender identity was obtained. Associations between SAGNC and school violence were examined using multivariate logistic regression adjusted for mischievous response bias. Two hundred ninety-one (19.5%) adolescents reported SAGNC. Having missed school due to a safety concern and being bullied in the past year were more common among socially assigned gender nonconforming adolescents than those who conformed to gender expression expectations. Socially assigned gender nonconforming adolescents, regardless of sexual orientation or gender identity, are at greater risk of missed school due to safety concerns, and bullying, as compared with those who conform to norms of gender expression. Future research should measure SAGNC, sexual orientation, gender identity, and expression with larger representative samples of school populations across contexts (urban and rural), and inclusive of structural factors (e.g., school climate) to guide the development of prevention efforts.",
"In recent years, puberty suppression by means of gonadotropin-releasing hormone analogs has become accepted in clinical management of adolescents who have gender dysphoria (GD). The current study is the first longer-term longitudinal evaluation of the effectiveness of this approach. A total of 55 young transgender adults (22 transwomen and 33 transmen) who had received puberty suppression during adolescence were assessed 3 times: before the start of puberty suppression (mean age, 13.6 years), when cross-sex hormones were introduced (mean age, 16.7 years), and at least 1 year after gender reassignment surgery (mean age, 20.7 years). Psychological functioning (GD, body image, global functioning, depression, anxiety, emotional and behavioral problems) and objective (social and educational/professional functioning) and subjective (quality of life, satisfaction with life and happiness) well-being were investigated. After gender reassignment, in young adulthood, the GD was alleviated and psychological functioning had steadily improved. Well-being was similar to or better than same-age young adults from the general population. Improvements in psychological functioning were positively correlated with postsurgical subjective well-being. A clinical protocol of a multidisciplinary team with mental health professionals, physicians, and surgeons, including puberty suppression, followed by cross-sex hormones and gender reassignment surgery, provides gender dysphoric youth who seek gender reassignment from early puberty on, the opportunity to develop into well-functioning young adults.",
"Background: The social challenges that non-binary people experience, due in part to social intolerance and the lack of validation of non-binary gender identities, may affect the mental health and quality of life of this population. However, studies that have distinguished between non-binary and binary transgender identities are lacking. Aim: To compare the mental health and quality of life of a community sample of non-binary transgender adults with controls (binary transgender people and cisgender people) matched on sex assigned at birth. Method: A total of 526 participants were included. Ninety-seven were classified as non-binary and were compared with two control groups: 91 people classified as binary and 338 cisgender people. Only transgender people not on gender affirming hormone treatment or who had not undergone gender affirming surgery were included. Participants were invited to complete an online survey that included mental health and quality of life measures. Results: Non-binary people reported significantly better mental health than binary transgender people, but worse than cisgender people. Overall, there were no significant differences in quality of life between non-binary and binary transgender participants assigned male at birth and transgender females, but non-binary assigned males at birth had better scores on the psychological and social domains of quality of life than transgender males. Quality of life was better across all domains in cisgender people than transgender groups. Conclusion: There is an inequality with regard to mental health and quality of life between non-binary (and binary) transgender people and the cisgender population that needs to be addressed. The better mental health scores in non-binary people may reflect lower levels of body dissatisfaction among the non-binary population. Mental health problems and poor quality of life are likely to have social causes and hence legislative measures and broader government-led inclusive directives should be put in place to recognize and to validate non-binary identifying people."
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Incidence and Risk Factors of Sleep-Disordered Breathing in Children
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This study aimed to identify the incidence and risk factors of sleep-disordered breathing (SDB) using an Arabic version of the pediatric sleep questionnaire (PSQ). A total of 2000 PSQs were circulated to children aged 6-12 years who were randomly selected from 20 schools in Al-Kharj city, Saudi Arabia. The questionnaires were filled out by the parents of participating children. The participants were further divided into two groups (younger group: 6-9 years and older group: 10-12 years). Out of 2000 questionnaires, 1866 were completed and analyzed (93.3% response rate), of which 44.2% were from the younger group and 55.8% were from the older group. Among all the participants, a total of 1027 participants were female (55%) and 839 were male (45%) with a mean age of 9.67 ± 1.78 years. It showed that 13% of children were suffering from a high risk of SDB. Chi-square test and logistic regression analyses within this study cohort showed a significant association between SDB symptoms (habitual snoring; witnessed apnea; mouth breathing; being overweight; and bedwetting) and risk of developing SDB. In conclusion: habitual snoring; witnessed apnea; mouth breathing; being overweight; and bedwetting strongly contribute the to development of SDB.
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[
"Epidemiological studies of sleep disturbances are essential to promote awareness among families and educational officials and deliver appropriate treatment at a very early timing. The aim of this population-based study was to determine the frequency of sleep-disordered breathing (SDB) symptoms and its association with obesity among schoolchildren in West Saudi Arabia. This cross-sectional study comprised 2,000 schoolchildren aged 6-12 years. Sleep-disordered breathing symptoms were assessed with Arabic version of Pediatric Sleep Questionnaire (PSQ). Overweight/obesity was evaluated using body mass index (BMI) and their association with SDB was tested using a regression analysis model. Overall, 23% of children were at high risk of SDB. Prevalence of habitual snoring was 15.9% and sleep apnea 4%. Boys were at higher risk of SDB than girls (p = 0.026), while age had no effect (p = 0.254). High-risk SDB had a strong association with sleep symptoms compared to low-risk SDB (p < 0.05). Sleep-disordered breathing increased significantly in overweight and obese children (p = 0.017 and p < 0.001, respectively). Around 23% Saudi schoolchildren are at risk of SDB. Related symptoms were strongly associated with high risk of SDB. Overweight and obesity had a strong and progressive association with SDB. The results will help in identifying children at high risk of developing SDB and plan for early intervention to avoid the progression of SDB later in life.",
"To examine modifications in sleep pattern and in craniofacial morphology of adolescents with mandibular retrognathism. Sixteen subjects at maximum pubertal growth (12.6 years [±11.5 months]) were selected and treated for 12 months with maxillary expansion and mandibular advancement with a Herbst appliance. Cephalometric radiography and magnetic resonance imaging were obtained prior to and after treatment and were compared using the paired Student's t-test or the nonparametric Wilcoxon rank-sum test. Four polysomnographic recordings were obtained with pressurized nasal cannulae and were analyzed by analysis of variance. The length of the mandible was increased, while the antero-posterior position of the maxilla remained stable. The posterior airway space was increased, the length of the tongue was preserved, and the hyoid bone was moved to a more anterior position. After Herbst treatment, sleep efficiency, sleep latency, rapid eye movement (REM) sleep latency, and percentage of REM sleep remained stable. We did observe a reduction (P < .05) in the relative proportions of stage 1 and stage 3-4 (from 4.30 ± 1.99 to 2.61 ± 1.83 for stage 1 and from 25.78 ± 7.00 to 19.17 ± 7.58 for stages 3-4) as well as an increase (P < .01) in the percentage of stage 2 after treatment (49.03 ± 6.25 to 56.90 ± 6.22). There was a reduction (P < .05) in the number of respiratory effort-related arousals (7.06 ± 5.37 to 1.31 ± 1.45 per hour of sleep) due to an increase (P < .01) in airway volume. In the short term, the increase in airway space improved nocturnal breathing associated with the correction of mandibular retrognathism.",
"This study aimed to determine the prevalence of sleep-disordered breathing (SDB) and its association with malocclusion among children in Recife, Brazil. This study included 390 children aged 7 to 8 years. The data comprised the measurement of body mass, orthodontic examination, and parental information required by the Sleep Disturbance Scale for Children. The statistics tools used were Pearson's chi-square test and the Lemeshow test. Positively screened for SDB was found in 33.3% of the children, and the association with overjet was P = .007 (odds ratio [OR], 95%, confidence interval [CI]: 1.93). The association with anterior open bite was P = .008 (OR, 95% CI: 2.03), and the association with posterior crossbite was P = .001 (OR, 95% CI: 2.89). This report was unable to indicate an association between body mass index and SDB. The multivariate logistic regression model revealed that the anterior open bite (P = .002; OR, 95% CI: 2.34) and posterior crossbite (P = .014; OR, 95% CI: 2.79) had an association with positively screened for SDB. The results of this study indicated that the prevalence of SDB was high and highly associated with malocclusion. Since posterior crossbite and anterior open bite were associated with positively screened for SDB, early diagnosis and intervention may prevent and minimize adverse effects of SDB on individuals lives.",
"To describe the prevalence, persistence, and characteristics associated with sleep disordered breathing (SDB) symptoms in a population-based cohort followed from 6 months to 6.75 years. Avon Longitudinal Study of Parents and Children (ALSPAC). England, 1991-1999. 12,447 children in ALSPAC with parental report of apnea, snoring, or mouth-breathing frequency on any one of 7 questionnaires. Symptom prevalence rates-assessed as \"Always\" and \"Habitually\"-are reported at 0.5, 1.5, 2.5, 3.5, 4.75, 5.75, and 6.75 years of age. The proportion of children in whom symptoms develop, persist or abate between observation points is reported. Exploratory multivariate analyses identified SDB risk factors at 1.5, 4.75, and 6.75 years. The prevalence of apnea (\"Always\") is 1%-2% at all ages assessed. In contrast, snoring \"Always\" ranges from 3.6% to 7.7%, and snoring \"Habitually\" ranges from 9.6% to 21.2%, with a notable increase from 1.5- 2.5 years. At 6 years old, 25% are habitual mouth-breathers. The \"Always\" and \"Habitual\" incidence of each symptom between time points is 1%-5% and 5%-10%, respectively. In multivariate analyses of combined symptoms, socioeconomic factors have stronger, more persistent effects upon increased SDB risk than gestational age, gender, or race (aside from 1.5 years); adenoidectomy decreases risk by 40%-50%. This is the first natural history study of the primary symptoms of SDB across a key 6-year period in the development of SDB symptoms. Snoring rates are higher and spike earlier than previously reported. Symptoms are dynamic, suggesting the need for early and continued vigilance in early childhood.",
"This study aimed to evaluate the severity of high-risk SDB in children and adolescents seeking paediatric dental care. Sleep-disordered breathing (SDB) has many untoward consequences that may interfere with children's health and is associated with several risk factors. In this cross-sectional study, the convenience sample included 65 healthy children and adolescents aged 7-16. High-risk SDB breathing was assessed using the Paediatric-Sleep-Questionnaire consisting of 22 questions. High-risk was defined as a positive response to 33% or more of the questions. The clinical examination included: tonsils' size, Body-Mass Index, orthodontic examination, and enamel defects. In this sample of 65 children with a mean age of 9.75 (± 2.60) years; 36 (55.4%) were boys, and 29 (44.6%) were girls. Overall, 12.3% of children in the sample were at high-risk of SDB, and this was significantly associated with tonsils' size (P = 0.001), Body-Mass Index (P = 0.03), Class-II molar relationship (P = 0.03), and posterior crossbite/s (P = 0.02). This study suggested that approximately 12% of the sample studied were potentially at risk of SDB. Tonsils' size, Body-Mass Index, Class-II molar relationship, and posterior crossbite/s were positively associated with the risk of SDB. Therefore, the importance of investigating the risk for sleep-disordered breathing should not be disregarded."
] |
Epithelial-mesenchymal transition genes in malignant mesothelioma
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Malignant mesothelioma (MESO) consists of epithelioid, biphasic, and sarcomatoid subtypes with different epithelial-mesenchymal transition (EMT) phenotypes. We previously identified a panel of four MESO EMT genes correlating with an immunosuppressive tumor microenvironment and poor survival. In this study, we investigated the correlation between these MESO EMT genes, the immune profile, and the genomic and epigenomic alterations to identify potential therapeutic targets to prevent or reverse the EMT process. Using multiomic analysis, we observed that the MESO EMT genes were positively correlated with hypermethylation of epigenetic genes and loss of CDKN2A/B expression. MESO EMT genes such as
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[
"Fibroblast growth factors (FGFs) and their receptors control a wide range of biological functions, regulating cellular proliferation, survival, migration and differentiation. Although targeting FGF signalling as a cancer therapeutic target has lagged behind that of other receptor tyrosine kinases, there is now substantial evidence for the importance of FGF signalling in the pathogenesis of diverse tumour types, and clinical reagents that specifically target the FGFs or FGF receptors are being developed. Although FGF signalling can drive tumorigenesis, in different contexts FGF signalling can mediate tumour protective functions; the identification of the mechanisms that underlie these differential effects will be important to understand how FGF signalling can be most appropriately therapeutically targeted.",
"Epithelial-mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it \"mesenchymal score.\" This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.",
"Oral squamous cell carcinoma (OSCC) is associated with high morbidity and ranks sixth among malignancies worldwide. Increasing evidence suggests that microRNAs (miRNAs or miRs) play a critical role in regulating cancer stem cells (CSCs), which drive the proliferation and spread of OSCC. Therefore, based on the alteration of aberrantly expressed miR-495 and homeobox C6 (HOXC6) by Gene Expression Omnibus (GEO) analysis, we subsequently explore the potential effect of miR-495 on the progression of CSCs in OSCC. After the isolation of CSCs from the clinical tissue samples of OSCC patients, the expression of miR-495 and HOXC6 was determined, followed by the validation of the relationship between miR-495 and HOXC6. Subsequently, gain- and loss-function approach was performed to detect the role of miR-495 and HOXC6 in cell proliferation, migration, invasion, cell cycle entry, apoptosis, and epithelial-mesenchymal transition (EMT) of CSCs in OSCC, as well as the tumor growth in vivo. HOXC6 was highly expressed while miR-495 was poorly expressed in OSCC. HOXC6 was verified to be a target gene of miR-495, and miR-495 could inhibit the activation of the TGF-β signaling pathway. CSCs with miR-495 overexpression or HOXC6 silencing exhibited reversed EMT process; reduced abilities of proliferation, migration, and invasion; and promoted cell apoptosis in vitro. Moreover, inhibited tumor growth was observed in vivo after injection with miR-495 agomir or sh-HOXC6. In contrast, the downregulation of miR-495 showed an induced role in the progression of OSCC. These findings suggest that miR-495 may suppress HOXC6 to inhibit EMT, proliferation, migration, and invasion while promoting apoptosis of CSCs in OSCC by inhibiting the TGF-β signaling pathway.",
"Malignant peritoneal mesothelioma (MPeM) is clinically distinct and less studied than malignant pleural mesothelioma. We report the genomic and immunophenotypic features of a prospectively collected MPeM cohort. Next-generation sequencing (NGS) was performed on MPeM tumors. Genomic near-haploidization (GNH) was assessed. WT1, BAP1, mesothelin, VISTA, and programmed death-ligand 1 were evaluated by immunohistochemistry (IHC) when tissue was available. Overall survival was stratified by selected genomic and IHC features. A total of 50 consented patients with MPeM (45 epithelioid, 5 nonepithelioid) were studied exhibiting common alterations in BAP1 (60%; 30 of 50), NF2 (24%; 12 of 50) SETD2 (22%; 11 of 50), and TP53 (16%; 8 of 50). A total of 76% (38 of 50) of specimens were assessable for allele-specific copy number analysis; 8% (3 of 38) had GNH. IHC positivity rates were 93% (37 of 40) for mesothelin, 96% (46 of 48) for WT1, 50% (19 of 38) for programmed death-ligand 1, and 89% (34 of 38) for VISTA. BAP1 loss by IHC was observed in 76% (29 of 38), including five wild-type on NGS. Combining NGS and IHC for BAP1, overall survival was worse with alteration or loss compared with wild-type or retained in all patients (n = 37 versus 13, 43.8 versus 117.3 mo, p = 0.04) Three of 30 patients had a pathogenic germline variant: POT1 I78T, MUTYH R109Y, and BAP1 E402∗. MPeM has distinct biology and genomic composition. CDKN2A/B alterations were rare in MPeM, whereas BAP1, NF2, TP53, SETD2, and LATS2 were common. BAP1 alteration/loss was associated with shorter survival when all patients were included. A notable minority of specimens had GNH associated with NF2, TP53, and SETDB1 mutations. Pathogenic germline mutations were found in 3 of 30 patients.",
"Objective: Infiltrating immune and stromal cells are essential for osteosarcoma progression. This study set out to analyze immune-stromal score-based gene signature and molecular subtypes in osteosarcoma. Methods: The immune and stromal scores of osteosarcoma specimens from the TARGET cohort were determined by the ESTIMATE algorithm. Then, immune-stromal score-based differentially expressed genes (DEGs) were screened, followed by univariate Cox regression analysis. A LASSO regression analysis was applied for establishing a prognostic model. The predictive efficacy was verified in the GSE21257 dataset. Associations between the risk scores and chemotherapy drug sensitivity, immune/stromal scores, PD-1/PD-L1 expression, immune cell infiltrations were assessed in the TARGET cohort. NMF clustering analysis was employed for characterizing distinct molecular subtypes based on immune-stromal score-based DEGs. Results: High immune/stromal scores exhibited the prolonged survival duration of osteosarcoma patients. Based on 85 prognosis-related stromal-immune score-based DEGs, a nine-gene signature was established. High-risk scores indicated undesirable prognosis of osteosarcoma patients. The AUCs of overall survival were 0.881 and 0.849 in the TARGET cohort and GSE21257 dataset, confirming the well predictive performance of this signature. High-risk patients were more sensitive to doxorubicin and low-risk patients exhibited higher immune/stromal scores, PD-L1 expression, and immune cell infiltrations. Three molecular subtypes were characterized, with distinct clinical outcomes and tumor immune microenvironment. Conclusion: This study developed a robust prognostic gene signature as a risk stratification tool and characterized three distinct molecular subtypes for osteosarcoma patients based on immune-stromal score-based DEGs, which may assist decision-making concerning individualized therapy and follow-up project.",
"Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial-mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK-AKT-GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance. IMPLICATIONS: This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.",
"Although cancer-associated fibroblasts (CAF) are key determinants in the malignant progression of cancer, their functional contribution to this process is still unclear. Analysis of the mutual interplay between prostate carcinoma cells and CAFs revealed a mandatory role of carcinoma-derived interleukin-6 in fibroblast activation. In turn, activated fibroblasts through secretion of metalloproteinases elicit in cancer cells a clear epithelial-mesenchymal transition (EMT), as well as enhancement of tumor growth and development of spontaneous metastases. CAF-induced EMT leads prostate carcinoma cells to enhance expression of stem cell markers, as well as the ability to form prostaspheres and to self-renew. Hence, the paracrine interplay between CAFs and cancer cells leads to an EMT-driven gain of cancer stem cell properties associated with aggressiveness and metastatic spread."
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Mutational signature analysis based on mutation co-occurrences
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Mutational signature analysis promises to reveal the processes that shape cancer genomes for applications in diagnosis and therapy. However, most current methods are geared toward rich mutation data that has been extracted from whole-genome or whole-exome sequencing. Methods that process sparse mutation data typically found in practice are only in the earliest stages of development. In particular, we previously developed the Mix model that clusters samples to handle data sparsity. However, the Mix model had two hyper-parameters, including the number of signatures and the number of clusters, that were very costly to learn. Therefore, we devised a new method that was several orders-of-magnitude more efficient for handling sparse data, was based on mutation co-occurrences, and imitated word co-occurrence analyses of Twitter texts. We showed that the model produced significantly improved hyper-parameter estimates that led to higher likelihoods of discovering overlooked data and had better correspondence with known signatures.
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[
"Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.",
"Mutational signatures are key to understanding the processes that shape cancer genomes, yet their analysis requires relatively rich whole-genome or whole-exome mutation data. Recently, orders-of-magnitude sparser gene-panel-sequencing data have become increasingly available in the clinic. To deal with such sparse data, we suggest a novel mixture model, Mix. In application to simulated and real gene-panel sequences, Mix is shown to outperform current approaches and yield mutational signatures and patient stratifications that are in higher agreement with the literature. We further demonstrate its utility in several clinical settings, successfully predicting therapy benefit and patient groupings from MSK-IMPACT pan-cancer data. Availability: https://github.com/itaysason/Mix-MMM .",
"Base substitution catalogues represent historical records of mutational processes that have been active in a cell. Such processes can be distinguished by various characteristics, like mutation type, sequence context, transcriptional and replicative strand bias, genomic distribution and association with (epi)-genomic features. We have created MutationalPatterns, an R/Bioconductor package that allows researchers to characterize a broad range of patterns in base substitution catalogues to dissect the underlying molecular mechanisms. Furthermore, it offers an efficient method to quantify the contribution of known mutational signatures within single samples. This analysis can be used to determine whether certain DNA repair mechanisms are perturbed and to further characterize the processes underlying known mutational signatures. MutationalPatterns allows for easy characterization and visualization of mutational patterns. These analyses willsupport fundamental research into mutational mechanisms and may ultimately improve cancer diagnosis and treatment strategies. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns .",
"Mutational signatures are patterns in the occurrence of somatic single-nucleotide variants that can reflect underlying mutational processes. The SomaticSignatures package provides flexible, interoperable and easy-to-use tools that identify such signatures in cancer sequencing data. It facilitates large-scale, cross-dataset estimation of mutational signatures, implements existing methods for pattern decomposition, supports extension through user-defined approaches and integrates with existing Bioconductor workflows. The R package SomaticSignatures is available as part of the Bioconductor project. Its documentation provides additional details on the methods and demonstrates applications to biological datasets. julian.gehring@embl.de, whuber@embl.de Supplementary data are available at Bioinformatics online."
] |
Effect of red LED light on radicle emergence and growth of pepper seeds
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Red LED light (R LED) is an efficient tool to improve seed germination and plant growth under controlled environments since it is more readily absorbed by photoreceptors' phytochromes compared to other wavelengths of the spectrum. In this work, the effect of R LED on the radicle emergence and growth (Phase III of germination) of pepper seeds was evaluated. Thus, the impact of R LED on water transport through different intrinsic membrane proteins, via aquaporin (AQP) isoforms, was determined. In addition, the remobilization of distinct metabolites such as amino acids, sugars, organic acids, and hormones was analysed. R LED induced a higher germination speed index, regulated by an increased water uptake.
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[
"The oxylipin jasmonate (JA) regulates many aspects of growth, development, and environmental responses in plants, particularly defense responses against herbivores and necrotrophic pathogens. Mutants of Arabidopsis helped researchers define the biochemical pathway for synthesis of jasmonoyl-isoleucine (JA-Ile), the active form of JA hormone, and demonstrated that JA is required for plant survival of insect and pathogen attacks and for plant fertility. Transcriptional profiling led to the discovery of the JASMONATE ZIM-DOMAIN (JAZ) proteins, which are repressors of JA signaling. JA-Ile relieves repression by promoting binding of the JAZ proteins to the F-box protein CORONATINE INSENSITIVE1 (COI1) and their subsequent degradation by the ubiquitination/26S-proteasome pathway. Although we now have a much better understanding of the molecular mechanism of JA action, many questions remain. Experimental answers to these questions will expand our knowledge of oxylipin signaling in plants and animals and will also provide new tools for efforts to improve crop protection and reproductive performance.",
"In this issue of Developmental Cell, Cho et al. (2012) uncover the mechanisms linking the light-regulated trigger and hormone-mediated induction of seed germination in Arabidopsis. When phytochrome B is activated by red light, seed germination is promoted by epigenetic transcriptional activation of gibberellic acid biosynthetic enzymes via histone demethylation.",
"Jasmonates are a family of plant hormones that regulate plant growth, development and responses to stress. The F-box protein CORONATINE INSENSITIVE 1 (COI1) mediates jasmonate signalling by promoting hormone-dependent ubiquitylation and degradation of transcriptional repressor JAZ proteins. Despite its importance, the mechanism of jasmonate perception remains unclear. Here we present structural and pharmacological data to show that the true Arabidopsis jasmonate receptor is a complex of both COI1 and JAZ. COI1 contains an open pocket that recognizes the bioactive hormone (3R,7S)-jasmonoyl-l-isoleucine (JA-Ile) with high specificity. High-affinity hormone binding requires a bipartite JAZ degron sequence consisting of a conserved α-helix for COI1 docking and a loop region to trap the hormone in its binding pocket. In addition, we identify a third critical component of the jasmonate co-receptor complex, inositol pentakisphosphate, which interacts with both COI1 and JAZ adjacent to the ligand. Our results unravel the mechanism of jasmonate perception and highlight the ability of F-box proteins to evolve as multi-component signalling hubs.",
"From a biomechanical perspective, the completion of seed (and fruit) germination depends on the balance of two opposing forces: the growth potential of the embryonic axis (radicle-hypocotyl growth zone) and the restraint of the seed-covering layers (endosperm, testa, and pericarp). The diverse seed tissues are composite materials which differ in their dynamic properties based on their distinct cell wall composition and water uptake capacities. The biomechanics of embryo cell growth during seed germination depend on irreversible cell wall loosening followed by water uptake due to the decreasing turgor, and this leads to embryo elongation and eventually radicle emergence. Endosperm weakening as a prerequisite for radicle emergence is a widespread phenomenon among angiosperms. Research into the biochemistry and biomechanics of endosperm weakening has demonstrated that the reduction in puncture force of a seed's micropylar endosperm is environmentally and hormonally regulated and involves tissue-specific expression of cell wall remodelling proteins such as expansins, diverse hydrolases, and the production of directly acting apoplastic reactive oxygen. The endosperm-weakening biomechanics and its underlying cell wall biochemistry differ between the micropylar (ME) and chalazal (CE) endosperm domains. In the ME, they involve cell wall loosening, cell separation, and programmed cell death to provide decreased and localized ME tissue resistance, autolysis, and finally the formation of an ME hole required for radicle emergence. Future work will further unravel the molecular mechanisms, environmental regulation, and evolution of the diverse biomechanical cell wall changes underpinning the control of germination by endosperm weakening.",
"Jasmonates (JAs) and salicylic acid (SA) are plant hormones that play pivotal roles in the regulation of induced defenses against microbial pathogens and insect herbivores. Their signaling pathways cross-communicate providing the plant with a regulatory potential to finely tune its defense response to the attacker(s) encountered. In Arabidopsis thaliana, SA strongly antagonizes the jasmonic acid (JA) signaling pathway, resulting in the downregulation of a large set of JA-responsive genes, including the marker genes PDF1.2 and VSP2. Induction of JA-responsive marker gene expression by different JA derivatives was equally sensitive to SA-mediated suppression. Activation of genes encoding key enzymes in the JA biosynthesis pathway, such as LOX2, AOS, AOC2, and OPR3 was also repressed by SA, suggesting that the JA biosynthesis pathway may be a target for SA-mediated antagonism. To test this, we made use of the mutant aos/dde2, which is completely blocked in its ability to produce JAs because of a mutation in the ALLENE OXIDE SYNTHASE gene. Mutant aos/dde2 plants did not express the JA-responsive marker genes PDF1.2 or VSP2 in response to infection with the necrotrophic fungus Alternaria brassicicola or the herbivorous insect Pieris rapae. Bypassing JA biosynthesis by exogenous application of methyl jasmonate (MeJA) rescued this JA-responsive phenotype in aos/dde2. Application of SA suppressed MeJA-induced PDF1.2 expression to the same level in the aos/dde2 mutant as in wild-type Col-0 plants, indicating that SA-mediated suppression of JA-responsive gene expression is targeted at a position downstream of the JA biosynthesis pathway.",
"Plant hormones have pivotal roles in the regulation of plant growth, development, and reproduction. Additionally, they emerged as cellular signal molecules with key functions in the regulation of immune responses to microbial pathogens, insect herbivores, and beneficial microbes. Their signaling pathways are interconnected in a complex network, which provides plants with an enormous regulatory potential to rapidly adapt to their biotic environment and to utilize their limited resources for growth and survival in a cost-efficient manner. Plants activate their immune system to counteract attack by pathogens or herbivorous insects. Intriguingly, successful plant enemies evolved ingenious mechanisms to rewire the plant's hormone signaling circuitry to suppress or evade host immunity. Evidence is emerging that beneficial root-inhabiting microbes also hijack the hormone-regulated immune signaling network to establish a prolonged mutualistic association, highlighting the central role of plant hormones in the regulation of plant growth and survival.",
"Cross talk between salicylic acid (SA)- and jasmonic acid (JA)-dependent defense signaling has been well documented in plants, but how this cross talk is executed and the components involved remain to be elucidated. We demonstrate that the plant-specific transcription factor WRKY70 is a common component in SA- and JA-mediated signal pathways. Expression of WRKY70 is activated by SA and repressed by JA. The early induction of WRKY70 by SA is NPR1-independent, but functional NPR1 is required for full-scale induction. Epistasis analysis suggested that WRKY70 is downstream of NPR1 in an SA-dependent signal pathway. Modulation of WRKY70 transcript levels by constitutive overexpression increases resistance to virulent pathogens and results in constitutive expression of SA-induced pathogenesis-related genes. Conversely, antisense suppression of WRKY70 activates JA-responsive/COI1-dependent genes. The effect of WRKY70 is not caused by subsequent changes in SA or JA levels. We suggest that WRKY70 acts as an activator of SA-induced genes and a repressor of JA-responsive genes, integrating signals from these mutually antagonistic pathways.",
"Water and nutrients required by developing seeds are mainly supplied by the phloem and have to be released from a maternal parenchyma tissue before being utilized by the filial tissues of embryo and endosperm. To identify aquaporins that could be involved in this process four full-length cDNAs were cloned and sequenced from a cDNA library of developing seed coats of pea (Pisum sativum L.). The cDNA of PsPIP1-1 appeared to be identical to that of clone 7a/TRG-31, a turgor-responsive gene cloned previously from pea roots. PsPIP1-1, PsPIP2-1, and PsTIP1-1, or their possible close homologues, were also expressed in cotyledons of developing and germinating seeds, and in roots and shoots of seedlings, but transcripts of PsNIP-1 were only detected in the seed coat. In mature dry seeds, high hybridization signals were observed with the probe for PsPIP1-1, but transcripts of PsPIP2-1, PsTIP1-1, and PsNIP-1 were not detected. Functional characterization after heterologous expression in Xenopus oocytes showed that PsPIP2-1 and PsTIP1-1 are aquaporins whereas PsNIP-1 is an aquaglyceroporin. PsNIP-1, like several other NIPs, contains a tryptophan residue corresponding with Trp-48 in GlpF (the glycerol facilitator of Escherichia coli) that borders the selectivity filter in the permeation channel. It is suggested that PsPIP1-1 and/or its possible close homologues could play a role in water absorption during seed imbibition, and that PsPIP2-1, possibly together with PsPIP1-1, could be involved in the release of phloem water from the seed coat symplast, which is intimately connected with the release of nutrients for the embryo.",
"In shoots of the garden pea, the bioactive gibberellin (GA1) is synthesised from GA20, and the enzyme which catalyses this step (a GA 3-oxidase -- PsGA3ox1) is encoded by Mendel's LE gene. It has been reported previously that decapitation of the shoot (excision of the apical bud) dramatically reduces the conversion of [3H]GA20 to [3H]GA1 in stems, and here we show that endogenous GA1 and PsGA3ox1 transcript levels are similarly reduced. We show also that these effects of decapitation are completely reversed by application of the auxin indole-3-acetic acid (IAA) to the 'stump' of decapitated plants. Gibberellin A20 is also converted to an inactive product, GA29, and this step is catalysed by a GA 2-oxidase, PsGA2ox1. In contrast to PsGA3ox1, PsGA2ox1 transcript levels were increased by decapitation and reduced by IAA application. Decapitation and IAA treatment did not markedly affect the level of GA1 precursors. It is suggested that in intact pea plants, auxin from the apical bud moves into the elongating internodes where it (directly or indirectly) maintains PsGA3ox1 transcript levels and, consequently, GA1 biosynthesis.",
"Seed germination is a complex trait determined by the interaction of hormonal, metabolic, genetic, and environmental components. Variability of this trait in crops has a big impact on seedling establishment and yield in the field. Classical studies of this trait in crops have focused mainly on the analyses of one level of regulation in the cascade of events leading to seed germination. We have carried out an integrative and extensive approach to deepen our understanding of seed germination in Brassica napus by generating transcriptomic, metabolic, and hormonal data at different stages upon seed imbibition. Deep phenotyping of different seed germination-associated traits in six winter-type B. napus accessions has revealed that seed germination kinetics, in particular seed germination speed, are major contributors to the variability of this trait. Metabolic profiling of these accessions has allowed us to describe a common pattern of metabolic change and to identify the levels of malate and aspartate metabolites as putative metabolic markers to estimate germination performance. Additionally, analysis of seed content of different hormones suggests that hormonal balance between ABA, GA, and IAA at crucial time points during this process might underlie seed germination differences in these accessions. In this study, we have also defined the major transcriptome changes accompanying the germination process in B. napus. Furthermore, we have observed that earlier activation of key germination regulatory genes seems to generate the differences in germination speed observed between accessions in B. napus. Finally, we have found that protein-protein interactions between some of these key regulator are conserved in B. napus, suggesting a shared regulatory network with other plant species. Altogether, our results provide a comprehensive and detailed picture of seed germination dynamics in oilseed rape. This new framework will be extremely valuable not only to evaluate germination performance of B. napus accessions but also to identify key targets for crop improvement in this important process."
] |
Eukaryotic Initiation Factors and Hepatocellular Carcinoma
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The liver is a metabolic hub characterized by high levels of protein synthesis. Eukaryotic initiation factors, eIFs, control the first phase of translation, initiation. Initiation factors are essential for tumor progression and, since they regulate the translation of specific mRNAs downstream of oncogenic signaling cascades, may be druggable. In this review, we address the issue of whether the massive translational machinery of liver cells contributes to liver pathology and to the progression of hepatocellular carcinoma (HCC); it represents a valuable biomarker and druggable target. First, we observe that the common markers of HCC cells, such as phosphorylated ribosomal protein S6, belong to the ribosomal and translational apparatus. This fact is in agreement with observations that demonstrate a huge amplification of the ribosomal machinery during the progression to HCC. Some translation factors, such as eIF4E and eIF6, are then harnessed by oncogenic signaling. In particular, the action of eIF4E and eIF6 is particularly important in HCC when driven by fatty liver pathologies. Indeed, both eIF4E and eIF6 amplify at the translational level the production and accumulation of fatty acids. As it is evident that abnormal levels of these factors drive cancer, we discuss their therapeutic value.
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"To study the expression of eukaryotic translation initiation factor 4E (eIF4E), which is closely correlated with malignant tumors, and its relationship to prognosis in hepatocellular carcinoma. Western blotting was performed to quantify the elF4E protein expression in the normal human liver cell line L02 and the hepatoma cell lines Hep3B, HepG2, and Huh7. Forty-six hepatocellular carcinoma samples with complete clinical data were obtained from Changzheng Hospital during the period of December 2008 to July 2009. The expression of eIF4E in the tumor samples and their adjacent tissues were detected by immunohistochemistry. The relationship between the test results and hepatocellular carcinoma (HCC) prognosis was statistically analysed by using a COX proportional hazard model. Western blotting analysis showed that there were distinct eIF4E protein bands in all three of the hepatoma cell lines. In particular, the HepG2 cell line had the highest level of eIF4E protein expression. The L02 cell group had a low eIF4E expression. Immunohistochemical assay showed that there were 32 cases in which the tumour tissue expression was higher than their adjacent tissues, accounting for 69.57%. There were also 14 cases in which the tumour tissue expression was lower or no significant difference was found, accounting for 30.43%. COX proportional hazards model analysis showed that HCC prognosis was related to the depth of invasion, the overexpression of eIF4E and p53, possibly as independent HCC prognostic predictors. In summary, eIF4E expression is associated with liver cancer, and patients with high eIF4E expression levels have a higher risk of recurrence.",
"Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.",
"Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation. This complex is regulated by the 4E-BPs, which compete with eIF4G for binding to eIF4E and which have tumor-suppressor activity. To pharmacologically mimic 4E-BP function we developed a high-throughput screening assay for identifying small-molecule inhibitors of the eIF4E/eIF4G interaction. The most potent compound identified, 4EGI-1, binds eIF4E, disrupts eIF4E/eIF4G association, and inhibits cap-dependent translation but not initiation factor-independent translation. While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells. 4EGI-1 inhibits cellular expression of oncogenic proteins encoded by weak mRNAs, exhibits activity against multiple cancer cell lines, and appears to have a preferential effect on transformed versus nontransformed cells. The identification of this compound provides a new tool for studying translational control and establishes a possible new strategy for cancer therapy.",
"Clinical data identified an association between the use of HMG-CoA reductase inhibitors (statins) and incident diabetes in patients with underlying diabetes risk factors such as obesity, hypertension and dyslipidemia. The molecular mechanisms however are unknown. An observational cross-sectional study included 910 severely obese patients, mean (SD) body mass index (BMI) 46.7 (8.7), treated with or without statins (ABOS cohort: a biological atlas of severe obesity). Data and sample collection took place in France between 2006 and 2016. Transcriptomic signatures of statin treatment in human liver obtained from genome-wide transcriptomic profiling of five different statin drugs using microarrays were correlated to clinico-biological phenotypes and also assigned to biological pathways and mechanisms. Patients from the non-statin-users group were matched to patients in the statin users group by propensity score analysis to minimize confounding effects from age, gender, parental familial history of diabetes, BMI, waist circumference, systolic and diastolic blood pressure and use of anti-hypertensive drugs as pre-specified covariates. We determined the hepatic, statin-related gene signature from genome-wide transcriptomic profiling in severely obese patients with varying degrees of glucose tolerance and cardio-metabolic comorbidities. One hundred and fifty seven patients on statin treatment in the matched cohort showed higher diabetes prevalence (OR = 2.67; 95%CI, 1.60-4.45; P = 0.0002) and impairment of glucose homeostasis. This phenotype was associated with molecular signatures of increased hepatic de novo lipogenesis (DNL) via activation of sterol regulatory element-binding protein 1 (SREBP1) and concomitant upregulation of the expression of key genes in both fatty acid and triglyceride metabolism. A DNL gene activation profile in response to statins is associated with insulin resistance and the diabetic status of the patients. Identified molecular signatures thus suggest that statin treatment increases the risk for diabetes in humans at least in part via induction of DNL. NCT01129297 . Registered May 242,010 (retrospectively registered).",
"Treacle ribosome biogenesis factor 1 (TCOF1) is a nucleolar factor that regulates ribosomal DNA (rDNA) transcription in the nucleolus. TCOF1 has been previously reported to be implicated in Treacher Collins-Franceschetti syndrome (TCS), a congenital disorder of craniofacial development. Except TCS, TCOF1 has not been reported to be involved in other diseases so far. Here, we show that TCOF1 expression is aberrantly elevated in human hepatocellular carcinoma (HCC) and correlates with HCC progression and poor outcome. In vitro and in vivo studies reveal oncogenic roles of TCOF1 in HCC. Mechanistically, TCOF1 regulates KRAS-activated genes and epithelial-mesenchymal transition (EMT) genes in HCC and is required for the increased ribosomal RNA (rRNA) production, a hallmark of cancer. Interestingly, our analysis reveals an inverse correlation between TCOF1 expression and tumor infiltration of antitumor immune cells, suggesting that TCOF1 may also have an important impact on antitumor immune responses in HCC. Together, our findings support a model in which TCOF1 coordinates oncogenic activation and rRNA production to promote HCC tumorigenesis. The inverse correlation between TCOF1 expression and the infiltration of antitumor immune cells opens a new avenue to understanding the promoting role of TCOF in HCC tumorigenesis.",
"Flavaglines are a family of natural products from the genus Aglaia that exhibit anti-cancer activity in vitro and in vivo and inhibit translation initiation. They have been shown to modulate the activity of eIF4A, the DEAD-box RNA helicase subunit of the eukaryotic initiation factor (eIF) 4F complex, a complex that stimulates ribosome recruitment during translation initiation. One flavagline, silvestrol, is capable of modulating chemosensitivity in a mechanism-based mouse model. Among a number of flavagline family members tested herein, we find that silvestrol is the more potent translation inhibitor among these. We find that silvestrol impairs the ribosome recruitment step of translation initiation by affecting the composition of the eukaryotic initiation factor (eIF) 4F complex. We show that silvestrol exhibits significant anticancer activity in human breast and prostate cancer xenograft models, and that this is associated with increased apoptosis, decreased proliferation, and inhibition of angiogenesis. We demonstrate that targeting translation by silvestrol results in preferential inhibition of weakly initiating mRNAs. Our results indicate that silvestrol is a potent anti-cancer compound in vivo that exerts its activity by affecting survival pathways as well as angiogenesis. We propose that silvestrol mediates its effects by preferentially inhibiting translation of malignancy-related mRNAs. Silvestrol appears to be well tolerated in animals.",
"Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing. We highlight similarities between the methods. Although the accuracy of predictions was not optimal, we find that computational prediction of compound-pair activity is possible, and that community challenges can be useful to advance the field of in silico compound-synergy prediction."
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The Role of Thyroid Hormones in Energy Homeostasis
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The energy homeostasis of the organism is orchestrated by a complex interplay of energy substrate shuttling, breakdown, storage, and distribution. Many of these processes are interconnected via the liver. Thyroid hormones (TH) are well known to provide signals for the regulation of energy homeostasis through direct gene regulation via their nuclear receptors acting as transcription factors. In this comprehensive review, we summarize the effects of nutritional intervention like fasting and diets on the TH system. In parallel, we detail direct effects of TH in liver metabolic pathways with regards to glucose, lipid, and cholesterol metabolism. This overview on hepatic effects of TH provides the basis for understanding the complex regulatory network and its translational potential with regards to currently discussed treatment options of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) involving TH mimetics.
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"We have studied the rat malic enzyme gene as a model for thyroid hormone (triiodothyronine (T3)) regulation of transcription. Our previous studies showed that transcription of this gene is controlled by T3 in vivo. In this study, we used COS-7 cells in culture to determine the location of a T3 response element (TRE) within this gene. Cotransfection of the rat T3 alpha-receptor cDNA with a reporter gene linked to 5'-deletion mutants of the malic enzyme gene 5'-flanking region revealed the presence of a TRE between positions -315 and -248. Using T3 receptors synthesized in vitro from their cDNAs, we have identified, through the use of gel shift assays and footprinting, a single DNA-binding site (positions -281 to -261) for the receptor within the rat malic enzyme gene TRE. The site was capable of binding either the rat alpha- or human beta-receptor with similar affinities. Competition binding studies indicated that the apparent affinity of receptor binding to the malic enzyme gene was similar to that of the rat alpha-myosin heavy chain gene TRE (positions -151 to -122) and was significantly greater than that of the rat growth hormone TRE (positions -192 to -163). These results indicate that both the alpha- and beta-forms of the nuclear T3 receptor are capable of binding directly to the malic enzyme gene 5'-flanking region at a site which functions as a hormone-inducible cis-regulatory element. In conjunction with our previous finding that T3 induces or activates essential transcription factors which bind to the promoter, it appears that the regulation of transcription of the malic enzyme gene by thyroid hormone involves at least two regulatory pathways.",
"Fatty acid synthase (FAS) is a key enzyme of hepatic lipogenesis responsible for the synthesis of long-chain saturated fatty acids. This enzyme is mainly regulated at the transcriptional level by nutrients and hormones. In particular, glucose, insulin, and T(3) increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T(3) and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T(3) response element (TRE) that mediates the T(3) genomic effect, on the FAS promoter between -741 and -696 bp that mediates the T(3) genomic effect. We show that both T(3) and insulin regulate FAS transcription via this sequence. The TRE binds a TR/RXR heterodimer even in the absence of hormone, and this binding is increased in response to T(3) and/or insulin treatment. The use of H7, a serine/threonine kinase inhibitor, reveals that a phosphorylation mechanism is implicated in the transcriptional regulation of FAS in response to both hormones. Specifically, we show that T(3) is able to modulate FAS transcription via a nongenomic action targeting the TRE through the activation of a PI 3-kinase-ERK1/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERK1/2 MAPK and PI 3-kinase/Akt. Finally, our data suggest that the nongenomic actions of T(3) and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence.",
"Important enzymes for thyroid hormone metabolism, antioxidative defense, and intracellular redox control contain selenocysteine (Sec) in their active centers. Expression of these selenoproteins is tightly controlled, and a sex-specific phenotype is observed on disturbance of selenium (Se) transport in mice. Therefore, we analyzed Se concentrations and expression levels of several selenoproteins including type I iodothyronine deiodinase (Dio1) and glutathione peroxidase (GPx) isozymes in male and female mice. On regular lab chow, serum Se levels were comparable, but serum GPx3 activity was higher in females than males (1.3-fold). Selenoprotein P (SePP) mRNA levels were higher in livers (1.3-fold) and lower in kidneys (to 31%) in female compared with male mice. Orchidectomy alleviated the sex-specific differences in SePP mRNA amounts, indicating modulatory effects of androgens on SePP expression. Female mice expressed higher levels of Dio1 mRNA in kidney (2.6-fold) and liver (1.4-fold) in comparison with male mice. This sexual dimorphic expression of Dio1 mRNA was paralleled by increased Dio1 activity in female kidney (1.8-fold) but not in liver in which males expressed higher Dio1 activity (2.8-fold). Interestingly, Se deficiency decreased Dio1 activity more effectively in males than females, and resulting hepatic enzyme levels were then comparable between the sexes. At the same time, the sex-specific difference of Dio1 activity widened in kidney. Orchidectomy or estradiol treatment of ovariectomized females impacted stronger on renal than hepatic Dio1 expression. Thus, we conclude that Se-dependent posttranscriptional mechanisms are operational that affect either translational efficiency or Dio1 stability in a sex- and tissue-specific manner.",
"While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor alpha (FXR-alpha; NR1H4). FXR-alpha regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR-alpha-mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/- mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-alpha, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA-TGR5-cAMP-D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control.",
"Thyroid hormone influences diverse metabolic pathways important in lipid and glucose metabolism, lipolysis and regulation of body weight. Recently, it has been recognized that thyroid hormone receptor interacts with transcription factors that predominantly respond to nutrient signals including the peroxisome proliferator-activated receptors, liver X receptor and others. Crosstalk between thyroid hormone signaling and these nutrient responsive factors occurs through a variety of mechanisms: competition for retinoid X receptor heterodimer partners, DNA binding sites and transcriptional cofactors. This review focuses on the mechanisms of interaction of thyroid hormone signaling with other metabolic pathways and the importance of understanding these interactions to develop therapeutic agents for treatment of metabolic disorders, such as dyslipidemias, obesity and diabetes.",
"We have previously shown that triiodothyronine (T3) regulates rat fatty acid synthesis in a tissue specific manner. Here, we determined the effects of thyroid state on mRNAs encoding the lipogenic enzymes, acetyl CoA carboxylase (ACC) and fatty acid synthase (FAS). S14 mRNA, a sequence tightly associated with lipogenesis, was also measured. Levels of the three mRNA were 9-13-fold higher in hyper- than hypothyroid liver. Limited expression in kidney and heart was also increased by thyroid hormone. In brown adipose tissue, highest levels were recorded in hypothyroid animals. Thyroid state did not affect expression in lung and brain. All these changes are consistent with those previously measured in fatty acid synthesis. In white adipose tissue, mRNA expression was increased by hyperthyroidism. This increase may not be reflected in fatty acid synthesis, since we recently showed lipogenesis to be reduced under these circumstances. All three mRNAs responded rapidly to T3 in liver, but more slowly in kidney and fat. Thus, T3 regulates lipogenesis by altering levels of ACC and FAS mRNAs. S14 mRNA changes in parallel.",
"Sirtuin 1 (SIRT1) NAD(+)-dependent deacetylase regulates energy metabolism by modulating expression of genes involved in gluconeogenesis and other liver fasting responses. While many effects of SIRT1 on gene expression are mediated by deacetylation and activation of peroxisome proliferator activated receptor coactivator α (PGC-1α), SIRT1 also binds directly to DNA bound transcription factors, including nuclear receptors (NRs), to modulate their activity. Since thyroid hormone receptor β1 (TRβ1) regulates several SIRT1 target genes in liver and interacts with PGC-1α, we hypothesized that SIRT1 may influence TRβ1. Here, we confirm that SIRT1 cooperates with PGC-1α to enhance response to triiodothyronine, T3. We also find, however, that SIRT1 stimulates TRβ1 activity in a manner that is independent of PGC-1α but requires SIRT1 deacetylase activity. SIRT1 interacts with TRβ1 in vitro, promotes TRβ1 deacetylation in the presence of T3 and enhances ubiquitin-dependent TRβ1 turnover; a common response of NRs to activating ligands. More surprisingly, SIRT1 knockdown only strongly inhibits T3 response of a subset of TRβ1 target genes, including glucose 6 phosphatase (G-6-Pc), and this is associated with blockade of TRβ1 binding to the G-6-Pc promoter. Drugs that target the SIRT1 pathway, resveratrol and nicotinamide, modulate T3 response at dual TRβ1/SIRT1 target genes. We propose that SIRT1 is a gene-specific TRβ1 co-regulator and TRβ1/SIRT1 interactions could play important roles in regulation of liver metabolic response. Our results open possibilities for modulation of subsets of TR target genes with drugs that influence the SIRT1 pathway.",
"Acetyl-CoA carboxylases (ACC) 1 and 2 are central enzymes in lipid metabolism. To further investigate their relevance for the development of obesity and type 2 diabetes, expression of both ACC isoforms was analyzed in obese fa/fa Zucker fatty and Zucker diabetic fatty rats at different ages in comparison to Zucker lean controls. ACC1 and ACC2 transcript levels were measured by quantitative real-time polymerase chain reaction in metabolically relevant tissues of Zucker fatty, Zucker diabetic fatty and Zucker lean control animals. Quantitative real-time polymerase chain reaction was also applied to measure ACC tissue distribution in human tissues. For confirmation on a protein level, quantitative mass spectrometry was used. Disease-related transcriptional changes of both ACC isoforms were observed in various tissues of Zucker fatty and Zucker diabetic fatty rats including liver, pancreas and muscle. Changes were most prominent in oxidative tissues of diabetic rats, where ACC2 was significantly increased and ACC1 was reduced compared with Zucker lean control animals. A comparison of the overall tissue distribution of both ACC isoforms in humans and rats surprisingly revealed strong differences. While in rats ACC1 was mainly expressed in lipogenic and ACC2 in oxidative tissues, ACC2 was predominant in oxidative and lipogenic tissues in humans. Our data support a potential role for both ACC isoforms in the development of obesity and diabetes in rats. However, the finding of fundamental species differences in ACC1 and ACC2 tissue expression might be indicative for different functions of both isoforms in humans and rats and raises the question to which degree these models are predictive for the physiology and pathophysiology of lipid metabolism in humans.",
"Fasting in rodents is characterized by decreases in serum T4 and T3 levels but no compensatory increase in serum TSH level. The types 1 and 2 deiodinases (D1 and D2) are postulated to play key roles in mediating these changes. However, serum T4 and T3 levels in fasted 5'-deiodinase-deficient mice decreased by at least the same percentage as that observed in wild-type mice, whereas serum TSH level was unaffected. D3 activity was increased in kidney, muscle, and liver up to 4-fold during fasting, and the mean serum rT3 level was increased 3-fold in fasted D1-deficient mice, compared with fed animals. In wild-type mice, the tissue contents of T4 and T3 in liver, kidney, and muscle were unchanged or increased in fasted animals, and after the administration of [(125)I]T4 or [(125)I]T3, the radioactive content in the majority of tissues from fasted mice was increased 2- or 4-fold, respectively. These findings suggest that the observed fasting-induced reductions in the circulating T3 and T4 levels are mediated in part by increased D3 activity and by the sequestration of thyroid hormone and their metabolites in tissues. Studies performed in D3-deficient mice demonstrating a blunting of the fasting-induced decrease in serum T4 and T3 levels were consistent with this thesis. Thus, the systemic changes in thyroid hormone economy as a result of acute food deprivation are not dependent on the D1 or D2 but are mediated in part by sequestration of T4 and T3 in tissues and their enhanced metabolism by the D3.",
"Transcription of the gene for phosphoenolpyruvate carboxy-kinase (PEPCK) is stimulated by thyroid hormone (T3), glucagon (via cyclic AMP) and glucocorticoids. A region of the PEPCK promoter between -332 and -308 mediates the induction of transcription by T3. To characterize this region further, mutations were introduced into this region of the PEPCK promoter and the modified promoters ligated to the chloramphenicol acetyltransferase (CAT) reporter gene. Using these PEPCK-CAT vectors in transient transfections in HepG2 cells, it was found that T3 stimulates PEPCK transcription through two direct repeats of the AGGTCA motif located between nucleotides -330 and -319 [PEPCK-thyroid-hormone-responsive element (TRE)]. The beta form of the T3 receptor (TR beta) bound PEPCK-TRE as a homodimer but bound far more efficiently as a heterodimeric complex with the retinoid X receptor (RXR). An additional region called P3(I) (-250 to -234) is required for T3 responsiveness and binds members of the CCAAT-enhancer-binding protein (C/EBP) family. P3(I) contains an AGGTCA-like motif that can bind the TR beta-RXR heterodimer. Mutagenesis of this motif abolished TR beta-RXR binding without reducing T3 induction. Mutation of the C/EBP-binding site or insertion of a cyclic AMP-responsive-binding-protein site at P3(I) eliminated the T3 response. Our results indicate that T3 stimulation of PEPCK transcription is mediated by TR beta bound to PEPCK-TRE and requires C/EBP to be bound at the P3(I) site."
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Development of hypoallergenic wheat products for wheat-dependent exercise-induced anaphylaxis
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Immunoglobulin E (IgE)-mediated food allergies to wheat that develop after school age typically shows a type of wheat-dependent exercise-induced anaphylaxis (WDEIA). At present, avoidance of wheat products or postprandial rest after ingesting wheat is recommended for patients with WDEIA, depending on the severity of the allergy symptoms. ω5-Gliadin has been identified as the major allergen in WDEIA. In addition, α/β-, γ-, and ω1,2-gliadins, high and low molecular weight-glutenins, and a few water-soluble wheat proteins have been identified as IgE-binding allergens in a small proportion of patients with IgE-mediated wheat allergies. A variety of approaches have been manufactured to develop hypoallergenic wheat products that can be consumed by patients with IgE-mediated wheat allergies. In order to analyze such approaches, and to contribute to the further improvement, this study outlined the current status of these hypoallergenic wheat productions, including wheat lines with a reduced allergenicity that are mostly constructed for the patients sensitized to ω5-gliadin, hypoallergenic wheat by enzymic degradation/ion exchanger deamidation, and hypoallergenic wheat by thioredoxin treatment. The wheat products obtained by these approaches significantly reduced the reactivity of Serum IgE in wheat-allergic patients. However, either these were not effective on some populations of the patients, or low-level IgE-reactivity to some allergens of the products was observed in the patients. These results highlight some of the difficulties faced in creating hypoallergenic wheat products or hypoallergenic wheat lines through either traditional breeding or biotechnology approaches in developing hypoallergenic wheat completely safe for all the patients allergic to wheat.
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"Celiac disease is a food-sensitive enteropathy triggered by the ingestion of wheat gluten proteins and related proteins from barley, rye, and some varieties of oat. There are no interventional therapies and the only solution is a lifelong gluten-free diet. The down-regulation of gliadins by RNAi provides wheat lines with all the gliadin fractions strongly down-regulated (low-gliadin). The technological properties of doughs prepared from the low-gliadin lines indicated a general weakening effect, although some of the lines displayed similar properties to that of the wild-type lines. In contrast, the stability was increased significantly in some of the transgenic lines, indicating better tolerance to over-mixing. Results reported here are the first analyses of the mixing and bread-making quality of the wheat lines with all gliadin fractions strongly down-regulated. Flour from these lines may be an important breakthrough in the development of new products for the celiac community. These lines might be used directly or blended with other non-toxic cereals, as raw material for developing food products that can be safely tolerated by CD patients and others with gluten intolerance or gluten sensitivity, incrementing the range of available food products and enhancing their diet.",
"We propose a novel method to produce hypoallergenic wheat flour suitable for patients allergic to wheat by using enzymatic fragmentation with cellulase and actinase. The hypoallergenic flour displayed potent inhibitory activity against allergen absorption and actively suppressed allergic reactions, probably inducing oral tolerance. The results suggest that hypoallergenic wheat flour has allergy-suppressive effects without inducing side effects.",
"Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a severe IgE-mediated allergic reaction provoked by the combination of wheat-ingestion with intensive physical exercise over the next few hours. Among wheat proteins, omega-5 gliadin, which is one of the components of fast omega-gliadin, has been reported as a major allergen in the anaphylaxis. In this study, we detected IgE-binding epitopes within the primary sequence of omega-5 gliadin using arrays of overlapping peptides synthesized on derivatized cellulose membranes. Sera from four patients with WDEIA having specific IgE to the fast omega-gliadin were used to probe the membrane. Seven epitopes, QQIPQQQ, QQLPQQQ, QQFPQQQ, QQSPEQQ, QQSPQQQ, QQYPQQQ, and PYPP, were detected within the primary sequence of omega-5 gliadin. By using sera of 15 patients, 4 of them, QQIPQQQ, QQFPQQQ, QQSPEQQ, and QQSPQQQ, were found to be dominant epitopes. Mutational analysis of the QQIPQQQ and QQFPQQQ indicated that amino acids at positions Gln(1), Pro(4), Gln(5), Gln(6), and Gln(7) were critical for IgE binding. These results will provide a useful tool for developing safer wheat products in addition to diagnostic and immunotherapy techniques for WDEIA.",
"Patients with wheat-dependent, exercise-induced anaphylaxis experience severe allergic reactions when exercising after ingestion of wheat. The major wheat allergen associated with these reactions is a omega-5 gliadin, and patients following a gluten-free diet have remained free of symptoms. The aim of this study was to examine whether allergens cross-reacting with wheat omega-5 gliadin are present in rye, barley and oats. Sera from 23 adult patients with wheat-dependent, exercise-induced anaphylaxis were examined. Cereal allergens cross-reacting with wheat omega-5 gliadin were identified by immunoblot inhibition. The cross-reactive allergens were purified by gel filtration and reversed-phase chromatography and submitted to amino acid sequencing. Cross-reactivity was further studied by IgE ELISA and ELISA inhibition, and in vivo reactivity by skin prick testing. In immunoblotting rabbit anti-omega-5 gliadin antibodies bound to 70 kDa and 32 kDa proteins in rye and a 34-kDa protein in barley, but not to proteins in oats. N-terminal sequencing identified these proteins as rye gamma-70 secalin, rye gamma- 35 secalin and barley gamma-3 hordein, correspondingly. In ELISA 21/23 (91%) patients with wheat-dependent, exercise-induced anaphylaxis showed IgE antibodies to purified gamma-70 secalin, 19/23 (83%) to gamma-35 secalin and 21/23 (91%) to gamma-3 hordein. In ELISA inhibition omega-5 gliadin inhibited over 90% of the IgE binding of pooled patient sera to solid-phase gamma-secalins and gamma-3 hordein. Skin prick testing gave positive reactions to gamma-70 secalin in 10/15 (67%) patients, to gamma-35 secalin in 3/15 (20%) patients and to gamma-3 hordein in 7/15 (47%) patients. The results of this study show that gamma-70 and gamma-35 secalins in rye and gamma-3 hordein in barley cross-react with omega-5 gliadin, a major allergen in wheat-dependent, exercise-induced anaphylaxis. These findings suggest that also rye and barley may elicit symptoms in patients with wheat-dependent, exercise-induced anaphylaxis.",
"The end-use quality of wheat flour varies as a result of the growth conditions of the plant. Among the wheat gluten proteins, the omega-5 gliadins have been identified as a major source of environmental variability, increasing in proportion in grain from plants that receive fertilizer or are subjected to high temperatures during grain development. The omega-5 gliadins also have been associated with the food allergy wheat-dependent exercise-induced anaphylaxis (WDEIA). Recently, transgenic lines with reduced levels of omega-5 gliadins were developed using RNA interference (RNAi). These lines make it possible to determine whether changes in the levels of omega-5 gliadins in response to environmental conditions and agronomic inputs may be responsible for changes in flour end-use quality. Two transgenic wheat lines and a non-transgenic control were grown under a controlled temperature regimen with or without post-anthesis fertilizer and the protein composition of the resulting flour was analyzed by quantitative two-dimensional gel electrophoresis (2-DE). In one transgenic line, all 2-DE spots identified as omega-5 gliadins were substantially reduced without effects on other proteins. In the other transgenic line, the omega-5 gliadins were absent and there was a partial reduction in the levels of the omega-1,2 gliadins and the omega-1,2 chain-terminating gliadins as well as small changes in several other proteins. With the exception of the omega gliadins, the non-transgenic control and the transgenic plants showed similar responses to the fertilizer treatment. Protein contents of flour were determined by the fertilizer regimen and were similar in control and transgenic samples produced under each regimen while both mixing time and mixing tolerance were improved in flour from transgenic lines when plants received post-anthesis fertilizer. The data indicate that omega-5 gliadins have a negative effect on flour quality and suggest that changes in quality with the growth environment may be due in part to alterations in the levels of the omega gliadins. Because a known food allergen and one of the major sources of environmentally-induced variation in wheat flour protein composition has been eliminated, the transgenic lines may yield flour with both improved end-use quality and more consistent functionality when grown in different locations.",
"Food-dependent exercise induced anaphylaxis (FDEIA) is a distinct form of food allergy induced by physical exercise. Symptoms are typically generalized urticaria and severe allergic reactions such as shock or hypotension. Whereas various food items are responsible for the development of FDEIA, wheat is reported to be the allergen with the highest frequency in Japan. Recently aspirin has been known to be an additional exacerbating factor. Skin tests and in vitro serum food-specific IgE assays are currently used, however their sensitivity and specificity are not always satisfactory. A challenge test consisting of ingestion of assumed food followed by intense physical exercise is the only reliable method to determine the causative food and to diagnose the disease. The challenge test is not always safe because in some cases the test induces an anaphylactic shock. So a reliable in vitro diagnostic method is necessary for the patients with FDEIA. We revealed that wheat omega-5 gliadin and high molecular weight glutenin subunit are major allergens in wheat-dependent exercise-induced anaphylaxis (WDEIA). A simultaneous detection of specific IgE to epitope sequences of both omega-5 gliadin and high molecular weight glutenin is found to achieve higher sensitivity and specificity compared with the in vitro serum food-specific IgE assays currently used for diagnosis of WDEIA. On the other hand, immunoreactive gliadins appeared in the sera of patients during the provocation test with both wheat-exercise and wheat-aspirin challenges in parallel with allergic symptoms. These findings suggest that FDEIA is IgE-mediated hypersensitivity reaction to foods and both exercise and aspirin facilitate allergen absorption from the gastrointestinal tract.",
"Wheat is involved in different forms of respiratory, food and contact allergy. The IgE of patients generally reacts with various flour proteins. It is not known if antigenic relationships could explain some of these reactions and if proteins could be involved in different pathologies. Two sera were selected as representative of patients with either wheat-dependent exercise-induced anaphylaxis (WDEIA) or hypersensitivity to hydrolyzed wheat proteins (HHWP). Their IgE specificity was studied with wheat, barley and rye proteins, using immunoblot, and immunoblot inhibition with recombinant gamma-3 hordein. This protein was chosen for its cross-reactivity with omega-5 gliadin, a major allergen in WDEIA. The IgE from both sera strongly reacted with natural and recombinant gamma-3 hordein but displayed different patterns of reactivity with wheat, barley and rye proteins. Those from the WDEIA patient showed expected reactions with omega-5 gliadin, gamma-35 and gamma-75 secalins, but also with wheat low-molecular-weight glutenin subunits (LMW-GS), and not with C hordeins. On the contrary, IgE from a HHWP patient reacted with C hordeins, various omega gliadins, and gamma-75 secalin, but very weakly with gamma-35 secalin and LMW-GS. Recombinant gamma-3 hordein inhibited strongly but not totally the WDEIA patient's IgE binding to prolamins. No such inhibition could be observed for the HHWP patient's IgE. At least part of the reactions of prolamins with the IgE from the WDEIA patient was due to antigenic homologies. The occurrence of cross-reacting carbohydrates was unlikely. These common IgE epitopes were not involved in the pathology of the HHWP patient."
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Specific and genome-wide effect of mTOR-S6 on translation in pancreatic cancer cells
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Pancreatic cancer cells adapt molecular mechanisms to activate the protein synthesis to support tumor growth. This study reports the mTOR inhibitor rapamycin's specific and genome-wide effect on mRNA translation. Using ribosome footprinting in pancreatic cancer cells that lack the expression of 4EBP1, we establish the effect of mTOR-S6-dependent mRNAs translation. Rapamycin inhibits the translation of a subset of mRNAs including p70-S6K and proteins involved in the cell cycle and cancer cell growth. In addition, we identify translation programs that are activated following mTOR inhibition. Interestingly, rapamycin treatment results in the translational activation of kinases that are involved in mTOR signaling such as p90-RSK1. We further show that phospho-AKT1 and phospho-eIF4E are upregulated following mTOR inhibition suggesting a feedback activation of translation by rapamycin. Next, targeting eIF4E and eIF4A-dependent translation by using specific eIF4A inhibitors in combination with rapamycin shows significant growth inhibition in pancreatic cancer cells. In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer.
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[
"PIK3CA and PTEN alterations are common in human cancer, but only a fraction of such tumors are dependent upon AKT signaling. AKT independence is associated with redundant activation of cap-dependent translation mediated by convergent regulation of the translational repressor 4E-BP1 by the AKT and ERK pathways. This provides mechanistic bases for the limited activity of AKT and MEK inhibitors in tumors with comutation of both pathways and the profound synergy observed with combined inhibition. Whereas such tumors are sensitive to a dominant active 4E-BP1 mutant, knockdown of 4E-BP1 expression reduces their dependence on AKT/ERK signaling for translation or survival. Thus, 4E-BP1 plays a prominent role in mediating the effects of these pathways in tumors in which they are activated by mutation.",
"Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.",
"The mammalian target of rapamycin (mTOR) regulates cell growth by integrating nutrient and growth factor signaling and is strongly implicated in cancer. But mTOR is not an oncogene, and which tumors will be resistant or sensitive to new adenosine triphosphate (ATP) competitive mTOR inhibitors now in clinical trials remains unknown. We screened a panel of over 600 human cancer cell lines to identify markers of resistance and sensitivity to the mTOR inhibitor PP242. RAS and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) mutations were the most significant genetic markers for resistance and sensitivity to PP242, respectively; colon origin was the most significant marker for resistance based on tissue type. Among colon cancer cell lines, those with KRAS mutations were most resistant to PP242, whereas those without KRAS mutations most sensitive. Surprisingly, cell lines with co-mutation of PIK3CA and KRAS had intermediate sensitivity. Immunoblot analysis of the signaling targets downstream of mTOR revealed that the degree of cellular growth inhibition induced by PP242 was correlated with inhibition of phosphorylation of the translational repressor eIF4E-binding protein 1 (4E-BP1), but not ribosomal protein S6 (rpS6). In a tumor growth inhibition trial of PP242 in patient-derived colon cancer xenografts, resistance to PP242-induced inhibition of 4E-BP1 phosphorylation and xenograft growth was again observed in KRAS mutant tumors without PIK3CA co-mutation, compared with KRAS wild-type controls. We show that, in the absence of PIK3CA co-mutation, KRAS mutations are associated with resistance to PP242 and that this is specifically linked to changes in the level of phosphorylation of 4E-BP1.",
"The eIF4E translation initiation factor has oncogenic properties and concordantly, the inhibitory eIF4E-binding protein (4EBP1) is considered a tumor suppressor. The exact molecular effects of 4EBP1 activation in cancer are still unknown. Surprisingly, 4EBP1 is a target of genomic copy number gains (Chr. 8p11) in breast and lung cancer. We noticed that 4EBP1 gains are genetically linked to gains in neighboring genes, including WHSC1L1 and FGFR1. Our results show that FGFR1 gains act to attenuate the function of 4EBP1 via PI3K-mediated phosphorylation at Thr37/46, Ser65, and Thr70 sites. This implies that not 4EBP1 but instead FGFR1 is the genetic target of Chr. 8p11 gains in breast and lung cancer. Accordingly, these tumors show increased sensitivity to FGFR1 and PI3K inhibition, and this is a therapeutic vulnerability through restoring the tumor-suppressive function of 4EBP1. Ribosome profiling reveals genes involved in insulin signaling, glucose metabolism, and the inositol pathway to be the relevant translational targets of 4EBP1. These mRNAs are among the top 200 translation targets and are highly enriched for structure and sequence motifs in their 5'UTR, which depends on the 4EBP1-EIF4E activity. In summary, we identified the translational targets of 4EBP1-EIF4E that facilitate the tumor suppressor function of 4EBP1 in cancer."
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High-dose methotrexate in primary central nervous system lymphoma: a systematic review
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Primary central nervous system lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma that is confined within the CNS. Due to its ability to cross the blood-brain barrier, high-dose methotrexate (HDMTX) is the backbone for induction chemotherapy. This systematic review was conducted to observe outcomes among different HDMTX doses (low, <3 g/m
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[
"Our goals were to evaluate the safety of adding rituximab to methotrexate (MTX)-based chemotherapy for primary CNS lymphoma, determine whether additional cycles of induction chemotherapy improve the complete response (CR) rate, and examine effectiveness and toxicity of reduced-dose whole-brain radiotherapy (WBRT) after CR. Thirty patients (17 women; median age, 57 years; median Karnofsky performance score, 70) were treated with five to seven cycles of induction chemotherapy (rituximab, MTX, procarbazine, and vincristine [R-MPV]) as follows: day 1, rituximab 500 mg/m2; day 2, MTX 3.5 gm/m2 and vincristine 1.4 mg/m2. Procarbazine 100 mg/m2/d was administered for 7 days with odd-numbered cycles. Patients achieving CR received dose-reduced WBRT (23.4 Gy), and all others received standard WBRT (45 Gy). Two cycles of high-dose cytarabine were administered after WBRT. CSF levels of rituximab were assessed in selected patients, and prospective neurocognitive evaluations were performed. With a median follow-up of 37 months, 2-year overall and progression-free survival was 67% and 57%, respectively. Forty-four percent of patients achieved a CR after five or fewer cycles, and 78% after seven cycles. The overall response rate was 93%. Nineteen of 21 CR patients received the planned 23.4 Gy WBRT. The most commonly observed grade 3 to 4 toxicities included neutropenia (43%), thrombocytopenia (36%), and leukopenia (23%). No treatment-related neurotoxicity has been observed. The addition of rituximab to MPV increased the risk of significant neutropenia requiring routine growth factor support. Additional cycles of R-MPV nearly doubled the CR rate. Reduced-dose WBRT was not associated with neurocognitive decline, and disease control to date is excellent.",
"A multicenter, phase II study of single-agent, intravenous methotrexate in newly diagnosed non-AIDS-related primary CNS lymphoma was conducted in the New Approaches to Brain Tumor Therapy (NABTT) CNS Consortium. Methotrexate (8 g/m(2)) was initially administered every 2 weeks. The primary end point was radiographic CR or PR, as defined by standard radiographic criteria, and secondary end points were survival and drug-related toxicity. Twenty-five patients were enrolled with a mean age of 60 years and median Karnofsky Performance Score of 80. Three of 14 patients who underwent lumbar puncture had malignant cells on CSF cytopathology, and five of 25 patients had ocular involvement. Two patients could not be evaluated for the primary end point because of the absence of measurable disease in one and death before radiologic imaging in another. All patients have completed the treatment program or progressed. Among 23 patients, there were 12 CR (52%), five PR (22%), one (4%) with stable disease, and five progressions (22%) while on therapy. Seven patients died of tumor progression, and two died of other causes. Median progression-free survival was 12.8 months. Median overall survival for the entire group had not been reached at 22.8+ months. The toxicity of this regimen was modest, with no grade 3 or 4 toxicity in 13 of 25 patients, grade 3 toxicity in eight of 25 patients, and grade 4 toxicity in four of 25 patients after 287 cycles of chemotherapy. These results indicate that high-dose methotrexate is associated with modest toxicity and a radiographic response proportion (74%) comparable to more toxic regimens.",
"Primary central nervous system (CNS) diffuse large B-cell lymphoma (DLBCL) in immunocompetent individuals, although rare, has been rising in incidence. Currently, no reliable prognostic markers are available for these individuals. To study the implications of expression of a panel of oncogenic proteins (Bcl-2, Bcl-6, and c-Myc) and p53 for predicting clinical outcome, particularly overall survival, in immunocompetent individuals with primary CNS DLBCL. Fourteen primary CNS DLBCL cases were retrospectively studied by immunohistochemistry on formalin-fixed, paraffin-embedded sections for the expression of c-Myc, Bcl-2, Bcl-6, and p53. The overall frequencies of expression for p53, c-Myc, Bcl-2, and Bcl-6 in these cases were 29%, 50%, 71%, and 57%, respectively. Cases with expression of p53, c-Myc, or Bcl-6 had a poorer overall survival than those without (Kaplan-Meier survival analysis: 50% cumulative overall survival, 2 months vs 30-60 months, P =.02, log-rank test; 9-16 months vs 21-60 months, P =.03, log-rank test; and 9-16 months vs 21-60 months, P =.16, log-rank test, respectively). The expression of Bcl-2 or proliferation activity by MIB-1 showed no correlation with overall survival. Likewise, the clinical parameters, including age, location of tumors, multiplicity of tumor lesions, and lactase dehydrogenase levels revealed no impact on overall survival. Our results suggest that patients with expression of p53, c-Myc, or Bcl-6 have a poorer overall survival than those without. Since traditional prognostic markers in non-CNS DLBCL, such as staging and International Prognostic Index scores, are not applicable to primary CNS DLBCL, evaluation of p53, c-Myc, and Bcl-6 by immunohistochemistry may be warranted as part of prognostic evaluation in immunocompetent patients with primary CNS DLBCL. Further studies are indicated to confirm our observations.",
"Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.",
"To explore the efficacy of high-dose methotrexate (HD-MTX) combined with rituximab (R) in the treatment of primary central nervous system lymphoma (PCNSL). 108 PCNSL patients were randomly divided into Rituximab group (n=54) or control group (n=54). The patients in Rituximab group were treated with HD-MTX + R chemotherapy, while those in control group were given HD-MTX combined with whole brain radiotherapy (WBRT). The therapeutic effect, incidence rate of adverse reactions and the SF-36 score were compared between the two groups. The overall response rate was overtly higher in Rituximab group than that in control group (81.5% vs. 57.4%). After treatment, the scores of physical function, physical competence, health condition, social function and emotional function in the SF-36 scale were notably higher in Rituximab group than those in control group. The 1-year overall survival (OS) rate was 83.3% (45/54) and 63.0% (34/54), 1-year progression-free survival (PFS) rate was 70.4% (38/54) and 46.3% (25/68), 3-year OS rate was 57.4% (31/54) and 31.5% (17/54), and 3-year PFS rate was 27.8% (15/54) and 14.8% (8/54) in Rituximab group and control group, respectively. The results of log-rank test showed that the OS and PFS rates in Rituximab group were obviously better than those in control group. Compared with HD-MTX combined with WBRT, HD-MTX combined with R can remarkably improved the quality of life and survival rate of patients with PCNSL, with tolerable adverse reactions and is worthy of popularization and application in clinical practice.",
"High-dose methotrexate-based chemotherapy is the mainstay of treatment of primary central nervous system lymphoma (PCNSL), but relapses remain frequent. High-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) may provide an alternative to address chemoresistance and overcome the blood-brain barrier. In this single-center phase-2 study, newly diagnosed PCNSL patients received 5 to 7 cycles of chemotherapy with rituximab, methotrexate (3.5 g/m(2)), procarbazine, and vincristine (R-MPV). Those with a complete or partial response proceeded with consolidation HDC with thiotepa, cyclophosphamide, and busulfan, followed by ASCT and no radiotherapy. Primary end point was 1-year progression-free survival (PFS), N = 32. Median age was 57, and median Karnofsky performance status 80. Following R-MPV, objective response rate was 97%, and 26 (81%) patients proceeded with HDC-ASCT. Among all patients, median PFS and overall survival (OS) were not reached (median follow-up: 45 months). Two-year PFS was 79% (95% confidence interval [CI], 58-90), with no events observed beyond 2 years. Two-year OS was 81% (95% CI, 63-91). In transplanted patients, 2-year PFS and OS were 81%. There were 3 treatment-related deaths. Prospective neuropsychological evaluations suggested relatively stable cognitive functions posttransplant. In conclusion, this treatment was associated with excellent disease control and survival, an acceptable toxicity profile, and no evidence of neurotoxicity thus far. This trial was registered at www.clinicaltrials.gov as NCT00596154.",
"Several biomarkers have been identified as prognostic factors in primary central nervous system lymphoma (PCNSL). However, the correlation between the histogenetic origin of PCNSL and the response to therapy is still unclear. To elucidate the utility of immunophenotypic markers in predicting clinical outcomes, we investigated 27 immunocompetent patients with PCNSL treated with high-dose methotrexate therapy. Of the 27 patients, 25 received whole-brain radiotherapy after high-dose methotrexate. Immunostaining for CD5, CD10, BCL-6, and MUM-1 was used to determine the immunophenotypic profile of diffuse large B-cell lymphoma of PCNSL. We then evaluated whether immunophenotypic markers were associated with the response to therapy or patients' survival. The response to induction high-dose methotrexate therapy was determined by magnetic resonance imaging after three courses of i.v. high-dose methotrexate. We categorized B-cell lymphomas into three known subtypes: germinal center B-cell (GCB), activated-GCB, and post-GCB subtypes according to immunohistochemical profile. All the BCL-6-positive samples were co-positive for MUM-1 and therefore classified into activated-GCB subtype. BCL-6 expression in this study was associated with poor progression-free survival (P = 0.038). No immunophenotypic markers or subtypes had a significant effect on the response to high-dose methotrexate therapy. However, the response itself was a significant predictor for both progression-free survival (P < 0.001) and overall survival (P = 0.003). Further investigation is needed to assess BCL-6 as a potential prognostic factor in PCNSL."
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Detection and remediation of contaminated water bodies and effluents in the American continent
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Currently, water pollution represents a serious environmental threat, causing an impact not only to fauna and flora but also to human health. Among these pollutants, inorganic and organic pollutants are predominantly important representing high toxicity and persistence and being difficult to treat using current methodologies. For this reason, several research groups are searching for strategies to detect and remedy contaminated water bodies and effluents. Due to the above, a current review of the state of the situation has been carried out. The results obtained show that in the American continent a high diversity of contaminants is present in the water bodies affecting several aspects, in which in some cases, there exists alternatives to realize the remediation of contaminated water. It is concluded that the actual challenge is to establish sanitation measures at the local level based on the specific needs of the geographical area of interest. Therefore, water treatment plants must be designed according to the contaminants present in the water of the region and tailored to the needs of the population of interest.
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"The dominant source of drinking water in rural Nevada, United States, is privately-owned domestic wells. Because the water from these wells is unregulated with respect to government guidelines, it is the owner's responsibility to test their groundwater for heavy metals and other contaminants. Arsenic, lead, cadmium, and uranium have been previously measured at concentrations above Environmental Protection Agency (EPA) guidelines in Nevada groundwater. This is a public health concern because elevated levels of these metals are known to have negative health effects. We recruited individuals through a population health study, the Healthy Nevada Project, to submit drinking water samples from domestic wells for testing. Water samples were returned from 174 households with private wells. We found 22 % had arsenic concentrations exceeding the EPA maximum contaminant level (MCL) of 10 μg/L. Additionally, federal, state, or health-based guidelines were exceeded for 8 % of the households for uranium and iron, 6 % for lithium and manganese, 4 % for molybdenum, and 1 % for lead. The maximum observed concentrations of arsenic, uranium, and lead were ∼80, ∼5, and ∼1.5 times the EPA guideline values, respectively. 41 % of households had a treatment system and submitted both pre- and post-treatment water samples from their well. The household treatments were shown to reduce metal concentrations, but concentrations above guideline values were still observed. Many treatment systems cannot reduce the concentration below guideline values because of water chemistry, treatment failure, or improper treatment techniques. These results show the pressing need for continued education and outreach on regular testing of domestic well waters, proper treatment types, and health effects of metal contamination. These findings are potentially applicable to other arid areas where groundwater contamination of naturally occurring heavy metals occurs.",
"Pharmaceutical contamination of shallow groundwater is a substantial concern in effluent-dominated streams, due to high aqueous mobility, designed bioactivity, and effluent-driven hydraulic gradients. In October and December 2012, effluent contributed approximately 99% and 71%, respectively, to downstream flow in Fourmile Creek, Iowa, USA. Strong hydrologic connectivity was observed between surface-water and shallow-groundwater. Carbamazepine, sulfamethoxazole, and immunologically-related compounds were detected in groundwater at greater than 0.02 μg L(-1) at distances up to 6 m from the stream bank. Direct aqueous-injection HPLC-MS/MS revealed 43% and 55% of 110 total pharmaceutical analytes in surface-water samples in October and December, respectively, with 16% and 6%, respectively, detected in groundwater approximately 20 m from the stream bank. The results demonstrate the importance of effluent discharge as a driver of local hydrologic conditions in an effluent-impacted stream and thus as a fundamental control on surface-water to groundwater transport of effluent-derived pharmaceutical contaminants.",
"Lake Chapala is the largest natural freshwater reservoir in Mexico and the third largest lake in Latin America. Lakes are often considered the final deposit of polluting materials; they can be concentrated in the organisms that inhabit them, the water, and the sediments. The PCBs and PBDEs are environmental pollutants highly studied for their known carcinogenic and mutagenic effects. PCB and PBDE bioaccumulation levels were determined in Chirostoma spp., Cyprinus carpio, and Oreochromis aureus. In addition, we monitored the concentrations of PCBs and PBDEs in sediment and water from Lake Chapala were monitored. Samples were collected during two periods, in October 2018 and May 2019. The samples were analyzed by gas chromatography coupled with mass spectrometry. Two bioaccumulation factors were determined in fish, one in relation to the concentration of PCBs and PBDEs in sediments and the other in relation to the concentration of PCBs and PBDEs in water. The PCB levels were 0.55-3.29 ng/g dry weight (dw) in sediments, 1.43-2.98 ng/mL in water, 0.30-5.31 ng/g dw in Chirostoma spp., 1.06-6.07 ng/g dw in Cyprinus carpio, and 0.55-7.20 ng/g dw in Oreochromis aureus. The levels of PBDEs were 0.17-0.35 ng/g dw in sediments, 0.13-0.32 ng/mL in water, 0.01-0.23 ng/g dw in Chirostoma spp., 0-0.31 ng/g dw in Cyprinus carpio, and 0.1-0.22 ng/g dw in Oreochromis aureus. This study provides information for a better understanding of the movement, global distribution, and bioaccumulation of PCBs and PBDEs. The results show that the fish, water, and sediments of Lake Chapala are potential risks to the biota and the local human population.",
"Source water protection has gained considerable attention in the water resources literature particularly after several well publicized (non-First Nations) water contamination events in Canada. This short report explores health and place through an examination of access to safe drinking water in a developed country. For First Nations in Canada, safe drinking water remains a serious, albeit under-reported, problem. The incidence of contaminated drinking water is pervasive in many First Nations communities. Attempts to \"fix\" water quality problems using technology alone have produced only limited success. It will be shown that greater attention to source water protection has potential for both to improve drinking water quality as well as to re-connect health and place for First Nations in Canada.",
"The presence of pharmaceuticals in drinking water is a topic of concern. Previous risk assessments indicate that their low concentrations are very unlikely to pose risks to human health, however often conclusions had to be based on small datasets and mixture effects were not included. The objectives of this study were to a) investigate if pharmaceuticals in surface and polder water penetrate in drinking water, b) assess the lifelong exposure of consumers to pharmaceuticals via drinking water and c) assess the possible individual and mixture health risks associated with this exposure. To fulfill these aims, a 2-year set of 4-weekly monitoring data of pharmaceuticals was used from three drinking water production plants. The 42 pharmaceuticals that were monitored were selected according to their consumption volume, earlier detection, toxicity and representation of the most relevant therapeutic classes. Lifelong exposures were calculated from concentrations and compared with therapeutic doses. Health risks were assessed by benchmarking concentrations with provisional guideline values. Combined risks of mixtures of pharmaceuticals were estimated using the concept of Concentration Addition. The lifelong exposure to pharmaceuticals via drinking water was calculated to be extremely low, i.e. a few mg, in total corresponding to <10% of the dose a patient is administered on one day. The risk of adverse health effects appeared to be negligibly low. Application of Concentration Addition confirmed this for the mixture of pharmaceuticals simultaneously present. The investigated treatment plants appeared to reduce the (already negligible) risk up to 80%. The large available monitoring dataset enabled the performance of a realistic risk assessment. It showed that working with maximum instead of average concentrations may overestimate the risk considerably.",
"In 2030, the World Health Organization estimates that more than 350 million people will be diagnosed with diabetes. Consequently, Metformin - the biguanide drug of choice orally administered for diabetes type II - is anticipated to see a spike in production. Unlike many pharmaceutical drugs, Metformin (Met) is not metabolized by humans but passes through the body unchanged. Entering aquatic compartments, such as in sewage, it can be bacterially transformed to the ultimate transformation product Guanylurea (Gua). Sampling over one week (n=5) from a Southern German sewage treatment plant revealed very high average (AV) concentrations in influent (AVMet=111,800ng/L, AVGua=1300ng/L) and effluent samples (AVMet=4800ng/L, AVGua=44,000ng/L). To provide a more complete picture of the distribution and potential persistence of these compounds in the German water cycle, a new, efficient and highly sensitive liquid chromatography mass spectrometric method with direct injection was used for the measurement of Metformin and Guanylurea in drinking, surface, sewage and seawater. Limits of quantification (LOQ) ranging from 2-10ng/L allowed the detection of Metformin and Guanylurea in different locations such as: Lake Constance (n=11: AVMet=102ng/L, AVGua=16ng/L), river Elbe (n=12: AVMet=472ng/L, AVGua=9ng/L), river Weser (n=6: AVMet=349ng/L, AVGua=137ng/L) and for the first time in marine North Sea water (n=14: AVMet=13ng/L, AVGua=11ng/L). Based on daily water discharges, Metformin loads of 15.2kg/d (Elbe) and 6.4kg/d (Weser) into the North Sea were calculated. Lake Constance is used to abstract potable water which is further purified to be used as drinking water. A first screening of two tap water samples contained 2ng/L and 61ng/L of Metformin, respectively. The results of this study suggest that Metformin and Guanylurea could be distributed over a large fraction of the world's potable water sources and oceans. With no natural degradation processes, these compounds can be easily reintroduced to humans as they enter the food chain.",
"Freshwater mussels are frequently found in rivers receiving effluent from wastewater treatment plants (WWTP), and there is strong evidence that poor water quality is deleterious to freshwater mussel populations. WWTPs are among the main sources of pharmaceuticals and personal care products (PPCPs) in surface waters. We monitored 145 PPCPs in wild and caged mussels both upstream and downstream of the Kitchener WWTP in the Grand River, Ontario, as well as 118 PPCPs in water samples. Our objectives were to characterize the seasonal changes in PPCP concentrations in water, to calculate bioaccumulation factors (BAFs) of PPCPs in mussels, and to determine the chemical and physical properties of PPCPs driving the bioaccumulation. Seventy PPCPs were detected in water, and concentrations were highest in the summer or early fall, which corresponded to low river flow. Forty-three PPCPs from many pharmaceutical classes were detected in mussel tissues, including stimulants, a contrasting agent, anti-inflammatory drugs, anti-bacterial agents, antibiotics, antidepressants, antihistamines, progestins, and illicit drugs such as cocaine and amphetamines. The BAFs ranged from 0.66 for metformin to 32,022 for sertraline. Using partial least squares to predict BAFs based upon chemical properties, log KOC, Log KOW, and fugacity ratio (sediment) all had similar and positive loadings with BAFs (R(2)X = 0.70; caged mussels). BAFs of PPCPs in mussels were predictable from fugacity models that estimate bioconcentration factors using log KOW. Our study demonstrated that mussels readily bioaccumulate PPCPs, in a manner consistent with expectations based upon BCF models and the chemical characteristics of each compound.",
"The coastline of the department of Antioquia, in Colombia, exhibits a wide variety of aquatic and land ecosystems rich in both diversity and abundance. However, it is exposed to a variety of human activities, including industry, tourism, and mining. Banana cultivation is the main activity carried out in this region, which offers large economic benefits. In addition, there are diverse fishery resources that are main basis of the economy and nutrition for the population. Over the years, the Gulf of Urabá has been affected by serious pollution problems due to elevated contents toxic compounds that deteriorate the aquatic ecosystem, even our laboratory has conducted previous studies in heavy metals in fish from this same area. The aim of this study was to evaluate the contents of chromium (Cr), lead (Pb), and mercury (Hg) in seawater and fish muscle in three fish species from the Gulf of Urabá that are commercialized and consumed by the population of the municipality of Turbo, using microwave-induced plasma optical emission spectrometry (MIP OES). The occurrence of toxic metals in seawater in this area has not been reported, and to the best of our knowledge, this is the first study. Cr and Pb concentrations in seawater from several sampling points were detected ranged from 0.025 to 0.369 mg/L and 0.012-0.165 mg/L, respectively, while Hg levels were below detection limit. Regarding fish samples, Pb and Hg levels range 0.64-1.91 mg/kg and 0.11-1.09 mg/kg, respectively. Sea catfish species exhibited the highest content of metals, followed by stone head catfish and anchovy, it which showed the lowest contamination by metals. In this study, levels that exceed the limits in Colombian regulations regarding metal contents in discharge points to surface water and fishery products for human consumption were found.",
"Pharmaceuticals are emerging contaminants in the environment. Little has been published about the presence of pharmaceuticals in waterbodies nearby or on reserve land of First Nations in Canada. The objectives of this study were to (1) quantify the level of pharmaceuticals in First Nations' surface waters, (2) calculate the human health risks of the mixtures found, and (3) measure the exposure to pharmaceuticals in First Nations' drinking water where source water was highly contaminated. This participatory study measured the levels of 43 pharmaceuticals from surface water samples taken at three water sampling sites chosen by the 95 participating First Nations. The sites were in proximity to recreational areas, fishing areas, drinking water sources, and/or wastewater outflows. When elevated levels of pharmaceutical mixtures were found in samples, drinking water samples were obtained and analyzed for potential pharmaceuticals. Human health risks were calculated by an established protocol. In total, 432 samples were collected at 302 water sampling sites (285 surface water, 11 drinking water, and 6 wastewater sites). Quantifiable levels of 35 pharmaceuticals were found in 79 of the 95 (83%) participating First Nations at 193 of the 285 surface water sites (68%). Overall, the levels found were comparable to or lower than those found in other studies in Canada and worldwide. In almost all participating First Nations, there is no human health risk from consuming surface water for drinking. However, surface water in the vicinity of major urban centres should not be used as secondary untreated water sources due to the elevated human health risk associated with exposure to the mixtures of multiple pharmaceuticals detected.",
"To promote international collaboration on environmental pollution management and human health protection, we conducted a global-level study on the management of pesticides for surface freshwater quality. Prior to actions being taken in terms of water treatment or remediation, it is essential that clear and definite regulations be disseminated. In our study, 3094 surface freshwater quality standards for 184 different pesticides were recorded from 53 countries and categorized according to pesticide types and standard types, as well as diverse use of freshwater by humans, and compared water quality standards related to human health. Our results indicate large variations in pesticide regulations, standard types (i.e., long- or short-term water quality standards), and related numerical values. With regard to the protection of human health, the 10 most frequently regulated pesticides account for approximately 47% of the total number of standards across 184 considered pesticides. The average occurrence-weighted variations of standard values (i.e., numerical values provided in a standard in terms of residue limits of a given pesticide in water) for the 20 most regulated persistent organic pollutants (POPs) and other phase-out pesticides (i.e., pesticides not currently-approved for use in agriculture across various countries) are 4.1 and 2.6 orders of magnitude, respectively, with human-exposure related standard values for some pesticides varying with over 3 orders of magnitude (e.g., lindane). In addition, variations in water quality standard values occurred across standard types (e.g., maximum and average), water use types (e.g., unspecified waters and human consumption), and standard values (e.g., pesticide individuals and groups). We conclude that regulatory inconsistencies emphasize the need for international collaboration on domestic water treatment, environmental management as well as specific water quality standards for the wider range of current-use pesticides, thereby improving global harmonization in support of protecting human health."
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anthropometric measures as baseline risk factors for cardiovascular disease in type 2 diabetes
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In clinical practice, anthropometric measures other than BMI are rarely assessed yet may be more predictive of cardiovascular (CV) risk. We analyzed the placebo group of the REWIND CV Outcomes Trial to compare several anthropometric measures as baseline risk factors for cardiovascular disease (CVD)-related outcomes in participants with type 2 diabetes (T2D).
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"To quantify the association of indices of central obesity, including waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, with the risk of all cause mortality in the general population, and to clarify the shape of the dose-response relations. Systematic review and meta-analysis. PubMed and Scopus from inception to July 2019, and the reference lists of all related articles and reviews. Prospective cohort studies reporting the risk estimates of all cause mortality across at least three categories of indices of central fatness. Studies that reported continuous estimation of the associations were also included. A random effects dose-response meta-analysis was conducted to assess linear trend estimations. A one stage linear mixed effects meta-analysis was used for estimating dose-response curves. Of 98 745 studies screened, 1950 full texts were fully reviewed for eligibility. The final analyses consisted of 72 prospective cohort studies with 2 528 297 participants. The summary hazard ratios were as follows: waist circumference (10 cm, 3.94 inch increase): 1.11 (95% confidence interval 1.08 to 1.13, I2=88%, n=50); hip circumference (10 cm, 3.94 inch increase): 0.90 (0.81 to 0.99, I2=95%, n=9); thigh circumference (5 cm, 1.97 inch increase): 0.82 (0.75 to 0.89, I2=54%, n=3); waist-to-hip ratio (0.1 unit increase): 1.20 (1.15 to 1.25, I2=90%, n=31); waist-to-height ratio (0.1 unit increase): 1.24 (1.12 to 1.36, I2=94%, n=11); waist-to-thigh ratio (0.1 unit increase): 1.21 (1.03 to 1.39, I2=97%, n=2); body adiposity index (10% increase): 1.17 (1.00 to 1.33, I2=75%, n=4); and A body shape index (0.005 unit increase): 1.15 (1.10 to 1.20, I2=87%, n=9). Positive associations persisted after accounting for body mass index. A nearly J shaped association was found between waist circumference and waist-to-height ratio and the risk of all cause mortality in men and women. A positive monotonic association was observed for waist-to-hip ratio and A body shape index. The association was U shaped for body adiposity index. Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.",
"Epidemiological studies assessing general and abdominal obesity measures or their combination for mortality prediction have shown inconsistent results. We aimed to systematically review the associations of body mass index (BMI), waist-to-hip ratio (WHR), waist circumference (WC) and waist-to-height ratio (WHtR) with all-cause mortality in prospective cohort studies. In this systematic review, which includes a meta-regression analysis, we analysed the associations with all-cause mortality of BMI, WHR, WC and WHtR in prospective cohort studies available in Medline, Embase, the Cochrane Database of Systematic Reviews and Esbiobase from inception through 7 May 2010. A total of 18 studies met the inclusion criteria, comprising 689, 465 participants and 48, 421 deaths during 5-24 years of follow-up. The studies were heterogeneous, mainly due to differences in categorization of anthropometric parameters (AP) and different approaches to statistical analysis. Both general and abdominal obesity measures were significantly associated with mortality. In analyses using categorical variables, BMI and WC showed predominantly U- or J-shaped associations with mortality, whereas WHR and WHtR demonstrated positive relationships with mortality. All measures showed similar risk patterns for upper quantiles in comparison to reference quantiles. The parameters of general and abdominal obesity each remained significantly associated with mortality when adjusted for the other. This evidence suggests that abdominal obesity measures such as WC or WHR, show information independent to measures of general obesity and should be used in clinical practice, in addition to BMI, to assess obesity-related mortality in adults.",
"We aimed to assess the association between measures of obesity and outcomes in coronary artery disease (CAD) patients. We included consecutive patients referred to cardiac rehabilitation for previous CAD events, who were classified using body mass index (BMI) groups and gender-specific tertiles of waist-to-hip ratio (WHR). Follow-up was ascertained using a population-based, record linkage system. Major cardiovascular event (MACE) was defined as the composite outcome including acute coronary syndromes, coronary revascularization, ventricular arrhythmias, stroke, or death from any cause. We used Cox proportional hazards models adjusted for potential confounders. The cohort included 1,529 patients (74% men), 63.1 ± 12.5 years (mean age ± SD), of whom 40% were obese by BMI. Eighty-eight percent of men and 57% of women were classified as having central obesity by WHR. Median follow-up was 5.7 years and 415 patients had MACE. After adjustment, a high WHR tertile was a significant predictor for MACE in women (hazard ratio [HR] 1.85, 95% confidence interval [CI] 1.16, 2.94, p = 0.01) but not in men (HR 0.92, 95% CI 0.69, 1.22, p = 0.54). This relation in women persisted after further adjustment for BMI (HR 1.75, 95% CI 1.07, 2.87, p = 0.03). Obesity by BMI was not associated with MACE in either men (HR 1.07, 95% CI 0.76, 1.51, p = 0.69) or women (HR 0.98, 95% CI 0.62, 1.56, p = 0.95). In conclusion, WHR is associated with a higher risk of MACE among women with CAD but not in men. There was no obesity paradox when assessing obesity by BMI in patients with CAD when including nonfatal events.",
"The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy reduced the development and progression of retinopathy in type 1 diabetes (T1D) compared with conventional therapy. The Epidemiology of Diabetes Interventions and Complications (EDIC) study observational follow-up showed persistent benefits. In addition to glycemia, we now examine other potential retinopathy risk factors (modifiable and nonmodifiable) over more than 30 years of follow-up in DCCT/EDIC. The retinopathy outcomes were proliferative diabetic retinopathy (PDR), clinically significant macular edema (CSME), and ocular surgery. The survival (event-free) probability was estimated using the Kaplan-Meier method. Cox proportional hazards models assessed the association between risk factors and subsequent risk of retinopathy. Both forward- and backward-selection approaches determined the multivariable models. Rate of ocular events per 1,000 person-years was 12 for PDR, 14.5 for CSME, and 7.6 for ocular surgeries. Approximately 65%, 60%, and 70% of participants remained free of PDR, CSME, and ocular surgery, respectively. The greatest risk factors for PDR in descending order were higher mean HbA1c, longer duration of T1D, elevated albumin excretion rate (AER), and higher mean diastolic blood pressure (DBP). For CSME, risk factors, in descending order, were higher mean HbA1c, longer duration of T1D, and greater age and DBP and, for ocular surgeries, were higher mean HbA1c, older age, and longer duration of T1D. Mean HbA1c was the strongest risk factor for the progression of retinopathy. Although glycemic control is important, elevated AER and DBP were other modifiable risk factors associated with the progression of retinopathy.",
"Obesity has been posited as an independent risk factor for diabetic kidney disease (DKD), but establishing causality from observational data is problematic. We aimed to test whether obesity is causally related to DKD using Mendelian randomization, which exploits the random assortment of genes during meiosis. In 6,049 subjects with type 1 diabetes, we used a weighted genetic risk score (GRS) comprised of 32 validated BMI loci as an instrument to test the relationship of BMI with macroalbuminuria, end-stage renal disease (ESRD), or DKD defined as presence of macroalbuminuria or ESRD. We compared these results with cross-sectional and longitudinal observational associations. Longitudinal analysis demonstrated a U-shaped relationship of BMI with development of macroalbuminuria, ESRD, or DKD over time. Cross-sectional observational analysis showed no association with overall DKD, higher odds of macroalbuminuria (for every 1 kg/m(2) higher BMI, odds ratio [OR] 1.05, 95% CI 1.03-1.07, P < 0.001), and lower odds of ESRD (OR 0.95, 95% CI 0.93-0.97, P < 0.001). Mendelian randomization analysis showed a 1 kg/m(2) higher BMI conferring an increased risk in macroalbuminuria (OR 1.28, 95% CI 1.11-1.45, P = 0.001), ESRD (OR 1.43, 95% CI 1.20-1.72, P < 0.001), and DKD (OR 1.33, 95% CI 1.17-1.51, P < 0.001). Our results provide genetic evidence for a causal link between obesity and DKD in type 1 diabetes. As obesity prevalence rises, this finding predicts an increase in DKD prevalence unless intervention should occur.",
"Obesity and type 2 diabetes are well-known risk factors for heart failure (HF). Although obesity has increased in type 1 diabetes, studies regarding HF in this population are scarce. Therefore, we investigated the impact of body fat distribution on the risk of HF hospitalization or death in adults with type 1 diabetes at different stages of diabetic nephropathy (DN). From 5401 adults with type 1 diabetes in the Finnish Diabetic Nephropathy Study, 4668 were included in this analysis. The outcome was HF hospitalization or death identified from the Finnish Care Register for Health Care or the Causes of Death Register until the end of 2017. DN was based on urinary albumin excretion rate. A body mass index (BMI) ≥ 30 kg/m2 defined general obesity, whilst WHtR ≥ 0.5 central obesity. Multivariable Cox regression was used to explore the associations between central obesity, general obesity and the outcome. Then, subgroup analyses were performed by DN stages. Z statistic was used for ranking the association. During a median follow-up of 16.4 (IQR 12.4-18.5) years, 323 incident cases occurred. From 308 hospitalizations due to HF, 35 resulted in death. Further 15 deaths occurred without previous hospitalization. The WHtR showed a stronger association with the outcome [HR 1.51, 95% CI (1.26-1.81), z = 4.40] than BMI [HR 1.05, 95% CI (1.01-1.08), z = 2.71]. HbA1c [HR 1.35, 95% CI (1.24-1.46), z = 7.19] was the most relevant modifiable risk factor for the outcome whereas WHtR was the third. Individuals with microalbuminuria but no central obesity had a similar risk of the outcome as those with normoalbuminuria. General obesity was associated with the outcome only at the macroalbuminuria stage. Central obesity associates with an increased risk of heart failure hospitalization or death in adults with type 1 diabetes, and WHtR may be a clinically useful screening tool.",
"The Diabetes Control and Complications Trial (DCCT) and its observational follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) demonstrated the dominant role of glycemia, second only to age, as a risk factor for a first cardiovascular event in type 1 diabetes (T1D). We now investigate the association between established risk factors and the total cardiovascular disease (CVD) burden, including subsequent (i.e., recurrent) events. CVD events in the 1,441 DCCT/EDIC participants were analyzed separately by type (CVD death, acute myocardial infarction [MI], stroke, silent MI, angina, percutaneous transluminal coronary angioplasty/coronary artery bypass graft [PTCA/CABG], and congestive heart failure [CHF]) or as composite outcomes (CVD or major adverse cardiovascular events [MACE]). Proportional rate models and conditional models assessed associations between risk factors and CVD outcomes. Over a median follow-up of 29 years, 239 participants had 421 CVD events, and 120 individuals had 149 MACE. Age was the strongest risk factor for acute MI, silent MI, stroke, and PTCA/CABG, while glycemia was the strongest risk factor for CVD death, CHF, and angina, second strongest for acute MI and PTCA/CABG, third strongest for stroke, and not associated with silent MI. HbA1c was the strongest modifiable risk factor for a first CVD event (CVD: HR 1.38 [95% CI 1.21, 1.56] per 1% higher HbA1c; MACE: HR 1.54 [1.30, 1.82]) and also for subsequent CVD events (CVD: incidence ratio [IR] 1.28 [95% CI 1.09, 1.51]; MACE: IR 1.89 [1.36, 2.61]). Intensive glycemic management is recommended to lower the risk of initial CVD events in T1D. After a first event, optimal glycemic control may reduce the risk of recurrent CVD events and should be maintained."
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Effects of Physical Therapy on Pain, Frequency, or Duration Management in Adult Patients with Tension-Type Headache
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(1) Objective: The aim of this study is to synthesize the effects of physical therapy on pain, frequency, or duration management in the short, medium, and long term in adult patients diagnosed with Tension-type headache (TTH). (2) Background: Tension-type headache (TTH) is the most common headache with migraine and its pathophysiology and treatment has been discussed for years without reaching a consensus. (3) Methods: A systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review was registered in PROSPERO (CRD42020175020). The systematic search for clinical trials was performed in the databases PubMed, CINAHL, Cochrane Central Register of Controlled Trials, PEDro, Scopus, SciELO and Dialnet. Articles were selected according to the inclusion and exclusion criteria, regarding the effectiveness of physical therapy interventions on adult patients with TTH published in the last 11 years with a score ≥ 6 in the PEDro Scale (Physiotherapy Evidence Database). (4) Results: In total, 120 articles were identified, of which 15 randomized controlled trials were finally included in order to determine the inclusion criteria. Changes in pain intensity, headache frequency or headache duration of individual studies were described (5) Conclusions: This systematic review shows that there is no standardized physical therapy protocol for the approach to tension headache, although all the techniques studied to date address in one way or another the cranio-cervical-mandibular region. The approach to the cranio-cervical-mandibular region reports significant effects in terms of decreasing the intensity of pain and frequency of headache episodes in the short and medium term. More long-term longitudinal studies are needed.
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"To determine the differences of precipitating and relieving factors between migraine and tension type headache. This is a cross sectional study. We retrospectively reviewed the records of 250 migraine patients and 250 patients diagnosed as tension type headache from the specialized headache clinic in Dept. of Neurology, Dhaka Medical College Hospital. Data were collected through a predesigned questionnaire containing information on age, sex, social status and a predetermined list of precipitating and relieving factors. In this study, the female patients predominated (67%). Most of the patients were within 21-30 years age group (58.6%). About 58% of them belonged to middle class families. The common precipitating factors like stress, anxiety, activity, journey, reading, cold and warm were well distributed among both the migraine and tension type headache (TTH) patients. But significant difference was demonstrated for fatigue (p < 0.05), sleep deprivation (p < 0.05), sunlight (p < 0.01) and food (p < 0.05), which were common among migraineurs. In consideration of relieving factors of pain, different maneuvers were commonly tried by migraineurs and significant difference were observed for both analgesic drug and massage (p < 0.05), which relieved migraine headache. But maneuvers like sleep, rest and posture were used by both groups. The most frequent precipitating factors for headache appear to be identical for both migraine and TTH patients. Even though some factors like fatigue, sleep deprivation, sunlight and food significantly precipitate migraine and drug, massage are effective maneuver for relieving pain among migrianeurs.",
"To investigate the effects of Thai traditional massage (TTM) on pressure pain threshold (PPT) and headache intensity in patients with chronic tension-type and migraine headaches. Randomized controlled trial of TTM compared with the sham ultrasound (nine sessions each) during a 3-week period. Seventy-two participants who had had a headache diagnosis for at least 3 months before the experiment was recruited. After the treatment and at 3 and 9 weeks of follow-up, the TTM group showed a significant increase in PPT (p<0.01) compared with the sham ultrasound group. PPT values at baseline, after 3 weeks of treatment, and at 3- and 9-week follow-up for the TTM group were 2.71 ± 1.22, 3.57 ± 1.41, 3.72 ± 1.46, and 3.42 ± 1.46 pounds/cm(2), respectively; values in the sham ultrasound group were 2.85 ± 1.20, 2.62 ± 1.07, 2.58 ± 1.05 and 2.63 ± 0.94 pounds/cm(2). In both groups, headache intensity decreased significantly (p<0.05) at every end point of the outcome measures, and there were no differences between the groups (p>0.05). TTM could increase PPT and reduce headache intensity, suggesting that this is a possible alternative treatment for chronic headaches.",
"Review of epidemiological and clinical studies suggests that sleep disorders are disproportionately observed in specific headache diagnoses (eg, migraine, tension-type, cluster) and other nonspecific headache patterns (ie, chronic daily headache, \"awakening\" or morning headache). Interestingly, the sleep disorders associated with headache are of varied types, including obstructive sleep apnea (OSA), periodic limb movement disorder, circadian rhythm disorder, insomnia, and hypersomnia. Headache, particularly morning headache and chronic headache, may be consequent to, or aggravated by, a sleep disorder, and management of the sleep disorder may improve or resolve the headache. Sleep-disordered breathing is the best example of this relationship. Insomnia is the sleep disorder most often cited by clinical headache populations. Depression and anxiety are comorbid with both headache and sleep disorders (especially insomnia) and consideration of the full headache-sleep-affective symptom constellation may yield opportunities to maximize treatment. This paper reviews the comorbidity of headache and sleep disorders (including coexisting psychiatric symptoms where available). Clinical implications for headache evaluation are presented. Sleep screening strategies conducive to headache practice are described. Consideration of the spectrum of sleep-disordered breathing is encouraged in the headache population, including awareness of potential upper airway resistance syndrome in headache patients lacking traditional risk factors for OSA. Pharmacologic and behavioral sleep regulation strategies are offered that are also compatible with treatment of primary headache.",
"Migraine and tension-type headache often occur comorbid with temporomandibular disorder; occlusal splint therapy is the most common treatment for temporomandibular disorder. The aim of this study was to assess the effects of occlusal splint therapy on headache symptoms in patients with migraine and/or tension-type headache comorbid with temporomandibular disorder. Sixty adult patients with migraine and/or tension-type headache and comorbid temporomandibular disorder were randomly assigned to individualized occlusal splint therapy applied during day- and nighttime plus usual care (n = 30) or usual care alone (n = 30). Primary outcome was the change in current pain intensity on a 100 mm visual analogue scale from week 1 to week 12. Secondary outcomes included changes in headache days and headache hours assessed by headache diaries over a 2-week period, health-related quality of life (SF-36), and adverse events from week 1 to week 12 and (in the occlusal splint plus usual care group only) to week 24. No group differences in changes in pain intensity from week 1 to week 12 were found. The number needed to treat was 3.8. Physical quality of life reduced stronger in the usual care group than in the occlusal splint plus usual care group. In the occlusal splint plus usual care group, headache intensity significantly decreased and physical quality of life significantly increased from week 1 to week 12 and to week 24 (all P < .001). No adverse events were reported. A day- and night-time occlusal splint therapy in addition to usual care was not superior to usual care alone in patients with chronic headache and comorbid TMD. Four patients need to be treated to induce a minimal clinically relevant improvement in one patient. The small sample size and lack of power limit these findings.",
"Tension-type headache (TTH), also called muscle contraction headache or neurological headache, is mainly characterized by chronic and persistent bilateral headache in the neck and a severe sense of restraint in the head. This study aims to analyze the effect of warming acupuncture and moxibustion at temples combined with Deanxit on tension headache. A total of 252 patients with anxiety and tension headache were randomly divided into routine group and study group. The study group was treated with Dailixin on the basis of warm acupuncture and moxibustion. The headache score, pericranial muscle tenderness score, therapeutic effect, tension headache attack times and duration, HAMD and HAMA scores were analyzed before and after treatment. The effective cure rate of the study group was significantly higher than that of the routine group. The pericranial muscle tenderness scores of the study group were significantly lower than those of the routine group. Furthermore, the headache degree score, number of attacks, and duration of the study group after treatment were significantly lower than those of the routine group. And the HAMD and HAMA scores in the study group was significantly lower than those in the routine group. The use of warming acupuncture and moxibustion at temples combined with Deanxit in the treatment of tension headache significantly reduces the number and duration of headache attacks and decreases the degree of headache.",
"The neuroanatomical basis for cervicogenic headache is convergence in the trigeminocervical nucleus between nociceptive afferents from the field of the trigeminal nerve and the receptive fields of the first three cervical nerves. Only structures innervated by C1-C3 have been shown to be capable of causing headache. These are the muscles, joints and ligaments of the upper three cervical segments, but also include the dura mater of the spinal cord and posterior cranial fossa and the vertebral artery.",
"The purpose of this study was to investigate the effect of flexion exercise of the deep cervical muscles on headache and sleep disorders in patients with tension headaches and forward head posture. A total of 32 patients with tension headaches and forward head posture were randomly assigned to two groups: an experimental group (n = 16) and a control group (n = 16). The experimental group performed cervical deep muscle flexion exercises for 4 weeks, whereas the control group performed stretching exercises for the same period. The Henry Ford Hospital Headache Disability Inventory (HDI) was used for headache assessment, and the Korean version of the Pittsburgh Sleep Quality Index (PSQI-K) was used for sleep disorder assessment. The experimental group showed a significant reduction in both HDI and PSQI-K score after 4 weeks of intervention (p < 0.001), while no significant difference was found in the control group (p > 0.05). On comparing the experimental and control groups, we found a significant difference in changes in the HDI and PSQI-K between the groups (p < 0.05). The results indicate that flexion exercise of the deep cervical muscles in patients with tension headache and forward head posture will improve the quality of life and activities of daily life by mitigating headaches and sleep disorders."
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Metabolic syndrome among South Asians residing in non-native countries.
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South Asians (SAs) are among the fastest-growing ethnic groups in the U.S. Metabolic syndrome (MetS) is a condition that is characterized by multiple health factors that increase the risk for chronic diseases, such as cardiovascular disease (CVD) and diabetes. MetS prevalence among SA immigrants ranges from 27-47% in multiple cross-sectional studies using different diagnostic criteria, which is generally higher compared to other populations in the receiving country. Both genetic and environmental factors are attributed to this increased prevalence. Limited intervention studies have shown effective management of MetS conditions within the SA population. This review reports MetS prevalence in SAs residing in non-native countries, identifies contributing factors, and discusses ways to develop effective community-based strategies for health promotion targeting MetS among SA immigrants. There is a need for more consistently evaluated longitudinal studies to facilitate the development of directed public health policy and education to address chronic diseases in the SA immigrant community.
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[
"This study uses US national survey data to characterize trends in the prevalence of metabolic syndrome among adults in the US between 2011 and 2016.",
"The aim of this study was to evaluate the effects of pistachio nuts as an adjunct to diet and exercise on body composition, metabolic, inflammatory, and oxidative stress parameters in Asian Indians with metabolic syndrome. In this 24-wk randomized control trial, 60 individuals with the metabolic syndrome were randomized to either pistachio (intervention group) or control group (diet as per weight and physical activity profile, modulated according to dietary guidelines for Asian Indians) after 3 wk of a diet and exercise run in. In the first group, unsalted pistachios (20% energy) were given daily. A standard diet and exercise protocol was followed for both groups. Body weight, waist circumference (WC), magnetic resonance imaging estimation of intraabdominal adipose tissue and subcutaneous abdominal adipose tissue, fasting blood glucose (FBG), fasting serum insulin, glycosylated hemoglobin, lipid profile, high-sensitivity C-reactive protein (hs-CRP), adiponectin, free fatty acids (FFAs), tumor necrosis factor (TNF)-α, leptin, and thiobarbituric acid reactive substances (TBARS) were assessed before and after the intervention. Statistically significant improvement in mean values for various parameters in the intervention group compared with control group were as follows: WC (P < 0.02), FBG (P < 0.04), total cholesterol (P < 0.02), low-density lipoprotein cholesterol (P < 0.006), hs-CRP (P < 0.05), TNF-α (P < 0.03), FFAs (P < 0.001), TBARS (P < 0.01), and adiponectin levels (P < 0.001). A single food intervention with pistachios leads to beneficial effects on the cardiometabolic profile of Asian Indians with metabolic syndrome.",
"This study examined the association between metabolic syndrome, lifestyle behaviors, and perception and knowledge of current health and cardiovascular disease (CVD) among Asian Indians in the US. The sample comprised of 143 adult Asian Indians recruited through health fairs for survey and bioclinical measures. The prevalence of metabolic syndrome was 32%, much higher than other ethnic groups, did not vary by gender but increased with age. Respondents had high physical inactivity and poor knowledge of CVD risk factors. Dietary behavior, age, number of years lived in the US, self-rated physical and mental health and BMI were significant predictors and explained 40.1% of variance in metabolic syndrome score. Poorer physical health status had the greatest predictive influence on metabolic syndrome. Asian Indians are a high risk group for CVD.",
"The insulin resistance/metabolic syndrome is characterized by the variable co-existence of hyperinsulinemia, obesity, dyslipidemia (small dense low-density lipoprotein, hypertriglyceridemia, and decreased high-density lipoprotein cholesterol), and hypertension. The pathogenesis of the syndrome has multiple origins. However, obesity and sedentary lifestyle coupled with diet and still largely unknown genetic factors clearly interact to produce the syndrome. This multifactorial and complex trait of metabolic syndrome leads to increased risk of cardiovascular disease. The scope of this review is to examine the differences in prevalence of the metabolic syndrome in various groups (eg, according to age, sex, ethnicity, social status, or presence of obesity) that could help with the better understanding of the pathogenesis of this syndrome. This review also considers the impact of metabolic syndrome on cardiovascular disease.",
"The aim of this study was to study differences in the prevalence of the metabolic syndrome and its associations with prevalent CHD according to ethnicity and sex. We performed a combined analysis of two population-based cross-sectional studies conducted between 1988 and 1991 that followed identical protocols. Participants (aged 40-69 years) comprised 2,346 Europeans (76% male), 1,711 South Asians (83% male) and 803 African-Caribbeans (57% male) resident in west London. Fasting blood, overnight urine collection, clinical and anthropometric measurements were performed. Clinical history or major ECG changes defined prevalent CHD. The metabolic syndrome was defined according to the criteria recommended by the World Health Organization (WHO) and the National Cholesterol Education Programme (NCEP). The prevalence of the metabolic syndrome was highest in South Asians (WHO, men 46%, women 31%; NCEP, men 29%, women 32%) and lowest in European women (WHO, 9%; NCEP, 14%). The prevalence of CHD was 10% in South Asian men, 9% in European men, 5-6% in African-Caribbeans and European women, and 2% in South Asian women. The metabolic syndrome was associated with prevalent CHD in European men [NCEP, odds ratio (OR)=1.6, 95% CI 1.2-2.4; WHO, OR=1.7, 95% CI 1.2-2.5] and South Asian men (NCEP, OR=2.1, 95% CI 1.5-3.1; WHO, OR=1.6, 95% CI 1.1-2.3). Associations with CHD were weaker in African-Caribbeans and were inconsistent among European women. The current definitions of the metabolic syndrome give an inconsistent picture of cardiovascular disease risk when applied to different ethnic groups within the UK. Prospective studies are needed to validate workable ethnic-specific definitions.",
"The pattern of cardiovascular disease among (Asian) Indians appears to be changing rapidly. Although we do not have large epidemiological studies, clinical observations and mortality data indicate that, in the last three decades, there has been an escalating incidence of hypertension and coronary artery disease in Indians. Clearly, the incidence of hypertension among the urban population is steadily increasing. Whether this is due to heightened awareness and expanding accessibility to health care providers is not known. An alarming number of deaths due to premature coronary disease is being reported. Compared to their Western counterparts, Indians experience the first coronary event at an earlier age. Studies performed in the UK, US, Trinidad, and South Africa have confirmed a high rate of cardiovascular disease among expatriate Indians. Although the precise cause is not known, hypertension and altered lipoprotein metabolism may be playing a participatory role in the genesis of cardiovascular disease.",
"Environmental exposure is an important but underappreciated risk factor contributing to the development and severity of cardiovascular disease (CVD). The heart and vascular system are highly vulnerable to a number of environmental agents--ambient air pollution and the metals arsenic, cadmium, and lead are widespread and the most-extensively studied. Like traditional risk factors, such as smoking and diabetes mellitus, these exposures advance disease and mortality via augmentation or initiation of pathophysiological processes associated with CVD, including blood-pressure control, carbohydrate and lipid metabolism, vascular function, and atherogenesis. Although residence in highly polluted areas is associated with high levels of cardiovascular risk, adverse effects on cardiovascular health also occur at exposure levels below current regulatory standards. Considering the widespread prevalence of exposure, even modest contributions to CVD risk can have a substantial effect on population health. Evidence-based clinical and public-health strategies aimed at reducing environmental exposures from current levels could substantially lower the burden of CVD-related death and disability worldwide."
] |
Structurally distinct aptamers for the Ebola virus glycoprotein gene.
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The Ebola virus glycoprotein (GP) gene templates several mRNAs that produce either the virion-associated transmembrane protein or one of two secreted glycoproteins. Soluble glycoprotein (sGP) is the predominant product. GP1 and sGP share an amino terminal sequence of 295 amino acids but differ in quaternary structure, with GP1 being a heterohexamer with GP2 and sGP a homodimer. Two structurally different DNA aptamers were selected against sGP that also bound GP1,2. These DNA aptamers were compared with a 2'FY-RNA aptamer for their interactions with the Ebola GP gene products. The three aptamers have almost identical binding isotherms for sGP and GP1,2 in solution and on the virion. They demonstrated high affinity and selectivity for sGP and GP1,2. Furthermore, one aptamer, used as a sensing element in an electrochemical format, detected GP1,2 on pseudotyped virions and sGP with high sensitivity in the presence of serum, including from an Ebola-virus-infected monkey. Our results suggest that the aptamers interact with sGP across the interface between the monomers, which is different from the sites on the protein bound by most antibodies. The remarkable similarity in functional features of three structurally distinct aptamers suggests that aptamers, like antibodies, have preferred binding sites on proteins.
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[
"Phosphatidylserine (PtdSer) receptors that are responsible for the clearance of dying cells have recently been found to mediate enveloped virus entry. Ebola virus (EBOV), a member of the Filoviridae family of viruses, utilizes PtdSer receptors for entry into target cells. The PtdSer receptors human and murine T-cell immunoglobulin mucin (TIM) domain proteins TIM-1 and TIM-4 mediate filovirus entry by binding to PtdSer on the virion surface via a conserved PtdSer binding pocket within the amino-terminal IgV domain. While the residues within the TIM-1 IgV domain that are important for EBOV entry are characterized, the molecular details of virion-TIM-4 interactions have yet to be investigated. As sequences and structural alignments of the TIM proteins suggest distinct differences in the TIM-1 and TIM-4 IgV domain structures, we sought to characterize TIM-4 IgV domain residues required for EBOV entry. Using vesicular stomatitis virus pseudovirions bearing EBOV glycoprotein (EBOV GP/VSVΔG), we evaluated virus binding and entry into cells expressing TIM-4 molecules mutated within the IgV domain, allowing us to identify residues important for entry. Similar to TIM-1, residues in the PtdSer binding pocket of murine and human TIM-4 (mTIM-4 and hTIM-4) were found to be important for EBOV entry. However, additional TIM-4-specific residues were also found to impact EBOV entry, with a total of 8 mTIM-4 and 14 hTIM-4 IgV domain residues being critical for virion binding and internalization. Together, these findings provide a greater understanding of the interaction of TIM-4 with EBOV virions. With more than 28,000 cases and over 11,000 deaths during the largest and most recent Ebola virus (EBOV) outbreak, there has been increased emphasis on the development of therapeutics against filoviruses. Many therapies under investigation target EBOV cell entry. T-cell immunoglobulin mucin (TIM) domain proteins are cell surface factors important for the entry of many enveloped viruses, including EBOV. TIM family member TIM-4 is expressed on macrophages and dendritic cells, which are early cellular targets during EBOV infection. Here, we performed a mutagenesis screening of the IgV domain of murine and human TIM-4 to identify residues that are critical for EBOV entry. Surprisingly, we identified more human than murine TIM-4 IgV domain residues that are required for EBOV entry. Defining the TIM IgV residues needed for EBOV entry clarifies the virus-receptor interactions and paves the way for the development of novel therapeutics targeting virus binding to this cell surface receptor.",
"Ebola virus disease afflicts both human and animal populations and is caused by four ebolaviruses. These different ebolaviruses may have distinct reservoir hosts and ecological contexts that determine how, where, and when different ebolavirus spillover events occur. Understanding these virus-specific relationships is important for preventing transmission of ebolaviruses from wildlife to humans. We examine the ecological contexts surrounding 34 human index case infections of ebolaviruses from 1976-2014. Determining possible sources of spillover from wildlife, characterizing the environment of each event, and creating ecological niche models to estimate habitats suitable for spillover, we find that index case infections of two ebolaviruses, Ebola virus and Sudan virus, have occurred under different ecological contexts. The index cases of Ebola virus infection are more associated with tropical evergreen broadleaf forests and consuming bushmeat than the cases of Sudan virus. Given these differences, we emphasize caution when generalizing across different ebolaviruses and that location and virus-specific ecological knowledge will be essential to unravelling how human and animal behavior lead to the emergence of Ebola virus disease.",
"Neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker of early diagnosis and prediction for acute kidney injury (AKI). However, the current program for NGAL detection is not extensively applied in clinics due to the high expense of antibodies. Nucleic acid aptamers are single-strand DNAs or RNAs which could bind to targets with high specificity and affinity, and they have been widely used in the diagnosis and therapy for multiple diseases. It is valuable for us to develop a new method for NGAL detection using aptamers instead of antibodies to achieve increased efficiency and decreased cost. Nucleic acid aptamers against NGAL were obtained after SELEX process using magnetic beads, and an enzyme-linked aptamer analysis (ELAA), which can be widely used in clinical diagnosis at low cost, were successfully established. The feasibility of ELAA was further validated with urine samples harvested from 43 AKI patients and 30 healthy people. Three candidate aptamers, including NA36, NA42 and NA53, were obtained after 8 rounds of SELEX process with magnetic beads and verified by quantitative polymerase chain reaction (qPCR), and the Kd value of each aptamer was 43.59, 66.55 and 32.52 nM, respectively. Moreover, the linear relationship was consistent at the range of 125-4000 ng/mL, and the detection limit of ELAA assay was 30.45 ng/mL. We also found that NGAL could be exclusively detected with NA53, and no cross-reaction between NA53 and human albumin or globulin occurred, the coefficient of variation (CV) between inner-plate and inter-plate was less than 15%, and the recovery rate was between 80 and 110%. Moreover, the sensitivity and specificity of ELAA assay in this study are 100% and 90%, respectively. Consistently, these results could also diagnose whether the occurrence of AKI in lots of patients, which has been demonstrated with the ELAA method we established after using NA53. Taken together, NA53, the best candidate aptamer targeting NGAL protein, can be applied in clinical testing.",
"The massive outbreak of highly lethal Ebola hemorrhagic fever in West Africa illustrates the urgent need for diagnostic instruments that can identify and quantify infections rapidly, accurately, and with low complexity. Here, we report on-chip sample preparation, amplification-free detection and quantification of Ebola virus on clinical samples using hybrid optofluidic integration. Sample preparation and target preconcentration are implemented on a PDMS-based microfluidic chip (automaton), followed by single nucleic acid fluorescence detection in liquid-core optical waveguides on a silicon chip in under ten minutes. We demonstrate excellent specificity, a limit of detection of 0.2 pfu/mL and a dynamic range of thirteen orders of magnitude, far outperforming other amplification-free methods. This chip-scale approach and reduced complexity compared to gold standard RT-PCR methods is ideal for portable instruments that can provide immediate diagnosis and continued monitoring of infectious diseases at the point-of-care.",
"Neutrophil gelatinase-associated lipocalin (NGAL/Lipocalin-2/Lcn-2) is a 25kDa protein which is involved in host defence against certain Gram negative bacteria upon binding of iron loaded bacterial siderophores thereby limiting the availability of this essential nutrient to bacteria resulting in inhibition of their growth and pathogenicity. As iron is important for the growth of the intracellular bacterium Chlamydia pneumoniae we questioned whether Lcn-2 affects the course of this infection. We employed primary peritoneal macrophages obtained from wildtype and Lcn-2 -/- mice and RAW 264.7 cells which were infected with C. pneumoniae. In addition, we studied C. pneumoniae multiplication in vivo in mice receiving diets with varying iron contents. We analyzed C. pneumoniae numbers by immunohistochemistry and RT-PCR and studied the expression of iron metabolism and cytokine genes by RT-PCR, Western blot or ELISA. Infection with Chlamydiae ex vivo and in vivo revealed a significantly higher bacterial growth in peritoneal macrophages of Lcn-2 -/- than of wildtype mice. These differences were significantly more pronounced upon iron challenge, which stimulated bacterial growth. Accordingly, treatment with an anti-Lnc-2 antibody increased whereas addition of recombinant Lcn-2 reduced bacterial growth in infected macrophages. When investigating the underlying mechanisms we observed partly different expression of several iron metabolism genes between Lcn-2 +/+ and Lcn-2 -/- macrophages and most strikingly an increased formation of the anti-inflammatory cytokine IL-10 by Lcn-2 -/- macrophages. Upon treatment with an anti-IL10 antibody we experienced a significant increase of Chlamydial growth within Lcn-2 -/- macrophages along with a reduction of the major iron storage protein ferritin. Herein we provide first time evidence that Lcn-2 is involved in host defence against Chlamydia presumably by limiting the availability of iron to the pathogen. In the absence of Lcn-2, increased formation of IL-10 exerts protective effects by increasing the intracellular formation of ferritin, thereby reducing the access of iron for bacteria.",
"In current clinical practice, Serum Creatinine (SCr) is a commonly used marker for the diagnosis of acute kidney injury (AKI). Unfortunately, due to a delayed increase in SCr, it is unable to accurately estimate the timing of the injury. The purpose of this study was to assess the ability of plasma neutrophil gelatinase-associated lipocalin (pNGAL) to predict AKI in critically ill adult patients. The study was conducted at the Section of Chemical Pathology, Department of Pathology& Laboratory Medicine in collaboration with Department of Anesthesiology, at Aga Khan University Hospital in Karachi, Pakistan. Subjects in the age groups of18 to 60, that were admitted into the intensive care unit (ICU) with suspected sepsis were enrolled in this study.AKI was labeled by using Risk-Injury-Failure-loss-End Stage (RIFLE) criteria. Forty-eight patients, mean age being 46.5 ± 16.3, were recruited over a nine-month period. Multiple blood samples were collected from each patient at 12 h, 24 h, and 48 h. A total of 52.1% (n = 24) of ICU patients suspected of sepsis had developed AKI. Baseline characteristics of subjects with AKI were compared to those without AKI. Statistically significant difference was noted in gender (p-value< 0.05) and pNGAL (p-value< 0.001). However, no significant differences were seen with respect to age, in patients with and without AKI. The area under the curve (AUC) at12hr was 0.82 (95% CI 0.68-0.96) with a sensitivity of 70.8% and specificity of 90.9%.While AUCs at 24 h was 0.86(95% CI 0.74-0.97) with a sensitivity of 78.5% and specificity of 88.8%. Furthermore, there was a positive correlation between pNGAL and the length of ICU stay (r = 0.98). Non-survivors or expired patients had higher median pNGAL170 (202-117) ng/ml as compared to survivors 123(170-91) ng/ml. In conclusion, pNGAL is an early predictor of AKI in a heterogeneous adult ICU population. Plasma NGAL allows the diagnosis of AKI 48 h prior to a clinical diagnosis based on RIFLE criteria. Early identification of high-risk AKI in patients may allow earlier initiation of therapies and improve patient outcome.",
"Urinary calprotectin has recently been identified as a promising biomarker for the differentiation of pre-renal and intrinsic acute kidney injury (AKI). This study compares the diagnostic performance of calprotectin and neutrophil gelatinase-associated lipocalin (NGAL) in this differential diagnosis. Urinary calprotectin and NGAL concentrations were assessed in a study population of 87 subjects including 38 cases of intrinsic AKI, 24 cases of pre-renal AKI and 25 healthy controls. Urinary tract obstruction, renal transplantation and metastatic cancer were defined as exclusion criteria. Mean calprotectin concentrations were significantly lower in pre-renal (190.2 ± 205.7 ng mL(-1) ) than in intrinsic AKI (6250.1 ± 7167.2 ng mL(-1) , P < 0.001). Receiver-operating characteristic (ROC) analysis provided an AUC of 0.99. Mean NGAL concentrations were significantly higher in intrinsic than in pre-renal AKI as well (458.1 ± 695.3 vs. 64.8 ± 62.1 ng mL(-1) , P = 0.001) providing an AUC of 0.82. A combination of the present study population with the cohort of the proof of concept study led to a population of 188 subjects (58 pre-renal AKI, 90 intrinsic AKI, 40 healthy controls). ROC analyses provided an AUC of 0.97 for calprotectin and 0.76 for NGAL yielding sensitivity and specificity values of 93.3 and 94.8% (calprotectin) vs. 75.3 and 72.4% (NGAL). Optimal cut-off values were 440 ng mL(-1) (calprotectin) and 52 ng mL(-1) (NGAL). Pyuria increased calprotectin concentrations independent of renal failure. This study shows that both calprotectin and NGAL are able to differentiate between pre-renal and intrinsic AKI after exclusion of pyuria. In the present population, calprotectin presents a higher sensitivity and specificity than NGAL."
] |
A Comparative Study of Disability Weights in Anhui Province of China
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A universal set of disability weights(DWs) is mainly based on the survey of North America, Australia and Europe, whereas the participants in Asia was limited. The debate hasn't yet settled whether a universal DW is desirable or useful.The focus of the debate is its representativenes-s.After all, the DWs come from people's subjective evaluation of pain, and they may vary according to cultural background.The differences of the DWs could have implications for the magnitude or ranking of disease burdens.The DWs of Anhui Province has not been completely presented.This paper aims to obtain the DWs suitable for the general population of Anhui Province of China, and attempts to explore the differences between different DWs by comparing the DWs with the similar-cultural background and the DWs with cross-cultural background.
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[
"Cannabis legalization has led to significant health consequences, particularly to patients in emergency departments and hospitals in Colorado. The most concerning include psychosis, suicide, and other substance abuse. Deleterious effects on the brain include decrements in complex decision-making, which may not be reversible with abstinence. Increases in fatal motor vehicle collisions, adverse effects on cardiovascular and pulmonary systems, inadvertent pediatric exposures, cannabis contaminants exposing users to infectious agents, heavy metals, and pesticides, and hash-oil burn injuries in preparation of drug concentrates have been documented. Cannabis dispensary workers (\"budtenders\") without medical training are giving medical advice that may be harmful to patients. Cannabis research may offer novel treatment of seizures, spasticity from multiple sclerosis, nausea and vomiting from chemotherapy, chronic pain, improvements in cardiovascular outcomes, and sleep disorders. Progress has been slow due to absent standards for chemical composition of cannabis products and limitations on research imposed by federal classification of cannabis as illegal. Given these factors and the Colorado experience, other states should carefully evaluate whether and how to decriminalize or legalize non-medical cannabis use.",
"Many major causes of disability in the Global Burden of Disease (GBD) study present with a range of severity, and for most causes finding population distributions of severity can be difficult due to issues of sparse data, inconsistent measurement, and need to account for comorbidities. We developed an indirect approach to obtain severity distributions empirically from survey data. Individual-level data were used from three large population surveys from the US and Australia that included self-reported prevalence of major diseases and injuries as well as generic health status assessments using the 12-Item Short Form Health Survey (SF-12). We developed a mapping function from SF-12 scores to GBD disability weights. Mapped scores for each individual respondent were regressed against the reported diseases and injuries using a mixed-effects model with a logit-transformed response variable. The regression outputs were used to predict comorbidity-corrected health-state weights for the group of individuals with each condition. The distribution of these comorbidity-corrected weights were used to estimate the fraction of individuals with each condition falling into different GBD severity categories, including asymptomatic (implying disability weight of zero). After correcting for comorbid conditions, all causes analyzed had some proportion of the population in the asymptomatic category. For less severe conditions, such as alopecia areata, we estimated that 44.1 % [95 % CI: 38.7 %-49.4 %] were asymptomatic while 28.3 % [26.8 %-29.6 %] of anxiety disorders had asymptomatic cases. For 152 conditions, full distributions of severity were estimated. For anxiety disorders for example, we estimated the mean population proportions in the mild, moderate, and severe states to be 40.9 %, 18.5 %, and 12.3 % respectively. Thirty-seven of the analyzed conditions were used in the GBD 2013 estimates and are reported here. There is large heterogeneity in the disabling severity of conditions among individuals. The GBD 2013 approach allows explicit accounting for this heterogeneity in GBD estimates. Existing survey data that have collected health status together with information on the presence of a series of comorbid conditions can be used to fill critical gaps in the information on condition severity while correcting for effects of comorbidity. Our ability to make these estimates may be limited by lack of geographic variation in the data and by the current methodology for disability weights, which implies that severity must be binned rather than expressed in as a full distribution. Future country-specific data collection efforts will be needed to advance this research.",
"To determine, using longitudinal analyses, if retirement is followed by a change in the risk of incident chronic diseases, depressive symptoms, and fatigue. Design Prospective study with repeat measures from 7 years before to 7 years after retirement. Large French occupational cohort (the GAZEL study), 1989-2007. Participants 11 246 men and 2858 women. Respiratory disease, diabetes, coronary heart disease and stroke, mental fatigue, and physical fatigue, measured annually by self report over the 15 year observation period; depressive symptoms measured at four time points. The average number of repeat measurements per participant was 12.1. Repeated measures logistic regression with generalised estimating equations showed that the cumulative prevalence of self reported respiratory disease, diabetes, and coronary heart disease and stroke increased with age, with no break in the trend around retirement. In contrast, retirement was associated with a substantial decrease in the prevalence of both mental fatigue (odds ratio for fatigue one year after versus one year before retirement 0.19, 95% confidence interval 0.18 to 0.21) and physical fatigue (0.27, 0.26 to 0.30). A major decrease was also observed in depressive symptoms (0.60, 0.53 to 0.67). The decrease in fatigue around retirement was more pronounced among people with a chronic disease before retirement. Longitudinal modelling of repeat data showed that retirement did not change the risk of major chronic diseases but was associated with a substantial reduction in mental and physical fatigue and depressive symptoms, particularly among people with chronic diseases.",
"Disability weights (DWs) are weight factors that reflect the severity of health states for estimates of disability-adjusted life years. A new set of global DWs was published for the Global Burden of Diseases and Injuries (GBD) 2013 study, which relied on sampling from various world regions, but included little data for countries in East Asia. This study aimed to measure DWs in Japan using comparable methods, and compare the results with previous estimates from the GBD 2013 DW study. We conducted a web-based survey in 2019 to estimate DWs for 231 health states for the Japanese population. The survey included five new health states but otherwise followed the method of the GBD DW measurement study. The survey consisted of 15 paired comparison (PC) questions and 3 population health equivalence questions (PHE) per respondent. We analyzed PC data using probit regression and rescaled results to DW units between 0 (equivalent to full health) and 1 (equivalent to death). We considered 37,318 nationally representative respondents. The values of the resulting DWs ranged from 0.707 (95% uncertainty interval (UI) 0.527-0.842) for spinal cord injury at neck level (untreated) to 0.004 (UI 0.001-0.009) for mild anemia. High correlation between Japanese DW and GBD 2013 DW was observed, but there was considerable disagreement. Out of 226 comparable health states, 55 (24.3%) showed more than a factor-of-two difference, of which 41 (74.6%) had a higher value in Japanese DW. Many of the health states with higher DW in the Japan study were injuries, including amputation and fracture, and hearing and vision loss, while mental, behavioral, and substance use disorders generally tended to be lower. This study has created an empirical basis for assessment of Japanese DWs of health status. The findings from this study based on the Japanese population suggest that there might be contextual differences in rating the severity of health states compared to previous surveys conducted elsewhere."
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Circular RNA-Based Panel for Early Diagnosis of Chronic Lymphocytic Leukemia
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Chronic lymphocytic leukemia (CLL) is a known hematologic malignancy associated with a growing incidence and post-treatment relapse. Hence, finding a reliable diagnostic biomarker for CLL is crucial. Circular RNAs (circRNAs) represent a new class of RNA involved in many biological processes and diseases. This study aimed to define a circRNA-based panel for the early diagnosis of CLL. To this point, the list of the most deregulated circRNAs in CLL cell models was retrieved using bioinformatic algorithms and applied to the verified CLL patients' online datasets as the training cohort (
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[
"To better understand the stage(s) of differentiation reached by B-type chronic lymphocytic leukemia (B-CLL) cells and to gain insight into the potential role of antigenic stimulation in the development and diversification of these cells, we analyzed the rearranged VH genes expressed by 83 B-CLL cells (64 IgM+ and 19 non-IgM+). Our results confirm and extend the observations of a bias in the use of certain VH, D, and JH genes among B-CLL cells. In addition, they indicate that the VH genes of approximately 50% of the IgM+ B-CLL cells and approximately 75% of the non-IgM+ B-CLL cells can exhibit somatic mutations. The presence of mutation varies according to the VH family expressed by the B-CLL cell (VH3 expressers displaying more mutation than VH1 and VH4 expressers). In addition, the extent of mutation can be sizeable with approximately 32% of the IgM+ cases and approximately 68% of the non-IgM+ cases differing by > 5% from the most similar germline gene. Approximately 20% of the mutated VH genes display replacement mutations in a pattern consistent with antigen selection. However, CDR3 characteristics (D and JH gene use and association and HCDR3 length, composition, and charge) suggest that selection for distinct B cell receptors (BCR) occurs in many more B-CLL cells. Based on these data, we suggest three prototypic BCR, representing the VH genes most frequently encountered in our study. These data suggest that many B-CLL cells have been previously stimulated, placing them in the \"experienced\" or \"memory\" CD5(+) B cell subset.",
"The increasing availability and diversity of omics data in the post-genomic era offers new perspectives in most areas of biomedical research. Graph-based biological networks models capture the topology of the functional relationships between molecular entities such as gene, protein and small compounds and provide a suitable framework for integrating and analyzing omics-data. The development of software tools capable of integrating data from different sources and to provide flexible methods to reconstruct, represent and analyze topological networks is an active field of research in bioinformatics. BisoGenet is a multi-tier application for visualization and analysis of biomolecular relationships. The system consists of three tiers. In the data tier, an in-house database stores genomics information, protein-protein interactions, protein-DNA interactions, gene ontology and metabolic pathways. In the middle tier, a global network is created at server startup, representing the whole data on bioentities and their relationships retrieved from the database. The client tier is a Cytoscape plugin, which manages user input, communication with the Web Service, visualization and analysis of the resulting network. BisoGenet is able to build and visualize biological networks in a fast and user-friendly manner. A feature of Bisogenet is the possibility to include coding relations to distinguish between genes and their products. This feature could be instrumental to achieve a finer grain representation of the bioentities and their relationships. The client application includes network analysis tools and interactive network expansion capabilities. In addition, an option is provided to allow other networks to be converted to BisoGenet. This feature facilitates the integration of our software with other tools available in the Cytoscape platform. BisoGenet is available at http://bio.cigb.edu.cu/bisogenet-cytoscape/.",
"Several prognostic markers based on genetic, phenotypic, and molecular characteristics of chronic lymphocytic leukemia (CLL) B cells have emerged in the past decade. The clinical utility of these newer prognostic indicators, alone or in combination with each other and other clinical predictive systems, is still being determined. This chapter attempts to define biologic and molecular underpinnings of 3 sets of prognostic indicators in CLL: genetic abnormalities quantified by FISH and/or defined by exploratory sensitive molecular techniques, expression of specific proteins in or on CLL cells (ie, CD38, CD49d, and ZAP-70), and the IGHV mutation status of a CLL clone. Although not demonstrated conclusively, each probably reflects the biologic properties of the leukemic cells of individual CLL patients. This reflection may be direct, indicating a specific property of the CLL cell itself, or indirect, representing how the CLL cell interacts with the host's microenvironment. The new tyrosine kinase inhibitors that are currently in clinical trials support this interpretation. These and other biology-based indicators of patient clinical course and outcome can be used as starting points from which to understand and treat CLL.",
"Thousands of novel transcripts have been identified using deep transcriptome sequencing. This discovery of large and 'hidden' transcriptome rejuvenates the demand for methods that can rapidly distinguish between coding and noncoding RNA. Here, we present a novel alignment-free method, Coding Potential Assessment Tool (CPAT), which rapidly recognizes coding and noncoding transcripts from a large pool of candidates. To this end, CPAT uses a logistic regression model built with four sequence features: open reading frame size, open reading frame coverage, Fickett TESTCODE statistic and hexamer usage bias. CPAT software outperformed (sensitivity: 0.96, specificity: 0.97) other state-of-the-art alignment-based software such as Coding-Potential Calculator (sensitivity: 0.99, specificity: 0.74) and Phylo Codon Substitution Frequencies (sensitivity: 0.90, specificity: 0.63). In addition to high accuracy, CPAT is approximately four orders of magnitude faster than Coding-Potential Calculator and Phylo Codon Substitution Frequencies, enabling its users to process thousands of transcripts within seconds. The software accepts input sequences in either FASTA- or BED-formatted data files. We also developed a web interface for CPAT that allows users to submit sequences and receive the prediction results almost instantly.",
"As high-throughput transcriptome sequencing provides evidence for novel transcripts in many species, there is a renewed need for accurate methods to classify small genomic regions as protein coding or non-coding. We present PhyloCSF, a novel comparative genomics method that analyzes a multispecies nucleotide sequence alignment to determine whether it is likely to represent a conserved protein-coding region, based on a formal statistical comparison of phylogenetic codon models. We show that PhyloCSF's classification performance in 12-species Drosophila genome alignments exceeds all other methods we compared in a previous study. We anticipate that this method will be widely applicable as the transcriptomes of many additional species, tissues and subcellular compartments are sequenced, particularly in the context of ENCODE and modENCODE, and as interest grows in long non-coding RNAs, often initially recognized by their lack of protein coding potential rather than conserved RNA secondary structures. The Objective Caml source code and executables for GNU/Linux and Mac OS X are freely available at http://compbio.mit.edu/PhyloCSF CONTACT: mlin@mit.edu; manoli@mit.edu.",
"It is a challenge to classify protein-coding or non-coding transcripts, especially those re-constructed from high-throughput sequencing data of poorly annotated species. This study developed and evaluated a powerful signature tool, Coding-Non-Coding Index (CNCI), by profiling adjoining nucleotide triplets to effectively distinguish protein-coding and non-coding sequences independent of known annotations. CNCI is effective for classifying incomplete transcripts and sense-antisense pairs. The implementation of CNCI offered highly accurate classification of transcripts assembled from whole-transcriptome sequencing data in a cross-species manner, that demonstrated gene evolutionary divergence between vertebrates, and invertebrates, or between plants, and provided a long non-coding RNA catalog of orangutan. CNCI software is available at http://www.bioinfo.org/software/cnci.",
"Advanced-stage or relapsed/refractory Hodgkin's disease (HD) has a poor prognosis despite aggressive chemotherapy regimens and the use of high-dose therapy with autologous stem cell support. Mitoxantrone, vinblastine and CCNU (lomustine) (MVC) combines the most effective chemotherapeutic agents of previous regimens for poor prognosis HD, and eliminates marginally active agents with unnecessary toxicities, such as bleomycin and dacarbazine. Sixty-eight patients with HD (23 newly diagnosed and 45 with relapsed/refractory disease, one patient treated both de novo and years later in relapse) were treated with the MVC regimen (mitoxantrone 8 mg/m(2)/day i.v. days 1 - 3; vinblastine 8 m/m(2)/day days 1 and 22; and CCNU (lomustine) 100 mg/m(2) on day 1, repeated at 6 - 8 weeks) in a single-arm Phase II study. All patients responded to treatment in the newly diagnosed group (overall response = 100%). The median response duration was not reached, but was in the range 7.6 - 180 + months, and median survival was 94 months. Eleven complete responses are ongoing at 39 - 180 + months. In the previously-treated patients, 41 responded to MVC (OR = 91%). The median response duration for this group was 11 months, and the median survival was 34 months after initiating MVC. Four secondary myeloid leukemias occurred, three in de novo, and one in the relapsed/refractory group, at a median follow-up of 14 years. MVC regimen for HD is highly active, for both de novo and relapsed/refractory disease, with high response rates and survival that compare favourably with the results obtained by high-dose therapy with stem-cell transplantation. Although significant, the toxicities associated with this regimen were manageable."
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RNA Sequencing Study of Twist1 and Zeb1 in Mycosis Fungoides
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The purpose of this RNA sequencing study was to investigate the biological mechanism underlying how the transcription factors (TFs) Twist1 and Zeb1 influence the prognosis of mycosis fungoides (MF). We used laser-captured microdissection to dissect malignant T-cells obtained from 40 skin biopsies from 40 MF patients with stage I-IV disease. Immunohistochemistry (IHC) was used to determinate the protein expression levels of Twist1 and Zeb1. Based on RNA sequencing, principal component analysis (PCA), differential expression (DE) analysis, ingenuity pathway analysis (IPA), and hub gene analysis were performed between the high and low Twist1 IHC expression cases. The DNA from 28 samples was used to analyze the TWIST1 promoter methylation level. In the PCA, Twist1 IHC expression seemed to classify cases into different groups. The DE analysis yielded 321 significant genes. In the IPA, 228 significant upstream regulators and 177 significant master regulators/causal networks were identified. In the hub gene analysis, 28 hub genes were found. The methylation level of TWIST1 promoter regions did not correlate with Twist1 protein expression. Zeb1 protein expression did not show any major correlation with global RNA expression in the PCA. Many of the observed genes and pathways associated with high Twist1 expression are known to be involved in immunoregulation, lymphocyte differentiation, and aggressive tumor biology. In conclusion, Twist1 might be an important regulator in the disease progression of MF.
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[
"Like other cancers, renal cell carcinoma (RCC) derives the essential energy for proliferation and survival from high rates of glycolysis rather than from oxidative phosphorylation of the mitochondrial respiration pathway. NDUFA4 (NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex, 4) is encoding a protein belonging to the respiratory chain of mitochondria. For a better understanding of the tumor biology and for identification of a potential new biomarker, we analyzed the regulation of NDUFA4 in RCC compared to normal tissue cells. Downregulation of NDUFA4 mRNA and protein was detected in RCC compared to normal renal tissues in quantitative real-time PCR as well as in western blot and immunohistochemical staining. Histological analysis revealed higher NDUFA4 expression in the distal tubules compared to the proximal tubules and the loop of Henle. A higher molecular weight of the NDUFA4 protein was discovered in RCC samples, possibly indicating a posttranslational modification. Moreover, NDUFA4 protein expression was predictive for cancer-specific survival. Our analysis revealed a potential new biomarker, but future studies are warranted to investigate the prognostic value of NDUF4A expression.",
"Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.",
"To elucidate the correlations between tumor microenvironment and clinical characteristics as well as prognosis in clear cell renal cell cancer (ccRCC) and investigate the immune-associated genes by a comprehensive analysis of The Cancer Genome Atlas (TCGA) database. We collected mRNA expression profiles of 537 ccRCC samples from the TCGA database. Immune scores and stromal scores were calculated by applying the ESTIMATE algorithm. We evaluated the correlation between immune/stromal scores and clinical characteristics as well as prognosis. The differentially expressed genes (DEGs) were screened between high immune/stromal score and low immune/stromal score groups by the cutoff of |log (fold change)| > 1, P value <0.05 by using package \"limma\" in R. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction network of intersected DEGs between stromal score and immune score groups was conducted using the STRING database. The Kaplan-Meier method was used to explore DEGs with predictive values in overall survival, and the prognostic DEGs were further validated in a Gene Expression Omnibus (GEO) dataset GSE29609. A higher immune score was associated with T3/4 (vs. T1/2, P < 0.001), N1 (vs. N0, P=0.05), M1 (vs. M0, P=0.004), G3/4 (vs. G1/2, P < 0.001), advanced AJCC stage (P < 0.001), and shorter overall survival (P=0.04). Intersected DEGs between immune and stromal score groups were 48 upregulated and 47 downregulated genes, with 43 DEGs associated with overall survival in ccRCC. After validation by a cohort of 39 ccRCC cases with detailed follow-up information from GSE29609, six immune-associated DEGs including CASP5, HSD11B1, VSIG4, HMGCS2, HSD11B2, and OGDHL were demonstrated to be predictive of prognosis in ccRCC. Our study elucidated tight associations between immune score and clinical characteristics as well as prognosis in ccRCC. Moreover, six DEGs were explored and validated to exert predictive values in overall survival of ccRCC.",
"Genome sequencing projects and further systematic functional analyses of complete gene sets are producing an unprecedented mass of molecular information for a wide range of model organisms. This provides us with a detailed account of the cell with which we may begin to build models for simulating intracellular molecular processes to predict the dynamic behavior of living cells. Previous work in biochemical and genetic simulation has isolated well-characterized pathways for detailed analysis, but methods for building integrative models of the cell that incorporate gene regulation, metabolism and signaling have not been established. We, therefore, were motivated to develop a software environment for building such integrative models based on gene sets, and running simulations to conduct experiments in silico. E-CELL, a modeling and simulation environment for biochemical and genetic processes, has been developed. The E-CELL system allows a user to define functions of proteins, protein-protein interactions, protein-DNA interactions, regulation of gene expression and other features of cellular metabolism, as a set of reaction rules. E-CELL simulates cell behavior by numerically integrating the differential equations described implicitly in these reaction rules. The user can observe, through a computer display, dynamic changes in concentrations of proteins, protein complexes and other chemical compounds in the cell. Using this software, we constructed a model of a hypothetical cell with only 127 genes sufficient for transcription, translation, energy production and phospholipid synthesis. Most of the genes are taken from Mycoplasma genitalium, the organism having the smallest known chromosome, whose complete 580 kb genome sequence was determined at TIGR in 1995. We discuss future applications of the E-CELL system with special respect to genome engineering. The E-CELL software is available upon request. The complete list of rules of the developed cell model with kinetic parameters can be obtained via our web site at: http://e-cell.org/.",
"Background: Multiple myeloma (MM) is the second most common hematologic malignancy worldwide and does not have sufficient prognostic indicators. FCER1G (Fc fragment Of IgE receptor Ig) is located on chromosome 1q23.3 and is involved in the innate immunity. Early studies have shown that FCER1G participates in many immune-related pathways encompassing multiple cell types. Meanwhile, it is associated with many malignancies. However, the relationship between MM and FCER1G has not been studied. Methods: In this study, we integrated nine independent gene expression omnibus (GEO) datasets and analyzed the associations of FCER1G expression and myeloma progression, ISS stage, 1q21 amplification and survival in 2296 myeloma patients and 48 healthy donors. Results: The expression of FCER1G showed a decreasing trend with the advance of myeloma. As ISS stage and 1q21 amplification level increased, the expression of FCER1G decreased (P = 0.0012 and 0.0036, respectively). MM patients with high FCER1G expression consistently had longer EFS and OS across three large sample datasets (EFS: P = 0.0057, 0.0049, OS: P = 0.0014, 0.00065, 0.0019 and 0.0029, respectively). Meanwhile, univariate and multivariate analysis indicated that high FCER1G expression was an independent favorable prognostic factor for EFS and OS in MM patients (EFS: P = 0.006, 0.027, OS: P =0.002,0.025, respectively). Conclusions: The expression level of FCER1G negatively correlated with myeloma progression, and high FCER1G expression may be applied as a favorable biomarker in MM patients.",
"Comprehensive protein protein interaction maps promise to reveal many aspects of the complex regulatory network underlying cellular function. Recently, large-scale approaches have predicted many new protein interactions in yeast. To measure their accuracy and potential as well as to identify biases, strengths and weaknesses, we compare the methods with each other and with a reference set of previously reported protein interactions.",
"Life depends on the interaction of proteins. The availability of the complete human genome sequence has highlighted the need for a tool to analyse protein interactions and several databases have been compiled for this purpose. These databases document, categorize, and analyze interacting proteins and the cellular functions of the interactions."
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Consumers' knowledge, attitudes, and purchasing habits of food products with allergens in Lebanon
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The epidemiology of food allergies is increasing worldwide. International labeling standards were developed to enhance consumers' awareness of allergen-free foods. The main objective of the present study is to assess the characteristics of allergen labeling and consumers' knowledge, attitudes, and purchasing habits of food products with allergens in Lebanon. We evaluated the allergen labeling of 1000 food products form Lebanese supermarkets. A random sample of 541 consumers was recruited through an online survey (November 2020-February 2021). Descriptives and regression analysis were conducted. Results showed that wheat represents the largest group of food allergens on food labels, followed by milk and soybean. Furthermore, 42.9% of supermarket food products had a precautionary allergen labeling with "may contain traces of allergens". The majority of food products complied with local regulations for locally manufactured and imported products. One-quarter of survey respondents had a food allergy or were caregivers of food-allergic individuals. Regression analyses showed that "previous experience of a severe reaction" was negatively associated with food allergy-related knowledge and attitude scores respectively (
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[
"Food allergen labeling is an important tool to reduce risk of exposure and prevent anaphylaxis for individuals with food allergies. Health Canada released a Canadian food allergen labeling regulation (2008) and subsequent update (2012) suggesting that research is needed to guide further iterations of the regulation to improve food allergen labeling and reduce risk of exposure. The primary objective of this study was to examine consumer preferences in food labeling for allergy avoidance and anaphylaxis prevention. A secondary objective was to identify whether different subgroups within the consumer population emerged. A discrete choice experiment using a fractional factorial design divided into ten different versions with 18 choice-sets per version was developed to examine consumer preferences for different attributes of food labeling. Three distinct subgroups of Canadian consumers with different allergen considerations and food allergen labeling needs were identified. Overall, preferences for standardized precautionary and safety symbols at little or no increased cost emerged. While three distinct groups with different preferences were identified, in general the results revealed that the current Canadian food allergen labeling regulation can be improved by enforcing the use of standardized precautionary and safety symbols and educating the public on the use of these symbols.",
"In recent decades, food allergy has become an increasing concern for families, clinicians, and policymakers. This review aims to summarize what is currently known about the epidemiology and population-level burden of IgE-mediated food allergy, including its effects on quality of life. Prevalence surveys, healthcare utilization data, and findings from longitudinal cohort studies across the globe indicate that food allergy imposes a growing societal burden. Worryingly, recent data indicate that food allergies may be more prevalent among adult populations than previously acknowledged, with many reported cases of adult-onset allergies. While it remains unclear how much of the current population-level burden of disease results from true, IgE-mediated allergy, as much epidemiological data does not incorporate clinical confirmation of disease prevalence-it is clear that affected individuals suffer impairments in their quality of life and incur substantial economic costs-beyond the physical health burden imposed by anaphylaxis.",
"Accidental allergic reactions to food are frequent and can be severe and even fatal. We sought to analyze the culprit food products and levels of unexpected allergens in accidental reactions. A prospective cohort study was conducted in adults (n = 157) with a physician-confirmed diagnosis of food allergy. During a 1-year follow-up, 73 patients reported accidental allergic reactions and the culprit food products. Food samples received (n = 51) were analyzed for a wide range of suspected noningredient allergens, and risk was quantified. A very diverse range of food products was responsible for the unexpected allergic reactions. Thirty-seven percent (19/51) of products analyzed had 1 to 4 culprit allergens identified that were not supposed to be present according to the ingredient declaration. Concentrations varied from 1 to 5000 mg of protein of the allergenic food per kilogram of food product and were greatest for peanut, milk, and sesame. Milk proteins posed the highest estimated risk for objective allergic reactions. The intake of culprit allergens by patients varied considerably. For those cases in which culprit allergens were detected, the intake of at least 1 allergen exceeded the reference dose or a culprit allergen with a yet unknown reference dose was present. Both patient neglect of precautionary allergen labeling statements and omission of using a precautionary allergen labeling statement by food manufacturers seem to contribute to accidental reactions. A wide range of food products are causing accidental reactions in patients with food allergy. Eight different allergens not declared on the ingredient lists were detected in the culprit food products, all of which were representative of allergens regulated in the European Union.",
"Tremendous progress has been made in our understanding of food-based allergic disorders over the past 5 years. Recent epidemiologic studies suggest that nearly 4% of Americans are afflicted with food allergies, a prevalence much higher than appreciated in the past. In addition, the prevalence of peanut allergy was found to have doubled in American children less than 5 years of age in the past 5 years. Many food allergens have been characterized at the molecular level, which has contributed to our increased understanding of the immunopathogenesis of many allergic disorders and might soon lead to novel diagnostic and immunotherapeutic approaches. The management of food allergies continues to consist of educating patients on how to avoid relevant allergens, to recognize early symptoms of an allergic reaction in case of an accidental ingestion, and to initiate the appropriate emergency therapy. However, the recent successful clinical trial of anti-IgE therapy in patients with peanut allergy and the number of immunomodulatory therapies in the pipeline provide real hope that we will soon be able to treat patients with food allergy.",
"Discrete choice experiments (DCEs) are regularly used in health economics to elicit preferences for healthcare products and programmes. There is growing recognition that DCEs can provide more than information on preferences and, in particular, they have the potential to contribute more directly to outcome measurement for use in economic evaluation. Almost uniquely, DCEs could potentially contribute to outcome measurement for use in both cost-benefit and cost-utility analysis. Within this expanding remit, our intention is to provide a resource for current practitioners as well as those considering undertaking a DCE, using DCE results in a policy/commercial context, or reviewing a DCE. We present the fundamental principles and theory underlying DCEs. To aid in undertaking and assessing the quality of DCEs, we discuss the process of carrying out a choice study and have developed a checklist covering conceptualizing the choice process, selecting attributes and levels, experimental design, questionnaire design, pilot testing, sampling and sample size, data collection, coding of data, econometric analysis, validity, interpretation and welfare and policy analysis. In this fast-moving area, a number of issues remain on the research frontier. We therefore outline potentially fruitful areas for future research associated both with DCEs in general, and with health applications specifically, paying attention to how the results of DCEs can be used in economic evaluation. We also discuss emerging research trends. We conclude that if appropriately designed, implemented, analysed and interpreted, DCEs offer several advantages in the health sector, the most important of which is that they provide rich data sources for economic evaluation and decision making, allowing investigation of many types of questions, some of which otherwise would be intractable analytically. Thus, they offer viable alternatives and complements to existing methods of valuation and preference elicitation."
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Stress, Depression, and Neck Disability in Patients with Temporomandibular Disorder-Myofascial Pain with Referral
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The etiology of temporomandibular disorders (TMDs) is firmly anchored in the biopsychosocial model in which a special role is attributed to the stress, depression, somatic symptoms, and anxiety. The aim of the study was to assess the level of stress, depression and neck disability in patients with temporomandibular disorder-myofascial pain with referral. The study group enrolled 50 people (37 women and 13 men) with complete natural dentition. All the patients underwent a clinical examination according to the Diagnostic Criteria for Temporomandibular Disorders and were diagnosed as individuals with myofascial pain with referral. The questionnaires were associated with stress, depression, and neck disability; Perceived Stress Scale (PSS-10), Beck Depression Inventory(BDI), and Neck Disability Index (NDI) were evaluated. Of the individuals evaluated, 78% showed elevated levels of stress, and the average value of the PSS-10 in the study group was 18 points (Me = 17). Furthermore, 30% of the subjects presented depressive symptoms, with the average value of BDI was 8.94 points (Me = 8), and 82% of the subjects showed neck disability. The multiple linear regression model revealed that BDI and NDI allowed explanations for the 53% differentiation of PSS-10. In conclusion, stress, depression, and neck disability coexist with temporomandibular disorder-myofascial pain with referral.
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[
"The aim of the study was to test whether the definition of depressive mixed states (DMX) in bipolar II disorder should require satisfaction of full criteria for hypomania or if only a few hypomanic symptoms should be required. Consecutive outpatients with bipolar II major depressive episode (MDE) (n=260) were assessed with the Structured Clinical Interview for DSM-IV. Presence of hypomanic symptoms during MDE was systematically assessed, and symptoms were graded by rating scale. The following three definitions of DMX were compared: (1) MDE plus full criteria for hypomania, (2) MDE plus three or more hypomanic symptoms (DMX3), and (3) MDE plus one or two hypomanic symptoms (DMX1-2). DMX definitions were compared on variables typically associated with bipolar disorders (young age of onset, many recurrences, atypical features of depression, and bipolar family history). The distributions of hypomanic symptom scores, age, and age of onset were studied by Kernel density estimation curves and by histograms. Bimodality would support distinct disorders, whereas lack of bimodality would support continuity among the different DMX definitions. The frequency of DMX+full hypomania was 12.3%, that of DMX3 was 46.9%, and that of of DMX1-2 was 38.8%. Comparisons among the groups on bipolar validators found that most differences were not significant. Kernel density estimation curves and histograms did not show bimodality, and had near normal distribution shapes. The findings do not support a categorical definition of bipolar II DMX like that of DSM-IV for bipolar I mixed state but are consistent with a dimensional definition of bipolar II DMX. The high frequency of DMX in bipolar II MDE supports the need for controlled studies to test the effects of antidepressants on depressive mixed state (as clinical observations suggest possible negative effects).",
"The aim was to systematically review the relationship between muscular strength (MS) and depression symptoms (DS) among adults, and conduct a meta-analysis to determine the pooled odds ratio (OR) for the relationship between MS and DS. The strategies employed in this systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Studies published up to December 2019 were systematically identified by searching in the PubMed, Scopus, and Web of Science electronic databases. Inclusion criteria were: (1) cross-sectional, longitudinal and intervention studies; (2) outcomes included depression or DS; (3) participants were adults and older adults; and (4) the articles were published in English, French, Portuguese, or Spanish. A total of 21 studies were included in the review, totalling 87,508 adults aged ≥18 years, from 26 countries. The systematic review findings suggest that MS has a positive effect on reducing DS. Meta-analysis findings indicate that MS is inversely and significantly related to DS 0.85 (95% CI: 0.80, 0.89). Interventions aiming to improve MS have the potential to promote mental health and prevent depression. Thus, public health professionals could use MS assessment and improvement as a strategy to promote mental health and prevent depression.",
"The aim of the study was functional evaluation of soft tissue mobilization in patients with temporomandibular disorder-myofascial pain with referral. The study group consisted of 50 individuals-37 females and 13 males. The average age was 23.36 ± 2.14 years. All subjects were diagnosed with myofascial pain with referral (diagnostic criteria for temporomandibular disorders). Soft tissue mobilization was applied three times. Electromyography of selected masticatory muscles was performed six times-before and after the treatment. After each mobilization, a decreasing tendency of muscular activity was observed in the entire study group. The Friedman test indicated that mobilization altered the activity of the right temporal muscle (p = 0.00010), both masseters (p = 0.0000), right sternocleidomastoid (p = 0.00251), left sternocleidomastoid (p = 0.00033), and right and left digastric muscles (p = 0.00045 and p = 0.00000, respectively). With respect to symmetry a statistically significant difference was noted in the case of the sternocleidomastoid muscles (p = 0.00729). In conclusion, soft tissue mobilization seems to be effective in the relaxation of masticatory muscles in patients with temporomandibular disorders. Our findings proved that soft tissue mobilization does not improve the symmetry and synergy of the masticatory muscles limited by dental occlusion.",
"The association between cervical spine disorders (CSD) and temporomandibular disorders (TMD) has been extensively investigated. However, no studies investigating the relationship between the level of jaw disability and neck disability have been published. Therefore, the objective of this study was to determine whether there was a relationship between neck disability measured using the neck disability index (NDI) and jaw disability measured through the jaw function scale (JFS). A sample of 154 subjects who attended the TMD/Orofacial Pain clinic and students and staff at the University of Alberta participated in this study. All subjects were asked to complete the NDI, the JFS, the jaw disability checklist (JDC), and the level of chronic disability of TMD (chronic pain grade disability questionnaire used in the RDC/TMD). Spearman rho test was used to analyse the relationship between neck disability and jaw disability. Multiple regression analysis was used to determine the association between the level of chronic disability of TMD and neck disability. A strong relationship between neck disability and jaw disability was found (r = 0.82). A subject with a high level of TMD disability (grade IV) increased by about 19 points on the NDI when compared with a person without TMD disability. These results have implications for clinical practice. If patients with TMD have neck disability in addition to jaw disability, treatment needs to focus on both areas because the improvement of one could have an influence on the other.",
"The aim of the study was to evaluate occlusal parameters in patients with myofascial pain with referral before and after soft tissue mobilization. The study group consisted of 50 people (37 females and 13 males, average age 23.36 ± 2.14 years) diagnosed with myofascial pain with referral. All patients underwent triplicate soft tissue mobilization. Occlusal parameters were evaluated six times, before and after each treatment, using T-scan III. A decreasing tendency of the occlusion time was observed after the first, second, and third therapy. After the third treatment, the mean occlusion time in the entire study group was 0.119 s. The 1st soft tissue mobilization shortened both right and left disclusion times to 0.181 s and 0.185 s, respectively. After the third treatment, these parameters amounted to 0.159 s and 0.165 s, respectively. The Friedman test for the entire study group indicated that soft tissue mobilization altered the occlusion time and both disclusion times (p < 0.05). In conclusion, soft tissue mobilization affects biotensegrity of the masticatory system, thus modifying occlusal parameters. The occlusion time and both disclusion times cannot be considered as cofactors of the existing temporomandibular disorders-myofascial pain with referral.",
"There has been increasing interest in the depressed phase of bipolar disorder (bipolar depression). This paper aims to review the clinical characteristics of bipolar depression, focusing upon its prevalence and phenomenology, related neuropsychological dysfunction, suicidal behaviour, disability and treatment responsiveness. Studies on the prevalence of depression in bipolar disorder, the comparative phenomenology of bipolar and unipolar depression, as well as neuropsychology and brain imaging studies, are reviewed. To identify relevant papers, a literature search using MEDLINE and PubMed was undertaken. Depression is the predominant mood disturbance in bipolar disorder, and most frequently presents as subsyndromal, minor or dysthymic depression. Compared with major depressive disorder (unipolar depression), bipolar depression is more likely to manifest with psychosis, melancholic symptoms, psychomotor retardation (in bipolar I disorder) and 'atypical' symptoms. The few neuropsychological studies undertaken indicate greater impairment in bipolar depression. Suicide rates are high in bipolar disorder, with suicidal ideation, suicide attempts and completed suicides all occurring predominantly in the depressed phase of this condition. Furthermore, the depressed phase (even subsyndromal) appears to be the major contributant to the disability related to this condition. The significance of the depressed phase of bipolar disorder has been markedly underestimated. Bipolar depression accounts for most of the morbidity and mortality due to this illness. Current treatments have significant limitations.",
"Clinical presentations of depression in bipolar disorder are varied, inconsistent and often confusing. Most previous studies have focused on bipolar I (BP-I). Given that bipolar II (BP-II) is the more common bipolar phenotype, which is often confused with unipolar (UP), the aim of the current analyses is to delineate the symptomalogic differences between BP II vs. UP MDD in a large national sample. The data derived from the French National EPIDEP study (n = 452 DSM-IV major depressives), subdivided into BP-II (n = 196) and UP (n = 256). The BP II group included major depressives with both spontaneous and antidepressant-associated hypomania based on our finding of similarity in rates of familial bipolarity in the two subgroups. At index presentation, depression was assessed by the clinician (using HAM-D and the Rosenthal Atypical Depression Scale) and by the patient (using the Multi-Visual Analog Scale of Bipolarity, MVAS-BP). Principal component analyses (PCA with varimax rotation) were conducted on HAM-D and MVAS-BP in the total population and separately in BP-II and UP. We performed inter-group comparative tests (UP vs. BP-II) on factorial scores derived from PCAs and correlation tests between these factorial scores. The PCA on \"HAM-D + Rosenthal scale\" showed the presence of nine major factors: F1-2 \"weight changes\", F3-4 \"sleep disturbances\", F5 \"sadness-guilt\", F6 \"retardation-fatigue\", F7 \"somatic\", F8 \"diurnal variation\" and F9 \"insight-delusion\". The PCA on MVAS-BP revealed the presence of eight principal components: F1 \"psychomotor retardation\", F2 \"central pain\", F3 \"somatic\", F4 \"social contact\", F5 \"worry\", F6 \"loss of interest\", F7 \"guilt\" and F8 \"anger\". Despite uniformity in global intensity of depression, significant differences were observed as follows: higher score on \"psychomotor retardation\" (p = 0.03), \"loss of interest\" (p = 0.057) and \"insomnia\" (p = 0.05) in the UP group, and higher score on \"hypersomnia\" (p = 0.008) in the BP-II group. Correlation analyses between clinician- and self-rating revealed the presence of higher number of significant coefficients in the UP vs. BP-II group (p < or =0.001). A three-way comparison between BP-I, BP-II and UP may have yielded somewhat different results. Our data indicate greater psychomotor retardation, stability and uniformity in the clinical picture of strictly defined UP depression. By contrast, bipolar II depression appeared to be characterized, despite the hypersomnic tendency, by psychomotor activation. This would indicate greater mixed features than those observed in UP. Moreover, in BP-II, there was less agreement between clinician vs. self-rating on the presence of various features of depression. Taken together, these findings explain why BP-II depression is missed by clinicians as a genuine depression.",
"The current subtyping of depression is based on the Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision (DSM-IV-TR) categorical division of bipolar and depressive disorders. Current evidence, however, supports a dimensional approach to depression, as a continuum/spectrum of overlapping disorders, ranging from bipolar I depression to major depressive disorder. Types of depression which have recently been the focus of most research will be reviewed: bipolar II depression, mixed depression, agitated depression, atypical depression, melancholic depression, recurrent brief depression, minor depressive disorder, seasonal depression, and dysthymic disorder. Most research has focused on bipolar II depression, mixed depression (defined by depression and superimposed manic/hypomanic symptoms), and atypical depression. Mixed depression, by its combination of opposite polarity symptoms, has been found to be common by systematic probing for co-occurring manic/hypomanic symptoms. Mixed depression is a treatment challenge for clinicians, because antidepressants alone (ie, not protected by mood-stabilizing agents) may worsen its manic/hypomanic symptoms, such as irritability and psychomotor agitation, which the Food and Drug Administration (FDA) has listed as possible precursors to suicidality.",
"Depressive symptoms (DS) have been associated with increased risk of cognitive decline. Our aim was to evaluate the longitudinal influence of DS on cognition in independent older people, accounting for the severity of white matter changes (WMC). The LADIS (Leukoaraiosis And DISability in the elderly) prospective study evaluated the impact of WMC on the transition of independent older subjects into disability. Subjects were evaluated annually over a 3 year period with a comprehensive clinical and neuropsychological evaluation. Previous episodes of depression and current DS were assessed during each interview. Severity of DS was assessed using the self-rated 15 item Geriatric Depression Scale. A neuropsychological battery and clinical criteria for cognitive impairments were applied in all clinical visits, and cognitive compound measures were made based on neuropsychological results. MRI was performed at baseline and at year 3. 639 subjects were included (74.1 ± 5 years old, 55% women, 9.6 ± 3.8 years of schooling). Dementia was diagnosed in 90 patients and cognitive impairment not dementia in 147 patients at the last clinical evaluation. DS were an independent predictor of cognitive impairment (dementia and not dementia) during follow-up, independent of the effect of the severity of WMC, medial temporal lobe atrophy, age, education or global cognitive function at baseline. DS are associated with an increase risk of cognitive decline, independent of the effect of WMC, probably due to an additive or synergistic effect. In this context, DS probably represent a subtle ongoing organic dysfunction.",
"The study evaluated the DSM-IV definition of the atypical features specifier for a major depressive episode in major depressive disorder. Nonpsychotic patients with major depressive disorder were assessed to determine if the DSM-IV model and decision rules for the atypical features specifier for a major depressive episode could be supported. The five clinical features of the DSM-IV atypical features specifier for a major depressive episode showed weak internal consistency, and the mandatory criterion A feature of mood reactivity did not show specificity in relation to any of the four criterion B accessory symptoms. The more severe the depression, the less likely the patient was to report criterion A and hence to meet criteria for the atypical features specifier. Remodeling the five features favored the personality style descriptor of interpersonal rejection sensitivity as an alternate primary feature. A reformulated model also suggested lifetime panic disorder and social phobia as higher-order determinants of atypical features in major depressive disorder. Additional analyses of criteria suggested that interpersonal rejection sensitivity and leaden paralysis had a phenomenological base in anxiety, that mood reactivity was linked with irritability, and that neither weight gain nor hypersomnia were clearly aligned with anxiety or depression, raising questions about their status as symptoms. The current definition and modeling of the DSM-IV atypical features specifier for a major depressive episode in major depressive disorder appears problematic. As suggested by earlier descriptions of atypical depression, certain expressions of anxiety may have primacy, and some clinical features associated with the DSM-IV model may be adaptive homeostatic responses rather than pathological symptoms."
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Halloysite and sepiolite nanoclays as drug delivery systems
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The need for safe, therapeutically effective, and patient-compliant drug delivery systems continuously leads researchers to design novel tools and strategies. Clay minerals are widely used in drug products both as excipients and active agents but, in recent years, there has been a growing interest in research aimed at the development of new organic or inorganic nanocomposites. The attention of the scientific community has been drawn by nanoclays, thanks to their natural origin, worldwide abundance, availability, sustainability, and biocompatibility. In this review, we focused our attention on the studies inherent to the pharmaceutical and biomedical applications of halloysite and sepiolite, and their semi-synthetic or synthetic derivatives, as drug delivery systems. After having described the structure of both materials and their biocompatibility, we delineate the use of the nanoclays to enhance the stability, the controlled release, the bioavailability, and the adsorption properties of drugs. Several types of surface functionalization have been discussed, showing that these materials could be used for the development of an innovative therapeutic approach.
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"Halloysite, naturally occurring clay nanotubes, is described as an additive for functional polymer composites. Due to the empty tubular lumen capable of being loaded with chemically active agents, halloysite provides additional functions (drug delivery, antibiotic, flame-retardant, anticorrosion, and crack self-healing) to polymeric composites synergistically combined with enhanced tensile, impact and adhesive strength. Doping loaded clay nanotubes into a polymeric matrix provides a kind of ceramic \"skeleton\", and these \"skeleton bones\" are loaded with functional chemicals like real bones loaded with marrow. Tunable controlled release of active agents through synthesis of artificial nano-caps at the tube endings and halloysite lumen enlargement by selective etching allowed for tubular nanocontainers with chemicals release time from 10 to 200 h and a loading capacity of ca. 30 wt%. Halloysite is well mixable with polymers of high and medium polarities without any surface modification.",
"The arena of biomedical science has long been in quest of innovative mediums for diagnostic and therapeutic applications. The latest being the use of nanomaterials for such applications, thereby giving rise to the branch of nanomedicine. Halloysite nanotubes (HNTs) are naturally occurring tubular clay nanomaterials, made of aluminosilicate kaolin sheets rolled several times. The aluminol and siloxane groups on the surface of HNT facilitate the formation of hydrogen bonding with the biomaterials onto its surface. These properties render HNT pivotal in diverse range of applications, such as in environmental sciences, waste-water treatment, dye removal, nanoelectronics and fabrication of nanocomposites, catalytic studies, as glass coatings or anticorrosive coatings, in cosmetics, as flame retardants, stimuli response, and forensic sciences. The specific properties of HNT also lead to numerous applications in biomedicine and nanomedicine, namely drug delivery, gene delivery, tissue engineering, cancer and stem cells isolation, and bioimaging. In this review, recent developments in the use of HNT for various nanomedicinal applications have been discussed.",
"Nanocomposites hydrogel (nanohydrogel) composed of chitosan (CS) and montmorillonite (MMT) were prepared and systematically studied for drug release behavior following electrostimulation. The deterioration of the responsiveness and reversibility of CS upon repeated on-off electrostimulation switching operations are major limitations for clinical applications, as it suffers from too much structural instability for the precise control of the release of drug upon cyclic electrostimulation. To overcome these limitations, an inorganic phase, MMT, was incorporated in the CS matrix to enhance the anti-fatigue property and corresponding long-term stable release kinetics. X-ray diffraction analysis and time-dependent optical absorbance showed that the MMT incorporated into the nanohydrogel exhibited an exfoliated nanostructure. The exfoliated silica nanosheets are able to act as cross-linkers to form a network structure between the CS and MMT, and this difference in the cross-linking density strongly affects the release of vitamin B(12) under electrostimulation. With a lower MMT concentration (1 wt.%), the release kinetics of vitamin B(12) from the nanohydrogel shows a pseudo-zero-order release, and the release mechanism was changed from a diffusion-controlled mode to a swelling-controlled mode under electrostimulation. Further increasing the MMT content reduced both the diffusion exponent n and the responsiveness of the nanohydrogel to electrostimulation. In addition, a consecutively repeated \"on\" and \"off\" operation shows that the electroresponsiveness of the nanohydrogel with higher MMT concentrations was reduced, but its anti-fatigue behavior was considerably improved. In this work, the nanohydrogel with 2 wt.% MMT achieved a mechanically reliable and practically desirable pulsatile release profile and excellent anti-fatigue behavior, compared with that of the pure CS.",
"In this study, a series of chitosan-sepiolite (CS-SEP) nanocomposites films were prepared by using a conventional solution casting method. The effect of sepiolite on physicochemical and biological properties of the prepared nanocomposite films was studied by various techniques such as Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), and x-ray diffraction (XRD) to name a few. In WCA measurements, the decrease of contact angle from 78.51° (CS) to 71.29° (CS7SEP3) reaffirms the water holding nature of sepiolite, which enables to create moist environment essentially required for wound healing. Further, addition of sepiolite tremendously increased WVTR, folding endurance, porosity, and blood clotting ability of the prepared nanocomposites. Furthermore, CS-SEP nanocomposite films exhibit better antibacterial activity than that of chitosan against gram positive (B. subtilis) and gram negative bacteria (E. coli). Moreover, the percentage of hemolysis and degradation study indicated that the prepared nanocomposite films were non-hemolytic in nature and decomposed nearly 40% in four weeks. In addition, cytotoxicity assay showed that the prepared nanocomposite film i.e. CS7SEP3 exhibited better cell viability and cell proliferation rate against L929 mouse fibroblast cells as compared to CS and hence, the prepared nanocomposite film can be used as a promising candidate for wound management.",
"This paper presents the effect of modified halloysite nanotubes on the sustained drug release mechanisms of sodium salicylate. Acid treatment and composite polymer-halloysite modification techniques were adopted in this study. After each modification, sodium salicylate drug was loaded, and in vitro release properties were evaluated and compared with the raw unmodified halloysite nanotubes. The results obtained from SEM, TEM and FTIR analyses indicate that both acid treatment and composite formation have no effect on the tubular structure and morphology of halloysite. However, modification of the halloysite nanotubes did influence the drug release rate. In the acid treatment modification, there was an improved loading of sodium salicylate drug which resulted in the sustain release of large amount of the sodium salicylate. In the polymer/halloysite composite formation, a consistent layer of polymer was formed around the halloysite during the composite formation and thus delayed release providing sustained release of sodium salicylate drug over a longer period of time as compared to the acid treated and unmodified halloysite. The results from the invitro release were best fitted with the Higuchi and the Koresymer-Peppas models.",
"Halloysite nanotubes (HNTs) are a natural aluminosilicate clay with a chemical formula of Al2Si2O5(OH)4×nH2O and a hollow tubular structure. Due to their peculiar structure, HNTs can play an important role as a drug carrier system. Currently, the mechanism by which HNTs are internalized into living cells, and what is the transport pathway, is still unclear. Therefore, this study aimed at establishing the in vitro mechanism by which halloysite nanotubes could be internalized, using phagocytic and non-phagocytic cell lines as models. The HNT/CURBO hybrid system, where a fluorescent probe (CURBO) is confined in the HNT lumen, has been used as a model to study the transport pathway mechanisms of HNTs. The cytocompatibility of HNT/CURBO on cell lines model was investigated by MTS assay. In order to identify the internalization pathway involved in the cellular uptake, we performed various endocytosis-inhibiting studies, and we used fluorescence microscopy to verify the nanomaterial internalization by cells. We evaluated the haemolytic effect of HNT/CURBO placed in contact with human red blood cells (HRBCs), by reading the absorbance value of the supernatant at 570 nm. The HNT/CURBO is highly biocompatible and does not have an appreciable haemolytic effect. The results of the inhibition tests have shown that the internalization process of nanotubes occurs in an energy-dependent manner in both the investigated cell lines, although they have different characteristics. In particular, in non-phagocytic cells, clathrin-dependent and independent endocytosis are involved. In phagocytic cells, in addition to phagocytosis and clathrin-dependent endocytosis, microtubules also participate in the halloysite cellular trafficking. Upon internalization by cells, HNT/CURBO is localized in the cytoplasmic area, particularly in the perinuclear region. Understanding the cellular transport pathways of HNTs can help in the rational design of novel drug delivery systems and can be of great value for their applications in biotechnology.",
"Cellulose nanocrystals (CNCs) and/or sepiolite (SPT) were thermomechanically mixed with un-plasticised chitosan and chitosan/carboxymethyl cellulose (CMC) blends plasticised with 1-ethyl-3-methylimidazolium acetate ([C2mim][OAc]). Examination of the morphology of these materials indicates that SPT aggregates were reduced when CNCs or [C2mim][OAc] were present. Inclusion of CNCs and/or SPT had a greater effect on material properties when the matrices were un-plasticised. Addition of SPT or CNCs altered the crystalline structure of the un-plasticised chitosan matrix. Moreover, a combination of SPT and CNCs was more effective at suppressing re-crystallisation. Nonetheless, the mechanical properties and surface hydrophobicity were more related to CNC/SPT-biopolymer interactions. The un-plasticised bionanocomposites generally showed increased relaxation temperatures, enhanced tensile strength, and reduced surface wettability. For the [C2mim][OAc] plasticised matrices, the ionic liquid (IL) dominates the interactions with the biopolymers such that the effect of the nanofillers is diminished. However, for the [C2mim][OAc] plasticised chitosan/CMC matrix, CNCs and SPT acted synergistically suppressing re-crystallisation but resulting in increased tensile strength."
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Metabolomics and metabolome-microbiome analysis of human gut microbiota in patients with metabolic-related diseases
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Human gut microbiota seems to drive the interaction with host metabolism through microbial metabolites, enzymes, and bioactive compounds. These components determine the host health-disease balance. Recent metabolomics and combined metabolome-microbiome studies have helped to elucidate how these substances could differentially affect the individual host pathophysiology according to several factors and cumulative exposures, such as obesogenic xenobiotics. The present work aims to investigate and interpret newly compiled data from metabolomics and microbiota composition studies, comparing controls with patients suffering from metabolic-related diseases (diabetes, obesity, metabolic syndrome, liver and cardiovascular diseases, etc.). The results showed, first, a differential composition of the most represented genera in healthy individuals compared to patients with metabolic diseases. Second, the analysis of the metabolite counts exhibited a differential composition of bacterial genera in disease compared to health status. Third, qualitative metabolite analysis revealed relevant information about the chemical nature of metabolites related to disease and/or health status. Key microbial genera were commonly considered overrepresented in healthy individuals together with specific metabolites, e.g.,
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"In humans, the composition of gut commensal bacteria is closely correlated with obesity. The bacteria modulate metabolites and influence host immunity. In this study, we attempted to determine whether there is a direct correlation between specific commensal bacteria and host metabolism. As mice aged, we found significantly reduced body weight and fat mass in Atg7ΔCD11c mice when compared with Atg7f/f mice. When mice shared commensal bacteria by co-housing or feces transfer experiments, body weight and fat mass were similar in both mouse groups. By pyrosequencing analysis, Bacteroides acidifaciens (BA) was significantly increased in feces of Atg7ΔCD11c mice compared with those of control Atg7f/f mice. Wild-type C57BL/6 (B6) mice fed with BA were significantly more likely to gain less weight and fat mass than mice fed with PBS. Of note, the expression level of peroxisome proliferator-activated receptor alpha (PPARα) was consistently increased in the adipose tissues of Atg7ΔCD11c mice, B6 mice transferred with fecal microbiota of Atg7ΔCD11c mice, and BA-fed B6 mice. Furthermore, B6 mice fed with BA showed elevated insulin levels in serum, accompanied by increased serum glucagon-like peptide-1 and decreased intestinal dipeptidyl peptidase-4. These finding suggest that BA may have potential for treatment of metabolic diseases such as diabetes and obesity.",
"This study investigated the immune mechanisms whereby administration of Bacteroides uniformis CECT 7771 reduces metabolic dysfunction in obesity. C57BL/6 adult male mice were fed a standard diet or a Western diet high in fat and fructose, supplemented or not with B. uniformis CECT 7771 for 14 weeks. B. uniformis CECT 7771 reduced body weight gain, plasma cholesterol, triglyceride, glucose, and leptin levels; and improved oral glucose tolerance in obese mice. Moreover, B. uniformis CECT 7771 modulated the gut microbiota and immune alterations associated with obesity, increasing Tregs and reducing B cells, total macrophages and the M1/M2 ratio in both the gut and epididymal adipose tissue (EAT) of obese mice. B. uniformis CECT 7771 also increased the concentration of the anti-inflammatory cytokine IL-10 in the gut, EAT and peripheral blood, and protective cytokines TSLP and IL-33, involved in Treg induction and type 2 innate lymphoid cells activation, in the EAT. It also restored the obesity-reduced TLR5 expression in the ileum and EAT. The findings indicate that the administration of a human intestinal bacterium with immunoregulatory properties on the intestinal mucosa helps reverse the immuno-metabolic dysfunction caused by a Western diet acting over the gut-adipose tissue axis.",
"The human gut microbiota is involved in host health and disease development. Therefore, lifestyle-related diseases such as hypertension (HT), hyperlipidemia (HL), and type 2 diabetes mellitus (T2D) may alter the composition of gut microbiota. Here, we investigated gut microbiota changes related to these diseases and their coexistence. This study involved 239 Japanese subjects, including healthy controls (HC). The fecal microbiota was analyzed through the isolation of bacterial genomic DNA obtained from fecal samples. Although there were no significant differences in the microbial structure between groups, there was a significant difference in the α-diversity between HC and the patients in whom two diseases coexisted. Moreover, Actinobacteria levels were significantly increased, whereas Bacteroidetes levels were significantly decreased in all disease groups. At the genus level, Bifidobacterium levels were significantly increased in the HL and T2D groups, as were those of Collinsella in all disease groups. In contrast, Alistipes levels were significantly lower in the HL group. Furthermore, metabolic enzyme families were significantly increased in all disease groups. Interestingly, the structure and function of the gut microbiota showed similar profiles in all the studied diseases. In conclusion, several changes in the structure of the gut microbiota are associated with T2D, HT, and HL in Japanese subjects.",
"Variation of gut microbiota in metabolic diseases seems to be related to dysbiosis induced by exposure to multiple substances called Microbiota Disrupting Chemicals (MDCs), which are present as environmental and dietary contaminants. Some recent studies have focused on elucidating the alterations of gut microbiota taxa and their metabolites as a consequence of xenobiotic exposures to find possible key targets involved in the severity of the host disease triggered. Compilation of data supporting the triad of xenobiotic-microbiota-metabolic diseases would subsequently allow such health misbalances to be prevented or treated by identifying beneficial microbe taxa that could be Next Generation Probiotics (NGPs) with metabolic enzymes for MDC neutralisation and mitigation strategies. In this review, we aim to compile the available information and reports focused on variations of the main gut microbiota taxa in metabolic diseases associated with xenobiotic exposure and related microbial metabolite profiles impacting the host health status. We performed an extensive literature search using SCOPUS, Web of Science, and PubMed databases. The data retrieval and thorough analyses highlight the need for more combined metagenomic and metabolomic studies revealing signatures for xenobiotics and triggered metabolic diseases. Moreover, metabolome and microbiome compositional taxa analyses allow further exploration of how to target beneficial NGP candidates according to their alleged variability abundance and potential therapeutic significance. Furthermore, this holistic approach has identified limitations and the need of future directions to expand and integrate key knowledge to design appropriate clinical and interventional studies with NGPs. Apart from human health, the beneficial microbes and metabolites identified could also be proposed for various applications under One Health, such as probiotics for animals, plants and environmental bioremediation.",
"To identify fecal microbiota profiles associated with metabolic abnormalities belonging to the metabolic syndrome (MS), high count of white blood cells (WBCs) and insulin resistance (IR). Sixty-eight young patients with obesity were stratified for percentile distribution of MS abnormalities. A MS risk score was defined as low, medium, and high MS risk. High WBCs were defined as a count ≥ 7.0 103/µL; severe obesity as body mass index Z-score ≥ 2 standard deviations; IR as homeostatic assessment model algorithm of IR (HOMA) ≥ 3.7. Stool samples were analyzed by 16S rRNA-based metagenomics. We found reduced bacterial richness of fecal microbiota in patients with IR and high diastolic blood pressure (BP). Distinct microbial markers were associated to high BP (Clostridium and Clostridiaceae), low high-density lipoprotein cholesterol (Lachnospiraceae, Gemellaceae, Turicibacter), and high MS risk (Coriobacteriaceae), WBCs (Bacteroides caccae, Gemellaceae), severe obesity (Lachnospiraceae), and impaired glucose tolerance (Bacteroides ovatus and Enterobacteriaceae). Conversely, taxa such as Faecalibacterium prausnitzii, Parabacterodes, Bacteroides caccae, Oscillospira, Parabacterodes distasonis, Coprococcus, and Haemophilus parainfluenzae were associated to low MS risk score, triglycerides, fasting glucose and HOMA-IR, respectively. Supervised multilevel analysis grouped clearly \"variable\" patients based on the MS risk. This was a proof-of-concept study opening the way at the identification of fecal microbiota signatures, precisely associated with cardiometabolic risk factors in young patients with obesity. These evidences led us to infer, while some gut bacteria have a detrimental role in exacerbating metabolic risk factors some others are beneficial ameliorating cardiovascular host health.",
"Diabetes is associated with a high risk of developing cognitive impairment, but the underlying mechanism remains unclear. Recent studies have found that gut microbiota may be involved in the progression of diabetes-associated cognitive impairment. To analyze the diversity of gut microbiota in type 2 diabetes with or without cognitive impairment METHODS: 16S rRNA sequencing was used to detect the gut microbiota composition in 154 type 2 diabetes (T2DM) subjects RESULTS: Among 154 elderly T2DM participants included in our study, 73 with normal and 81 with impaired cognition. Lower levels of hemoglobin and HDL were observed in subjects with cognitive impairment. Patients with cognitive impairment had a lower abundance of Tenericutes. Comparison at the genus level revealed that T2DM patients with cognitive impairment had a decreased abundance of Bifidobacterium and unranked-RF39 and an increased abundance of Peptococcus and unranked-Leuconostocaceae. Additionally, the relative abundance of Veillonella and Pediococcus were decreased in subjects with cognitive impairment. Furthermore, the relative abundance of 7 sub-functions was significantly changed in the group with cognitive impairment. Calcium signaling pathways and the Renin-angiotensin system were upregulated in the cognitive impairment group while GnRH signaling, Fc gamma R-mediated phagocytosis, endocytosis, isoflavonoid biosynthesis, and cytochrome P450 were deregulated. Bifidobacterium may be associated with cognition in T2DM. Calcium signaling and renin-angiotensin system were shown to be associated with diabetes-associated cognitive impairment through gut microbiota.",
"Fibrotic liver injury is a progressive scarring event, which may permanently affect liver function and progress into devastating end-stage liver diseases due to the absence of effective therapies. Si-Wu-Tang (SWT), a traditional Chinese medicine formula used in clinic to treat gynecological disorders for centuries, has been investigated in recent preliminary findings for its role in alleviating chronic liver diseases. Here we aim to elucidate the therapeutic effects and possible mechanisms of SWT against fibrotic liver injury. UHPLC-MS/MS was performed to investigate the chemical characterization of SWT. After intragastrically administered with carbon tetrachloride (CCl4) every 3 days for 1-week, C57BL/6 mice were orally administered with SWT (5.2, 10.4 and 20.8 g/kg) once daily for 3 weeks along with CCl4 challenge. Liver function was determined by the measurement of serum biomarkers, hematoxylin and eosin (H&E) and Masson's trichrome staining. Intestinal inflammatory infiltration and the disruption of intestinal barrier were examined by H&E and E-cadherin immunohistochemical staining. The microbial composition of intestinal content was determined by 16S rRNA sequencing. Serum bile acids (BAs) profiling was analyzed by LC-MS/MS. Simultaneously, the expression of genes of interest was determined by qPCR and western blot. SWT exhibited remarkable therapeutic effects on CCl4-induced liver fibrosis, as indicated by improved collagen accumulation in livers, intestinal barrier injury and hepatic and intestinal inflammatory response. Results of 16S rRNA sequencing revealed that SWT treatment strikingly restructured intestinal microbiota in fibrotic mice by increasing the relative abundances of Bacteroides and Lachnoclostridium and decreasing the relative abundances of Alistipes and Rikenellaceae. UHPLC-MS/MS data suggested that SWT altered the composition of BAs in circulation as evidenced by increased unconjugated BAs like cholic acid and chenodeoxycholic acid but decreased conjugated BAs including taurocholic acid and taurodeoxycholic acid, compared to that in CCl4 mice. Notably, SWT efficiently improved the imbalance of BA homeostasis in livers caused by CCl4 via activating farnesoid X receptor (FXR)-fibroblast growth factor 15 enterohepatic and FXR-small heterodimer partner hepatic pathways. SWT decreased inflammatory response, reconstructed gut microbiota-mediated BA homeostasis as well as activated FXR pathways, which eventually protected against CCl4-induced fibrotic liver injury."
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Mitochondrial oxidative metabolism is not required for astrocyte survival and proliferation
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Understanding the role of astrocytes in the development of the nervous system and neurodegenerative disorders implies a necessary knowledge of the oxidative metabolism of proliferating astrocytes. The electron flux through mitochondrial respiratory complexes and oxidative phosphorylation may impact the growth and viability of these astrocytes. Here, we aimed at assessing to which extent mitochondrial oxidative metabolism is required for astrocyte survival and proliferation. Primary astrocytes from the neonatal mouse cortex were cultured in a physiologically relevant medium with the addition of piericidin A or oligomycin at concentrations that fully inhibit complex I-linked respiration and ATP synthase, respectively. The presence of these mitochondrial inhibitors for up to 6 days in a culture medium elicited only minor effects on astrocyte growth. Moreover, neither the morphology nor the proportion of glial fibrillary acidic protein-positive astrocytes in culture was affected by piericidin A or oligomycin. Metabolic characterization of the astrocytes showed a relevant glycolytic metabolism under basal conditions, despite functional oxidative phosphorylation and large spare respiratory capacity. Our data suggest that astrocytes in primary culture can sustainably proliferate when their energy metabolism relies only on aerobic glycolysis since their growth and survival do not require electron flux through respiratory complex I or oxidative phosphorylation.
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"As the result of genetic alterations and tumor hypoxia, many cancer cells avidly take up glucose and generate lactate through lactate dehydrogenase A (LDHA), which is encoded by a target gene of c-Myc and hypoxia-inducible factor (HIF-1). Previous studies with reduction of LDHA expression indicate that LDHA is involved in tumor initiation, but its role in tumor maintenance and progression has not been established. Furthermore, how reduction of LDHA expression by interference or antisense RNA inhibits tumorigenesis is not well understood. Here, we report that reduction of LDHA by siRNA or its inhibition by a small-molecule inhibitor (FX11 [3-dihydroxy-6-methyl-7-(phenylmethyl)-4-propylnaphthalene-1-carboxylic acid]) reduced ATP levels and induced significant oxidative stress and cell death that could be partially reversed by the antioxidant N-acetylcysteine. Furthermore, we document that FX11 inhibited the progression of sizable human lymphoma and pancreatic cancer xenografts. When used in combination with the NAD(+) synthesis inhibitor FK866, FX11 induced lymphoma regression. Hence, inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors. Our studies document a therapeutical approach to the Warburg effect and demonstrate that oxidative stress and metabolic phenotyping of cancers are critical aspects of cancer biology to consider for the therapeutical targeting of cancer energy metabolism.",
"This study sought to elucidate how oligomycin, an ATP synthase blocker, leads to underestimation of maximal oxygen consumption rate (maxOCR) and spare respiratory capacity (SRC) in tumor cells. T98G and U-87MG glioma cells were titrated with the protonophore CCCP to induce maxOCR. The presence of oligomycin (0.3-3.0 µg/mL) led to underestimation of maxOCR and a consequent decrease in SRC values of between 25% and 40% in medium containing 5.5 or 11 mM glucose. The inhibitory effect of oligomycin on CCCP-induced maxOCR did not occur when glutamine was the metabolic substrate or when the glycolytic inhibitor 2-deoxyglucose was present. ATP levels were reduced and ADP/ATP ratios increased in cells treated with CCCP, but these changes were minimized when oligomycin was used to inhibit reverse activity of ATP synthase. Exposing digitonin-permeabilized cells to exogenous ATP, but not ADP, resulted in partial inhibition of CCCP-induced maxOCR. We conclude that underestimation of maxOCR and SRC in tumor cells when ATP synthase is inhibited is associated with high glycolytic activity and that the glycolytic ATP yield may have an inhibitory effect on the metabolism of respiratory substrates and cytochrome c oxidase activity. Under CCCP-induced maxOCR, oligomycin preserves intracellular ATP by inhibiting ATP synthase reverse activity.",
"The role of astrocytes in the progression of Alzheimer's disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic APP23/GFAP-TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes. The loss of proliferating astrocytes resulted in significantly increased levels of monomeric amyloid-β (Aβ) in brain homogenates, associated with reduced enzymatic degradation and clearance mechanisms. In addition, our data revealed exacerbated memory deficits in mice lacking proliferating astrocytes concomitant with decreased levels of synaptic markers and higher expression of pro-inflammatory cytokines. Our data suggest that loss of reactive astrocytes in AD aggravates amyloid pathology and memory loss, possibly via disruption of amyloid clearance and enhanced neuroinflammation.",
"The genetic basis for the hereditary leiomyomatosis and renal cell cancer syndrome is germ-line inactivating mutation in the gene for the Krebs/tricarboxylic acid cycle enzyme, fumarate hydratase (FH), the enzyme that converts fumarate to malate. These individuals are predisposed to development of leiomyomas of the skin and uterus as well as highly aggressive kidney cancers. Inhibition of FH should result in significant decrease in oxidative phosphorylation necessitating that glycolysis followed by fermentation of pyruvate to lactate will be required to provide adequate ATP as well as to regenerate NAD+. Moreover, FH deficiency is known to up-regulate expression of hypoxia-inducible factor (HIF)-1alpha by enhancing the stability of HIF transcript. This leads to activation of various HIF-regulated genes including vascular endothelial growth factor and glucose transporter GLUT1 and increased expression of several glycolytic enzymes. Because lactate dehydrogenase-A (LDH-A), also a HIF-1alpha target, promotes fermentative glycolysis (conversion of pyruvate to lactate), a step essential for regenerating NAD+, we asked whether FH-deficient cells would be exquisitely sensitive to LDH-A blockade. Here, we report that hereditary leiomyomatosis and renal cell cancer tumors indeed overexpress LDH-A, that LDH-A inhibition results in increased apoptosis in a cell with FH deficiency and that this effect is reactive oxygen species mediated, and that LDH-A knockdown in the background of FH knockdown results in significant reduction in tumor growth in a xenograft mouse model.",
"Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by excessive deposition of amyloid-beta (Abeta) peptides in the brain. One of the earliest neuropathological changes in AD is the accumulation of astrocytes at sites of Abeta deposition, but the cause or significance of this cellular response is unclear. Here we show that cultured adult mouse astrocytes migrate in response to monocyte chemoattractant protein-1 (MCP-1), a chemokine present in AD lesions, and cease migration upon interaction with immobilized Abeta(1-42). We also show that astrocytes bind and degrade Abeta(1-42). Astrocytes plated on Abeta-laden brain sections from a mouse model of AD associate with the Abeta deposits and reduce overall Abeta levels in these sections. Our results suggest a novel mechanism for the accumulation of astrocytes around Abeta deposits, indicate a direct role for astrocytes in degradation of Abeta and implicate deficits in astroglial clearance of Abeta in the pathogenesis of AD. Treatments that increase removal of Abeta by astrocytes may therefore be a critical mechanism to reduce the neurodegeneration associated with AD.",
"Since its introduction 16 years ago, the astrocyte-neuron lactate shuttle (ANLS) model has profoundly modified our understanding of neuroenergetics by bringing a cellular and molecular resolution. Praised or disputed, the concept has never ceased to attract attention, leading to critical advances and unexpected insights. Here, we summarize recent experimental evidence further supporting the main tenets of the model. Thus, evidence for distinct metabolic phenotypes between neurons (mainly oxidative) and astrocytes (mainly glycolytic) have been provided by genomics and classical metabolic approaches. Moreover, it has become clear that astrocytes act as a syncytium to distribute energy substrates such as lactate to active neurones. Glycogen, the main energy reserve located in astrocytes, is used as a lactate source to sustain glutamatergic neurotransmission and synaptic plasticity. Lactate is also emerging as a neuroprotective agent as well as a key signal to regulate blood flow. Characterization of monocarboxylate transporter regulation indicates a possible involvement in synaptic plasticity and memory. Finally, several modeling studies captured the implications of such findings for many brain functions. The ANLS model now represents a useful, experimentally based framework to better understand the coupling between neuronal activity and energetics as it relates to neuronal plasticity, neurodegeneration, and functional brain imaging.",
"Mutations in the amyloid precursor protein (APP) gene cause early-onset familial Alzheimer disease (AD) by affecting the formation of the amyloid beta (A beta) peptide, the major constituent of AD plaques. We expressed human APP751 containing these mutations in the brains of transgenic mice. Two transgenic mouse lines develop pathological features reminiscent of AD. The degree of pathology depends on expression levels and specific mutations. A 2-fold overexpression of human APP with the Swedish double mutation at positions 670/671 combined with the V717I mutation causes A beta deposition in neocortex and hippocampus of 18-month-old transgenic mice. The deposits are mostly of the diffuse type; however, some congophilic plaques can be detected. In mice with 7-fold overexpression of human APP harboring the Swedish mutation alone, typical plaques appear at 6 months, which increase with age and are Congo Red-positive at first detection. These congophilic plaques are accompanied by neuritic changes and dystrophic cholinergic fibers. Furthermore, inflammatory processes indicated by a massive glial reaction are apparent. Most notably, plaques are immunoreactive for hyperphosphorylated tau, reminiscent of early tau pathology. The immunoreactivity is exclusively found in congophilic senile plaques of both lines. In the higher expressing line, elevated tau phosphorylation can be demonstrated biochemically in 6-month-old animals and increases with age. These mice resemble major features of AD pathology and suggest a central role of A beta in the pathogenesis of the disease."
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is corticosteroid resistant to sepsis?
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Corticosteroids affect variably survival in sepsis trials, suggesting heterogeneity in patients' response to corticosteroids. The RECORDS (Rapid rEcognition of COrticosteRoiD resistant or sensitive Sepsis) trial aimed at defining endotypes associated with adults with sepsis responsiveness to corticosteroids.
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"The survival benefit of corticosteroids in septic shock remains uncertain. To estimate the individual treatment effect (ITE) of corticosteroids in adults with septic shock in intensive care units using machine learning and to evaluate the net benefit of corticosteroids when the decision to treat is based on the individual estimated absolute treatment effect. This cohort study used individual patient data from 4 trials on steroid supplementation in adults with septic shock as a training cohort to model the ITE using an ensemble machine learning approach. Data from a double-blinded, placebo-controlled randomized clinical trial comparing hydrocortisone with placebo were used for external validation. Data analysis was conducted from September 2019 to February 2020. Intravenous hydrocortisone 50 mg dose every 6 hours for 5 to 7 days with or without enteral 50 μg of fludrocortisone daily for 7 days. The control was either the placebo or usual care. All-cause 90-day mortality. A total of 2548 participants were included in the development cohort, with median (interquartile range [IQR]) age of 66 (55-76) years and 1656 (65.0%) men. The median (IQR) Simplified Acute Physiology Score (SAPS II) was 55 [42-69], and median (IQR) Sepsis-related Organ Failure Assessment score on day 1 was 11 (9-13). The crude pooled relative risk (RR) of death at 90 days was 0.89 (95% CI, 0.83 to 0.96) in favor of corticosteroids. According to the optimal individual model, the estimated median absolute risk reduction was of 2.90% (95% CI, 2.79% to 3.01%). In the external validation cohort of 75 patients, the area under the curve of the optimal individual model was 0.77 (95% CI, 0.59 to 0.92). For any number willing to treat (NWT; defined as the acceptable number of people to treat to avoid 1 additional outcome considering the risk of harm associated with the treatment) less than 25, the net benefit of treating all patients vs treating nobody was negative. When the NWT was 25, the net benefit was 0.01 for the treat all with hydrocortisone strategy, -0.01 for treat all with hydrocortisone and fludrocortisone strategy, 0.06 for the treat by SAPS II strategy, and 0.31 for the treat by optimal individual model strategy. The net benefit of the SAPS II and the optimal individual model treatment strategies converged to zero for a smaller number willing to treat, but the individual model was consistently superior than model based on the SAPS II score. These findings suggest that an individualized treatment strategy to decide which patient with septic shock to treat with corticosteroids yielded positive net benefit regardless of potential corticosteroid-associated side effects.",
"Adaptive clinical trials have been increasingly commonly employed to select a potential target population for one trial without conducting trials separately. Such enrichment designs typically consist of two or three stages, where the first stage serves as a screening process for selecting a specific subpopulation. We propose a Bayesian design for randomized clinical trials with a binary outcome that focuses on restricting the inclusion to a subset of patients who are likely to benefit the most from the treatment during trial accrual. Several Bayesian measures of efficacy and treatment-by-subset interactions were used to dictate the enrichment, either based on Gail and Simon's or Millen's criteria. A simulation study was used to assess the performance of our design. The method is exemplified in a real randomized clinical trial conducted in patients with respiratory failure that failed to show any benefit of high flow oxygen supply compared with standard oxygen. The use of the enrichment rules allowed the detection of the existence of a treatment-by-subset interaction more rapidly compared with Gail and Simon's criteria, with decreasing proportions of enrollment in the whole sample, and the proportions of enrichment lower, in the presence of interaction based on Millen's criteria. In the real dataset, this may have allowed the detection of the potential interest of high flow oxygen in patients with a SOFA neurological score ≥ 1. Enrichment designs that handle the uncertainty in treatment efficacy by focusing on the target population offer a promising balance for trial efficiency and ease of interpretation.",
"Effective targeted therapy for sepsis requires an understanding of the heterogeneity in the individual host response to infection. We investigated this heterogeneity by defining interindividual variation in the transcriptome of patients with sepsis and related this to outcome and genetic diversity. We assayed peripheral blood leucocyte global gene expression for a prospective discovery cohort of 265 adult patients admitted to UK intensive care units with sepsis due to community-acquired pneumonia and evidence of organ dysfunction. We then validated our findings in a replication cohort consisting of a further 106 patients. We mapped genomic determinants of variation in gene transcription between patients as expression quantitative trait loci (eQTL). We discovered that following admission to intensive care, transcriptomic analysis of peripheral blood leucocytes defines two distinct sepsis response signatures (SRS1 and SRS2). The presence of SRS1 (detected in 108 [41%] patients in discovery cohort) identifies individuals with an immunosuppressed phenotype that included features of endotoxin tolerance, T-cell exhaustion, and downregulation of human leucocyte antigen (HLA) class II. SRS1 was associated with higher 14 day mortality than was SRS2 (discovery cohort hazard ratio (HR) 2·4, 95% CI 1·3-4·5, p=0·005; validation cohort HR 2·8, 95% CI 1·5-5·1, p=0·0007). We found that a predictive set of seven genes enabled the classification of patients as SRS1 or SRS2. We identified cis-acting and trans-acting eQTL for key immune and metabolic response genes and sepsis response networks. Sepsis eQTL were enriched in endotoxin-induced epigenetic marks and modulated the individual host response to sepsis, including effects specific to SRS group. We identified regulatory genetic variants involving key mediators of gene networks implicated in the hypoxic response and the switch to glycolysis that occurs in sepsis, including HIF1α and mTOR, and mediators of endotoxin tolerance, T-cell activation, and viral defence. Our integrated genomics approach advances understanding of heterogeneity in sepsis by defining subgroups of patients with different immune response states and prognoses, as well as revealing the role of underlying genetic variation. Our findings provide new insights into the pathogenesis of sepsis and create opportunities for a precision medicine approach to enable targeted therapeutic intervention to improve sepsis outcomes. European Commission, Medical Research Council (UK), and the Wellcome Trust.",
"The combination of gene expression profiling with linkage analysis has become a powerful paradigm for mapping gene expression quantitative trait loci (eQTL). To date, most studies have searched for eQTL by analyzing gene expression traits one at a time. As thousands of expression traits are typically analyzed, this can reduce power because of the need to correct for the number of hypothesis tests performed. In addition, gene expression traits exhibit a complex correlation structure, which is ignored when analyzing traits individually. To address these issues, we applied two different multivariate dimension reduction techniques, the Singular Value Decomposition (SVD) and Independent Component Analysis (ICA) to gene expression traits derived from a cross between two strains of Saccharomyces cerevisiae. Both methods decompose the data into a set of meta-traits, which are linear combinations of all the expression traits. The meta-traits were enriched for several Gene Ontology categories including metabolic pathways, stress response, RNA processing, ion transport, retro-transposition and telomeric maintenance. Genome-wide linkage analysis was performed on the top 20 meta-traits from both techniques. In total, 21 eQTL were found, of which 11 are novel. Interestingly, both cis and trans-linkages to the meta-traits were observed. These results demonstrate that dimension reduction methods are a useful and complementary approach for probing the genetic architecture of gene expression variation."
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Sex Differences in Musculoskeletal Pain Disorders
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Musculoskeletal (MSK) pain disorders are some of the most prevalent and disabling chronic pain conditions worldwide. These chronic conditions have a considerable impact on the quality of life of individuals, families, communities, and healthcare systems. Unfortunately, the burden of MSK pain disorders does not fall equally across the sexes. Females consistently demonstrate more prevalent and severe clinical presentations of MSK disorders, and this disparity increases in magnitude with age. The aim of the present article is to review recent studies that have examined sex differences between males and females in four of the most common MSK pain disorders: neck pain, low back pain, osteoarthritis, and rheumatoid arthritis.
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[
"Globally, chronic low back pain (CLBP) is the leading cause of disability associated with economic costs. However, it has received little attention in low-and-middle-income countries. This study estimated the prevalence and risk factors of CLBP among adults presenting at selected hospitals in KwaZulu-Natal. This cross-sectional study was conducted among adults aged ≥18 years who attended the selected hospitals in KwaZulu-Natal during the study period. A self-administered questionnaire was used to collect data on socio-demographic, work-related factors, and information about CLBP. The SPSS version 24.0 (IBM SPSS Inc) was used for data analysis. Descriptive statistics were used for demographic characteristics of participants. CLBP risk factors were assessed using multivariate logistic regression analysis. A p-value of ≤0.05 was deemed statistically significant. A total of 678 adults participated in this study. The overall prevalence of CLBP was 18.1% (95% CI: 15.3 - 21.3) with females having a higher prevalence than males, 19.8% (95% CI: 16.0 - 24.1) and 15.85% (95% CI: 11.8 - 20.6), respectively. Using multivariate regression analysis, the following risk factors were identified: overweight (aOR: 3.7, 95% CI: 1.1 - 12.3, p = 0.032), no formal education (aOR: 6.1, 95% CI: 2.1 - 18.1, p = 0.001), lack of regular physical exercises (aOR: 2.2, 95% CI: 1.0 - 4.8, p = 0.044), smoking 1 to 10 (aOR: 4.5, 95% CI: 2.0 - 10.2, p < 0.001) and more than 11 cigarettes per day (aOR: 25.3, 95% CI: 10.4 - 61.2, p < 0.001), occasional and frequent consumption of alcohol, aOR: 2.5, 95% CI: 1.1 - 5.9, p < 0.001 and aOR: 11.3, 95% CI: 4.9 - 25.8, p < 0.001, respectively, a sedentary lifestyle (aOR: 31.8, 95% CI: 11.2 - 90.2, p < 0.001), manual work (aOR: 26.2, 95% CI: 10.1 - 68.4, p < 0.001) and a stooped sitting posture (aOR: 6.0, 95% CI: 2.0 - 17.6, p = 0.001). This study concluded that the prevalence of CLBP in KwaZulu-Natal is higher than in other regions, and that it is predicted by a lack of formal education, overweight, lack of regular physical exercises, smoking, alcohol consumption, sedentary lifestyle, manual work, and a stooped posture.",
"There are suggestions that the relationship between inflammation and pain in osteoarthritis (OA) may differ by sex, yet studies have been limited. We investigated whether the relationship between knee-specific OA pain and systemic inflammatory markers differs by sex. 196 patients scheduled for knee arthroplasty for OA were included. Questionnaires were completed and blood samples drawn pre-surgery. Questionnaire data: knee pain (WOMAC), sex, age, height, weight, comorbidities, depressive symptoms, and symptomatic joint count. Systemic inflammatory markers (cytokines IL-6, IL-8, IL-10, IL-1β and TNF-α) were measured by multiplex ELISA. A series of regression models with interaction terms between sex and ln-transformed inflammatory markers were estimated with pain score as the outcome. The adjusted relationship between pain and inflammatory markers, by sex, were presented graphically. Mean age was 64 years (range 43-89); females comprised 58.7% of the sample. In adjusted analyses, similar relationships between knee pain and lnIL-10 (negative: β = -1.28, 95%CI (-1.97, -0.58)) and lnTNF-α (positive: β = 0.92, 95%CI (0.11, 1.76)) were found for females and males. In contrast, relationships between knee pain and lnIL-1β, lnIL-6 and lnIL-8 differed in direction for females and males. Specifically, for lnIL-1β and lnIL-8 they were positive for males, negative for females. The opposite was found with lnIL-6, negative for males, positive for females. These findings provide some evidence of sex-specific relationships between individual inflammatory markers and knee OA pain. They expose a need for further exploration of sex-differences in this context, with potential future implications for treatment or drug development in OA.",
"A cross-sectional study. To clarify the prevalence of chronic nonspecific low back pain (CNSLBP) and its associated factors among middle-aged and elderly Japanese individuals using data from a musculoskeletal examination conducted in general Japanese populations. Most studies evaluating low back pain-associated factors have been conducted in Western countries, but they have not always evaluated CNSLBP. We obtained data on 213 subjects aged >50 years who responded to a survey regarding age, gender, body mass index, lifestyle-related diseases (diabetes mellitus, hypertension, and hyperlipidemia), glucocorticoid use, smoking and alcohol-drinking habits, labor intensity, and chronic low back pain (CLBP) and underwent screening for lumbar spinal stenosis, evaluation for quality of life (QOL), and evaluation for specific spinal pathology via thoracolumbar spine X-rays. We investigated the prevalence of CNSLBP and association between CNSLBP and measured variables. The prevalence of CNSLBP and chronic specific low back pain (CSLBP) was 15.4% and 9.3%, respectively. Among the subjects with CLBP, 62.2% had CNSLBP. In age-adjusted logistic models, smoking habits (p=0.049, odds ratio [OR]=2.594), low back pain (p<0.001, OR=0.974), lumbar function (p=0.001, OR=0.967), and social function (p=0.023, OR=0.976) in the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were significantly associated with CNSLBP, whereas EQ-5D utility score (p=0.024, OR=0.068), low back pain (p=0.007, OR=0.981), lumbar function (p=0.001, OR=0.963), walking ability (p=0.001, OR=0.968), and social function (p=0.002, OR=0.966) in JOABPEQ were significantly associated with CSLBP. CNSLBP among middle-aged and elderly individuals was associated with smoking habits and decreased QOL; however, CSLBP was considered to be more multilaterally associated decreased QOL.",
"Many risk factors for osteoarthritis (OA) have been noted, while gender/sex differences have been understated. The work aimed to systematically review literature investigating as primary aim the relationship between gender/sex related discriminants and OA. The search was performed in PubMed, Science Direct and Web of Knowledge in the last 10 years. Inclusion criteria were limited to clinical studies of patients affected by OA in any joints, analyzing as primary aim gender/sex differences. Exclusion criteria were review articles, in vitro, in vivo and ex vivo studies, case series studies and papers in which gender/sex differences were adjusted as confounding variable. Of the 120 records screened, 42 studies were included. Different clinical outcomes were analyzed: morphometric differences, followed by kinematics, pain, functional outcomes after arthroplasty and health care needs of patients. Women appear to use more health care, have higher OA prevalence, clinical pain and inflammation, decreased cartilage volume, physical difficulty, and smaller joint parameters and dimensions, as compared to men. No in-depth studies or mechanistic studies analyzing biomarker differential expressions, molecular pathways and omic profiles were found that might drive preclinical and clinical research towards sex-/gender-oriented protocols.",
"The phenomenon of female preponderance in depression has been well-reported, which has been challenged by higher rates of suicide and addictive behaviors in males, and a longer life-span in females. We thus propose an alternative hypothesis \"Gender differences in self-reporting symptom of depression,\" suggesting mild-moderate depression tends to be reported more often by females, and severe depression and suicide tend to be reported more often by males. Potential mechanisms that account for this difference may include three aspects: covariation between estrogen levels and the incidence peak of female depression, gender differences in coping style (e.g., comparative emotional inexpressiveness and non-help-seeking in males), and gender differences in symptom phenotypes (e.g., atypical symptoms in male depression). Our newly presented hypothesis implied the overlooked under-diagnosis and under-treatment of depression in males. For effective diagnoses and timely treatment of male depression, it is critical to incorporate symptoms of depression in males into the relevant diagnostic criteria, encourage males to express negative emotions, and increase awareness of suicidal behavior in males.",
"Development of a gender sensitive depression screening (GSDS) to better identify depression in men. The scale was evaluated in a sample of 1020 German university students. To prove the external validity with respect to depressivity and normative masculinity, the shortform of the General Depression Scale and the German version of the Male Role Norms Scale were used. Exploratory factor analyses resulted in a six-factor solution. Factors referring to stress perception, aggressiveness, depressive symptoms and emotional suppression turned out as equally relevant. Sensitivity (86 %) and specifity (78 %) indicate sufficient discriminant validity. Compared to the General Depression Scale, the GSDS is able to identify more men at risk for depression. The GSDS-26 is a preliminary validated multidimensional scale for better identifying depression in men and may be suitable for routine use after further validation.",
"The prevalence of depression may be affected by changes in psychiatric practices and the availability of online mental health information in the past two decades. This study aimed to evaluate the aggregate prevalence of depression in communities from different countries between 1994 and 2014 and to explore the variations in prevalence stratified by geographical, methodological and socio-economic factors. A total of 90 studies were identified and met the inclusion criteria (n = 1,112,573 adults) with 68 studies on single point prevalence, 9 studies on one-year prevalence, and 13 studies on lifetime prevalence of depression. A random-effects model meta-analysis that was performed to calculate the aggregate point, one-year and lifetime prevalence of depression calculated prevalences of 12.9%, 7.2% and 10.8% respectively. Point prevalence of depression was significantly higher in women (14.4%), countries with a medium human development index (HDI) (29.2%), studies published from 2004 to 2014 (15.4%) and when using self-reporting instruments (17.3%) to assess depression. Heterogeneity was identified by meta-regression and subgroup analysis, and response rate, percentage of women and year of publication, respectively, were determined contribute to depression prevalence. This meta-analysis allows benchmarking of the prevalence of depression during the era when online health information emerged, facilitating future comparisons."
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Aortic pressure decreases immediately after annular contact by a self-expanding transcatheter heart valve
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During the transcatheter aortic valve replacement (TAVR) procedure, hemodynamic measurements can be used to evaluate transcatheter heart valve (THV) performance. We hypothesized that the occurrence of a significant decrease in invasive aortic pressure immediately after annular contact by a self-expanding THV indicates effective annular sealing. This phenomenon could thus be used as a marker for the occurrence of paravalvular leak (PVL).
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"Acute deterioration in renal function is a recognized complication after coronary angiography and intervention. The goal of this study was to determine the impact on acute and long-term mortality and morbidity of contrast-induced deterioration in renal function after coronary intervention. We studied 439 consecutive patients who had a baseline serum creatinine > or = 1.8 mg/dL (159.1 /micromol/L) who were not on dialysis who underwent percutaneous coronary intervention in a tertiary referral center. All patients were hydrated before the procedure, and almost all received ioxaglate meglumine; 161 (37%) patients had an increase in serum creatinine > or = 25% within 48 h or required dialysis and 278 (63%) did not. In-hospital and out-of-hospital clinical events (death, myocardial infarction, repeat revascularization) were assessed by source documentation. Independent predictors of renal function deterioration were left ventricular ejection fraction (p = 0.02) and contrast volume (p = 0.01). In-hospital mortality was 14.9% for patients with further renal function deterioration versus 4.9% for patients with no creatinine increase (p = 0.001); other complications were also more frequent. Thirty-one patients required hemodialysis; their in-hospital mortality was 22.6%. Four patients were discharged on chronic dialysis. The cumulative one-year mortality was 45.2% for those who required dialysis, 35.4% for those who did not require dialysis and 19.4% for patients with no creatinine increase (p = 0.001). Independent predictors of one-year mortality were creatinine elevation (p = 0.0001), age (p = 0.03) and vein graft lesion location (p = 0.08). For patients with pre-existing renal insufficiency, renal function deterioration after coronary intervention is a marker for poor outcomes. This is especially true for patients who require dialysis.",
"The definition, classification, and choice of management of acute renal failure (ARF) in the setting of the intensive care unit (ICU) remain subjects of debate. To improve our approach to ARF in the ICU setting, we retrospectively applied the new classification of ARF put forward by the Acute Dialysis Quality Initiative group, RIFLE (acronym indicating Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure), to evaluate its sensitivity and specificity to predict renal and patient outcomes. RIFLE classification was applied to 183 patients with ARF admitted to the ICU (2002 to 2003) at the Northern General Hospital, Sheffield, UK. Patients were divided into 4 groups according to percentage of decrease in glomerular filtration rate from baseline. The risk group included 60 patients; injury group, 56 patients; failure group, 43 patients; and control group, 24 patients. Demographic, biochemical, hematologic, clinical, and long-term health status were studied and compared in the 4 groups. An attempt was made to evaluate, by means of logistic regression analysis and receiver operator characteristic curve analysis, the predictive value of RIFLE classification for mortality in the ICU. The failure group showed the worst parameters with regard to Acute Physiology and Chronic Health Evaluation (APACHE) II score, pH, lowest and highest mean arterial pressures, and Glasgow Coma Scale (P < 0.001). Mortality rate in the ICU (1 month) was significantly greater in the failure group compared with all groups (32 of 43 patients [74.4%]; P < 0.001) and, again, 6-month mortality rate (37 of 43 patients [86%]; P < 0.001). Receiver operator characteristic curve analysis showed that Simplified Acute Physiology Score (SAPS) II was more sensitive than APACHE II score for prediction of patient death in the risk and injury groups compared with the failure and control groups (risk group: SAPS II, 0.8 +/- 0.06; P < 0.001; APACHE II, 0.63 +/- 0.07; P = 0.14; injury group: SAPS II, 0.76 +/- 0.08; P < 0.001; APACHE II, 0.72 +/- 0.07; P = 0.006). RIFLE classification can improve the ability of such older and established ICU scoring systems as APACHE II and SAPS II in predicting outcome of ICU patients with ARF.",
"Echocardiography may underestimate the degree of paravalvular aortic regurgitation (AR) after transcatheter aortic valve implantation (TAVI) using the Medtronic CoreValve bioprosthesis due to inherent limitations of ultrasound imaging in the evaluation of implanted cardiac prostheses. We aimed to evaluate the accuracy and feasibility of cardiovascular magnetic resonance (CMR) in quantifying regurgitant volume (RV) and regurgitant fraction (RF) in patients treated with this bioprosthesis for severe calcific aortic stenosis, and to compare the results with echocardiography and aortography. This study included 16 patients with a mean age of 78.7 years (eight women, eight men) who underwent successful TAVI using Medtronic CoreValve bioprosthesis. AR was evaluated by CMR, echocardiography, and aortography. Angiography was performed immediately after valve implantation. CMR and echocardiography were performed four weeks after valve implantation. There was a highly significant correlation between the CMR-derived and the angiographically-estimated degree of AR (r=0.86, p<0.001). On the other hand, there was only a limited correlation between CMR and echocardiography (r=0.374, p=0.15) as well as angiography and echocardiography (r=0.319, p=0.23) regarding the degree of AR. The weighted kappa for agreement between echocardiography and angiography was 0.14, for agreement between echocardiography and CMR 0.20, and for agreement between angiography and CMR 0.72. Echocardiography underestimated AR by one degree compared to CMR in five patients and 2 degrees in two patients; in six of these, the degree of AR obtained by CMR was similar to angiography. In patients undergoing TAVI, comparisons between purely quantitative measurements of AR by CMR and qualitative assessment by angiography showed better correlations than those with echocardiography. This suggests that echocardiography may underestimate the degree of AR and CMR in these circumstances has a great potential in reliably measuring the severity of AR in a quantitative manner.",
"To propose standardized consensus definitions for important clinical endpoints in transcatheter aortic valve implantation (TAVI), investigations in an effort to improve the quality of clinical research and to enable meaningful comparisons between clinical trials. To make these consensus definitions accessible to all stakeholders in TAVI clinical research through a peer reviewed publication, on behalf of the public health. Transcatheter aortic valve implantation may provide a worthwhile less invasive treatment in many patients with severe aortic stenosis and since its introduction to the medical community in 2002, there has been an explosive growth in procedures. The integration of TAVI into daily clinical practice should be guided by academic activities, which requires a harmonized and structured process for data collection, interpretation, and reporting during well-conducted clinical trials. The Valve Academic Research Consortium established an independent collaboration between Academic Research organizations and specialty societies (cardiology and cardiac surgery) in the USA and Europe. Two meetings, in San Francisco, California (September 2009) and in Amsterdam, the Netherlands (December 2009), including key physician experts, and representatives from the US Food and Drug Administration (FDA) and device manufacturers, were focused on creating consistent endpoint definitions and consensus recommendations for implementation in TAVI clinical research programs. Important considerations in developing endpoint definitions included (i) respect for the historical legacy of surgical valve guidelines; (ii) identification of pathophysiological mechanisms associated with clinical events; (iii) emphasis on clinical relevance. Consensus criteria were developed for the following endpoints: mortality, myocardial infarction, stroke, bleeding, acute kidney injury, vascular complications, and prosthetic valve performance. Composite endpoints for TAVI safety and effectiveness were also recommended. Although consensus criteria will invariably include certain arbitrary features, an organized multidisciplinary process to develop specific definitions for TAVI clinical research should provide consistency across studies that can facilitate the evaluation of this new important catheter-based therapy. The broadly based consensus endpoint definitions described in this document may be useful for regulatory and clinical trial purposes.",
"The optimal clinical protocol to detect fractures of transcatheter aortic valves is unknown. To the best of our knowledge, there are no published reports describing stent or frame fractures following transcatheter aortic valve implantation. The purpose of this study is two-fold: (1) to determine the optimal fluoroscopic protocol to identify potential fractures of the Medtronic CoreValve frame; and (2) to implement this protocol in the analysis of the fluoroscopic films of patients implanted with the CoreValve device with 1-year minimum follow-up. Considering the resolution of fluoroscopy (approximately 0.2 mm), we used a 0.2 mm diamond-cutter to create a single fracture in a single strut of two CoreValve frames. An intact CoreValve prosthesis was used as control. These prostheses were subsequently implanted in post-mortem heart specimens. A protocol involving still frames and rotational (left-right and cranial-caudal) fluoroscopic imaging was then applied to the heart specimens. The experimentally induced fractures were detectable on the rotational cine runs (left-right and cranial-caudal); in some of the fixed acquisition sequences, however, the fractures were undetectable. The fluoroscopic protocol was retrospectively applied to the films of 58 patients who underwent implantation with the CoreValve System between October 2005 and August 2008 and had at least 1-year follow-up. The mean and median follow-up times were 22 months and 24 months, respectively (range 12 to 36 months). Rotational cine films (only left-right lateral) were available in 39 patients (60%). No frame fractures of the CoreValve frame were identified. Rotational cine runs in the left-right and cranial-caudal directions should be mandatory in the clinical assessment of the structural integrity of the CoreValve frame. No frame fractures were identified in 58 patients implanted with the Medtronic CoreValve device with 2-year mean follow-up.",
"Conducting system defects are common in patients with aortic valve disease. Aortic valve replacement may result in further conduction abnormalities and necessitate permanent pacemaker implantation (PPM). We sought to identify the contemporary incidence and predictors for early postoperative PPM in patients undergoing isolated aortic valve replacement. Data were analyzed from 354 consecutive patients undergoing isolated aortic valve replacement at a referral cardiac unit during a 30-month period; data were unavailable on 4 patients and a further 8 had undergone preoperative PPM. Results for the remaining 342 patients (97%; mean age, 67 +/- 14 years), of whom 212 were males, are presented. The major indications for aortic valve replacement were valvular stenosis (n = 224), regurgitation (n = 70), or infective endocarditis (n = 25). Preoperative conducting system disease was present in 26% of patients. In-hospital mortality was 1.8% (6 of 342 patients). Postoperatively 29 patients (8.5%) required early PPM, of which 26 were during the index admission. Patients with preoperative conducting system disease (16% versus 6%; p = 0.004) and valvular regurgitation (16% versus 7%; p = 0.01) were more likely to require PPM as opposed to those without. Preoperative conducting system disease was the only independent predictor of PPM (p < 0.01); the relative risk of PPM requirement in this group was 2.88 (95% confidence interval, 1.31 to 6.33). Permanent pacemaker implantation requirement after aortic valve replacement is a common occurrence, and should be discussed as part of the preoperative consent process. Preexisting conducting disease and preoperative aortic regurgitation were predictors of PPM requirement.",
"Aim: We investigated the outcomes of transcatheter (TAVR) and surgical aortic valve replacement (SAVR) in Finland during the last decade. Methods: The nationwide FinnValve registry included data from 6463 patients who underwent TAVR or SAVR with a bioprosthesis for aortic stenosis from 2008 to 2017. Results: The annual number of treated patients increased three-fold during the study period. Thirty-day mortality declined from 4.8% to 1.2% for TAVR (p = .011) and from 4.1% to 1.8% for SAVR (p = .048). Two-year survival improved from 71.4% to 83.9% for TAVR (p < .001) and from 87.2% to 91.6% for SAVR (p = .006). During the study period, a significant reduction in moderate-to-severe paravalvular regurgitation was observed among TAVR patients and a reduction of the rate of acute kidney injury was observed among both SAVR and TAVR patients. Similarly, the rate of red blood cell transfusion and severe bleeding decreased significantly among SAVR and TAVR patients. Hospital stay declined from 10.4 ± 8.4 to 3.7 ± 3.4 days after TAVR (p < .001) and from 9.0 ± 5.9 to 7.8 ± 5.1 days after SAVR (p < .001). Conclusions: In Finland, the introduction of TAVR has led to an increase in the invasive treatment of severe aortic stenosis, which was accompanied by improved early outcomes after both SAVR and TAVR. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT03385915 Key Messages This study demonstrated that the introduction of transcatheter aortic valve replacement has led to its widespread use as an invasive treatment for severe aortic stenosis. Early and 2-year survival after transcatheter and surgical aortic valve replacement has improved during past decade. Transcatheter aortic valve replacement has fulfilled its previously unmet clinical needs and has surpassed surgical aortic valve replacement as the most common invasive treatment for aortic stenosis.",
"We sought to examine the short- and long-term outcomes of blood transfusion in patients presenting with ST-segment elevation myocardial infarction (STEMI). The short- and long-term consequences of blood transfusion in anemic patients with recent STEMI remain controversial. We evaluated 30-day, 6-month, and 1-year all-cause mortality among 4,131 STEMI patients enrolled in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial. Patients were categorized according to whether they received a blood transfusion during hospitalization. Cox proportional hazards survival models with transfusion as a time-dependent covariate were conducted for the whole and for the propensity-matched groups. Additionally, a series of sensitivity analyses assessed the magnitude of hidden bias that would need to be present to explain the associations actually observed. Death at 30 days (13.7% vs. 5.5%), 6 months (19.7% vs. 6.9%), and 1 year (21.8% vs. 8.7%) was significantly higher for transfused patients than for nontransfused patients, respectively. After adjusting for over 25 baseline characteristics, nadir hemoglobin, and propensity score for transfusion, and using transfusion as a time-dependent covariate, transfusion remained significantly associated with increased risk of mortality at 30 days (hazard ratio [HR]: 3.89, 95% confidence interval [CI]: 2.66 to 5.68, p < 0.001), 6 months (HR: 3.63, 95% CI: 2.67 to 4.95, p < 0.001), and 1 year (HR: 3.03, 95% CI: 2.25 to 4.08, p < 0.001). Similar results were observed in the propensity-matched patients. Blood transfusion is associated with increased short- and long-term mortality in the setting of STEMI.",
"Prosthetic heart valve thrombosis (PVT) is a rare but potentially life-threatening complication of heart valve replacement. An effective, quick, and easy diagnostic method is highly desirable. We evaluated the diagnostic efficacy of cine-fluoroscopy (CF), transthoracic (TTE), and transesophageal (TEE) echocardiography in 82 consecutive patients with mechanical valves and suspected PVT. Criteria for PVT were: leaflet(s) motion restriction at CF, increased Doppler gradients at TTE, and evidence of thrombi at TEE. Patients were divided in 4 groups (A, B, C, and D) according to results of CF and TTE. Group A was composed of 24 patients with positive CF and TTE. Thrombi were detected by TEE in all cases, suggesting that when both are positive, CF and TTE correctly identified PVT in all patients so that TEE may be deferred. Group B was composed of 12 patients with positive CF and negative TTE; TEE showed PVT in 4 patients (33%). These patients had very slight leaflet motion restriction as in the case of initial PVT. This suggests that CF compared with Doppler may identify patients with \"hemodynamically significant\" PVT. The remaining 8 patients in this group had monocuspid prostheses with negative TEE, suggesting that abnormal leaflet motion at CF may be due to functional changes. Therefore, TEE should always be performed in case of monocuspid prostheses with isolated CF abnormalities. Group C was composed of 18 asymptomatic patients with small-sized aortic prostheses and very high Doppler gradients on routine TTE. CF showed normal leaflet motion and TEE ruled out PVT in all cases outlining the diagnostic role of CF in this particular subset. Finally, group D was composed of 28 patients with negative CF and TTE. TEE did not show thrombi in 24 of 28 patients (86%), confirming that, when both yield negative results, CF and TTE are reliable methods to rule out valve thrombosis in most cases. However, in 4 of 28 patients (14%) TEE showed \"nonobstructive\" prosthetic thrombosis: these patients had mitral prostheses, chronic atrial fibrillation, and 3 of 4 had systemic embolisms. Thus, TEE should be performed in selected patients despite negative CF and TTE results. Sensitivity, specificity, and positive and negative predictive values were 87%, 78%, 80%, and 91% for CF and 75%, 64%, 57%, and 78% for TTE, respectively. CF and TTE correctly identified PVT in 70 of 82 patients (85%). TEE was actually required in 15% of the cases. Thus, CF and TTE are quick, effective, and complementary diagnostic tools to diagnose PVT in most patients. TEE still remains the gold standard technique in selected cases."
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[Pulmonary arterial hypertension and pregnancy].
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Pulmonary arterial hypertension (PAH) is defined as an elevated mean pulmonary artery pressure (mPAP) of >20 mmHg together with a pulmonary arterial wedge pressure (PAWP) of ≤15 mmHg and pulmonary vascular resistance (PVR) of>2 Wood units (WU). Although the total mortality of pregnant women with PAH has decreased significantly in recent years and is reported to be around 12% in some databases, total mortality is still at an unacceptably high percentage. Moreover, some subgroups, such as patients with Eisenmenger's syndrome, have a particularly high mortality rate of up to 36%. Pregnancy in patients with PAH is contraindicated; its appearance is an indication for a planned termination. Education of patients with PAH, including counseling on effective contraception, is essential. During pregnancy, blood volume, heart rate, and cardiac output increase, while PVR and systemic vascular resistance decrease. The hemostatic balance is shifted towards hypercoagulability. Among PAH-specific drugs, the use of inhaled or intravenous prostacyclins, phosphodiesterase inhibitors, and calcium channel blockers (in patients with preserved vasoreactivity) is acceptable. Endothelin receptor antagonists and riociguat are contraindicated. Childbirth can take place through either vaginal delivery or caesarean section; similarly, neuraxial and general anesthesia have proven indications. In a situation where all pharmacological options have been used in pregnant or postpartum patients in a serious condition, veno-arterial ECMO is a useful therapeutic option. For PAH patients who want to become mothers, an option that does not endanger their lives is adoption.
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[
"The U. S. Selected Practice Recommendations for Contraceptive Use 2013 (U.S. SPR), comprises recommendations that address a select group of common, yet sometimes controversial or complex, issues regarding initiation and use of specific contraceptive methods. These recommendations are a companion document to the previously published CDC recommendations U.S. Medical Eligibility Criteria for Contraceptive Use, 2010 (U.S. MEC). U.S. MEC describes who can use various methods of contraception, whereas this report describes how contraceptive methods can be used. CDC based these U.S. SPR guidelines on the global family planning guidance provided by the World Health Organization (WHO). Although many of the recommendations are the same as those provided by WHO, they have been adapted to be more specific to U.S. practices or have been modified because of new evidence. In addition, four new topics are addressed, including the effectiveness of female sterilization, extended use of combined hormonal methods and bleeding problems, starting regular contraception after use of emergency contraception, and determining when contraception is no longer needed. The recommendations in this report are intended to serve as a source of clinical guidance for health-care providers; health-care providers should always consider the individual clinical circumstances of each person seeking family planning services. This report is not intended to be a substitute for professional medical advice for individual patients. Persons should seek advice from their health-care providers when considering family planning options.",
"Introduction: Since pregnancy in women with pulmonary arterial hypertension (PAH) is associated with a high risk of morbidity and mortality, it is recommended that pregnancy should be avoided in PAH. However, some women with mild PAH may consider this recommendation as unsuitable. Unfortunately knowledge on pregnancy outcomes and best management of PAH during pregnancy is limited. Methods: Data from all women with PAH who were followed during pregnancy by a multidisciplinary team at a tertiary referral center for PAH and who delivered between 2004 and 2020 were retrospectively analyzed in a case series. PAH risk factor profiles including WHO functional class (WHO-FC), NT-pro-BNP, echocardiographic pulmonary arterial pressure (PAP) and right heart function were analyzed prior to, during and following pregnancy. Results: In seven pregnancies of five women with PAH (median age 29 (27; 31) years), there were no abortions or terminations. Five pregnancies were planned (all in WHO-FC I-II), two incidental (WHO-FC II, III). During pregnancy none of the women had complications or clinical worsening of PAH. After a median pregnancy duration of 37 1/7 weeks all gave birth to healthy babies by cesarean section in spinal anesthesia. During pregnancy, PAP tended to increase, whilst the course of WHO-FC and NT-pro-BNP were variable and no trend could be detected. Conclusion: Women with PAH with a low risk profile closely followed by a multidisciplinary team had a favorable course during and after pregnancy, resulting in successful deliveries of healthy newborns.",
"The cardiovascular effects of oxytocin in animal models and women undergoing Caesarean section include tachycardia, hypotension and decrease in cardiac output. These can be sufficient to cause significant compromise in high-risk patients. We aimed to find a simple way to decrease these risks whilst retaining the benefits of oxytocin in decreasing bleeding after delivery. Method. We recruited 30 women undergoing elective Caesarean section. They were randomly allocated to receive 5 u of oxytocin either as a bolus injection (bolus group) or an infusion over 5 min (infusion group). These women had their heart rate and intra-arterial blood pressure recorded every 5 s throughout the procedure. The haemodynamic data, along with the estimated blood loss, were compared between the groups. Marked cardiovascular changes occurred in the bolus group; the heart rate increased by 17 (10.7) beats min(-1) [mean (sd)] compared with 10 (9.7) beats min(-1) in the infusion group. The mean arterial pressure decreased by 27 (7.6) mm Hg in the bolus group compared with 8 (8.7) mm Hg in the infusion group. There were no differences in the estimated blood loss between the two groups. We recommend that bolus doses should be used with caution, and further studies should ascertain if oxytocin is equally effective in reducing blood loss when given at a slower rate.",
"Most small for gestational age pregnancies are unrecognised before birth, resulting in substantial avoidable perinatal mortality and morbidity. Our objective was to develop multivariable prediction models for small for gestational age combining clinical risk factors and biomarkers at 15±1 weeks' with ultrasound parameters at 20±1 weeks' gestation. Data from 5606 participants in the Screening for Pregnancy Endpoints (SCOPE) cohort study were divided into Training (n = 3735) and Validation datasets (n = 1871). The primary outcomes were All-SGA (small for gestational age with birthweight <10th customised centile), Normotensive-SGA (small for gestational age with a normotensive mother) and Hypertensive-SGA (small for gestational age with an hypertensive mother). The comparison group comprised women without the respective small for gestational age phenotype. Multivariable analysis was performed using stepwise logistic regression beginning with clinical variables, and subsequent additions of biomarker and then ultrasound (biometry and Doppler) variables. Model performance was assessed in Training and Validation datasets by calculating area under the curve. 633 (11.2%) infants were All-SGA, 465(8.2%) Normotensive-SGA and 168 (3%) Hypertensive-SGA. Area under the curve (95% Confidence Intervals) for All-SGA using 15±1 weeks' clinical variables, 15±1 weeks' clinical+ biomarker variables and clinical + biomarkers + biometry /Doppler at 20±1 weeks' were: 0.63 (0.59-0.67), 0.64 (0.60-0.68) and 0.69 (0.66-0.73) respectively in the Validation dataset; Normotensive-SGA results were similar: 0.61 (0.57-0.66), 0.61 (0.56-0.66) and 0.68 (0.64-0.73) with small increases in performance in the Training datasets. Area under the curve (95% Confidence Intervals) for Hypertensive-SGA were: 0.76 (0.70-0.82), 0.80 (0.75-0.86) and 0.84 (0.78-0.89) with minimal change in the Training datasets. Models for prediction of small for gestational age, which combine biomarkers, clinical and ultrasound data from a cohort of low-risk nulliparous women achieved modest performance. Incorporation of biomarkers into the models resulted in no improvement in performance of prediction of All-SGA and Normotensive-SGA but a small improvement in prediction of Hypertensive-SGA. Our models currently have insufficient reliability for application in clinical practice however, they have potential utility in two-staged screening tests which include third trimester biomarkers and or fetal biometry.",
"Despite advanced therapies, maternal mortality in women with pulmonary arterial hypertension (PAH) remains high in pregnancy and is especially high during the post-partum period. However, recent data indicates that morbidity and mortality during pregnancy and after birth have improved for PAH patients. The current European Society of Cardiology/European Respiratory Society guidelines recommend that women with PAH should not become pregnant. Therefore, the risks associated with pregnancy must be emphasised and counselling offered to women at the time of PAH diagnosis and to women with PAH who become pregnant. Early termination should be discussed. Women who choose to continue with their pregnancy should be treated at specialised pulmonary hypertension centres with experience in managing PAH during and after pregnancy.",
"The aim of this study was to assess the prevalence of fear of childbirth, and to find possible associations to selected sociodemographic factors and important life events. A secondary aim was to explore the relationship between these factors and pregnancy outcome. Questionnaire booklets were sent to 2680 women at 18 weeks of gestation, of whom 1452 women (54%) responded. The questionnaire included background factors (marital status, education, history of abuse, current pregnancy), W-DEQ (measurement of fear of childbirth), and STAI (measurement of subjective anxiety). Pregnancy outcome information was recorded. The prevalence of serious fear of childbirth (W-DEQ > 100) was 5.5%. The W-DEQ and STAI scores were positively correlated (r = 0.44, p < 0.001). Among the anxious women, a trend towards more frequent operative vaginal delivery (12.1% versus 6.9%, p = 0.07) was noted, but not for emergency cesarean section (10.6% versus 7.6%, p = 0.34). Women who reported being exposed to physical or sexual abuse in childhood had a higher W-DEQ score (71, SD 31 and 69, SD 27) than did the non-abused (61, SD 23, p < 0.01). Only half of women sexually or physically abused in childhood (54% and 57% respectively) had uncomplicated vaginal delivery at term versus 75% among non-abused (p < 0.001). The prevalence of serious fear of childbirth was 5.5%. Fear of childbirth was not associated with mode of delivery, whereas sexual or physical abuse in childhood influenced negatively mode of delivery.",
"To examine recent trends in Caesarean delivery rates as well as the indications for Caesarean delivery in Canada, excluding the provinces of Manitoba and Quebec. All deliveries (N = 1 807 388) recorded in the Canadian Institute for Health Information's Discharge Abstract Database for the years 1994/95 to 2000/01 were included in the study (all hospital deliveries in Canada except for those occurring in Manitoba and Quebec). Temporal trends and inter-provincial/territorial variations in Caesarean delivery rates were quantified, and the primary indications for Caesarean delivery during the study period were compared. The overall Caesarean delivery rate increased from 18.0% in 1994/95 to 22.1% in 2000/01. The primary Caesarean delivery rate increased from 12.7% to 16.3%, while the rate of vaginal birth after Caesarean decreased from 33.3% to 28.5% over the same period. Most of the increase in primary Caesarean deliveries was due to increases in Caesarean deliveries for dystocia, which increased from 6.9% in 1994/95 to 9.2% in 2000/01. The largest increase in repeat Caesarean deliveries was due to elective repeat Caesarean sections, which increased from 37.7% to 40.3%. Approximately 15% of the increase in overall Caesarean delivery rates was explained by increases in maternal age. The rate of vaginal deliveries following forceps rotation declined from 1.9% in 1994/95 to 1.3% in 2000/01. Most of the recent increase in Caesarean delivery rates in Canada was attributed to increases in primary Caesarean delivery for dystocia and elective repeat Caesarean deliveries.",
"Pulmonary hypertension during pregnancy is associated with considerable risks of maternal mortality and morbidity. Our systematic review of the literature on the use of targeted treatments for pulmonary arterial hypertension during pregnancy indicates a considerable decrease of mortality since a previous review in 1998 (16% v 38%), and a further non-significant decrease in mortality since the latest review in 2009 (16% v 25%). In addition to the use of targeted treatments, the timely institution of these treatments, and early planned delivery, may contribute to better outcome. Furthermore, research suggests that women with mild pulmonary hypertension or favourable functional class may have a better prognosis, but there is yet no proof of decreased mortality among these women. Despite an improved prognosis, pregnancy is contra-indicated in women with pulmonary hypertension and, when pregnancy occurs, termination should be considered. When pregnancy continues, management by a multidisciplinary team in a specialist centre is indicated.",
"To estimate the contribution of changes in maternal characteristics (namely, age, parity, prepregnancy weight, weight gain in pregnancy, smoking status) and obstetric practice (namely, labor induction, epidural anesthesia, delivery by an obstetrician, midpelvic forceps delivery) to recent increases in primary cesarean delivery rates. We studied all deliveries in Nova Scotia, Canada, between 1988 and 2000 after excluding women who had a previous cesarean delivery (n = 127,564). Logistic regression was used to study the effect of changes in maternal characteristics and obstetric practice on primary cesarean delivery rates. The effect of changes in midpelvic forceps delivery was examined through ecologic Poisson regression. Primary cesarean delivery rates increased from 13.4% of deliveries in 1988 to 17.5% in 2000. This was due to increases in cesarean deliveries for dystocia (14% increase), breech (24% increase), suspected fetal distress (21% increase), hypertension (47% increase), and miscellaneous indications (73% increase). Adjustment for maternal characteristics reduced the temporal increase in primary cesarean delivery rates between 1988-1991 and 1998-2000 from 21% (95% confidence interval [CI] 16%, 25%) to 2% (95% CI -2%, 7%). Additional adjustment for obstetric practice factors further reduced period effects. Midpelvic forceps delivery was significantly and negatively associated with primary cesarean delivery (P =.001). Recent increases in primary cesarean delivery rates are a consequence of changes in maternal characteristics. Obstetric practice, which has altered due to changes in maternal characteristics and concerns related to fetal and maternal safety, has also contributed to increases in primary cesarean delivery.",
"This study examined the quality of data for delivering mothers and their newborns (April 1, 1984 to March 31, 1995) recorded by the Canadian Institute for Health Information (CIHI). The number of illogical and out-of-range values in the CIHI data were quite few; the occurrence of maternal and infant diseases estimated from CIHI data was quite similar to that in the literature; and major medical/obstetric complications recorded in CIHI were, in general, good predictors of adverse pregnancy outcomes. The authors conclude that CIHI data contain some of the information pertinent to perinatal surveillance that may be used to monitor maternal and infant health and to assess intrapartum care and hospital resource utilization. To adequately monitor and analyze patterns of health determinants and outcomes in all pregnant women and their infants in Canada, additional data collection mechanisms are needed to cover all recognized pregnancies and to collect antenatal and postpartum information and more detailed information on intrapartum care."
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Conformation-biased mutants of adenosine A adenosine A receptor
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Understanding the roles of intermediate states in signaling is pivotal to unraveling the activation processes of G protein-coupled receptors (GPCRs). However, the field is still struggling to define these conformational states with sufficient resolution to study their individual functions. Here, we demonstrate the feasibility of enriching the populations of discrete states via conformation-biased mutants. These mutants adopt distinct distributions among five states that lie along the activation pathway of adenosine A
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[
"G protein-coupled receptors (GPCRs) form both the largest family of membrane proteins and drug targets, mediating the action of one-third of medicines. The GPCR database, GPCRdb serves >4 000 researchers every month and offers reference data, analysis of own or literature data, experiment design and dissemination of published datasets. Here, we describe new and updated GPCRdb resources with a particular focus on integration of sequence, structure and function. GPCRdb contains all human non-olfactory GPCRs (and >27 000 orthologs), G-proteins and arrestins. It includes over 2 000 drug and in-trial agents and nearly 200 000 ligands with activity and availability data. GPCRdb annotates all published GPCR structures (updated monthly), which are also offered in a refined version (with re-modeled missing/distorted regions and reverted mutations) and provides structure models of all human non-olfactory receptors in inactive, intermediate and active states. Mutagenesis data in the GPCRdb spans natural genetic variants, GPCR-G protein interfaces, ligand sites and thermostabilising mutations. A new sequence signature tool for identification of functional residue determinants has been added and two data driven tools to design ligand site mutations and constructs for structure determination have been updated extending their coverage of receptors and modifications. The GPCRdb is available at https://gpcrdb.org.",
"A 31 amino acid fragment of the extracellular N-terminus of the human G-protein coupled receptor for parathyroid hormone (PTH1R) has been structurally characterized by NMR and molecular dynamics simulations. The fragment PTH1R[168-198] includes residues 173-189, shown by photoaffinity cross-linking to be a contact domain with position 13 of parathyroid hormone (PTH). The structure of PTH1R[168-198], determined in a micellar solution of dodecylphosphocholine to mimic the membrane environment, consists of three alpha-helices, separated by a well-defined turn and a flexible region. The topological orientation of PTH1R[168-198] was determined from nitroxide-radical induced relaxation of NMR signals utilizing 5- and 16-doxylstearic acid. The C-terminal helix (residues 190-196), consisting of seven amino acids of the first transmembrane domain, is very hydrophobic and embedded in the lipid core. This helix is preceded by a well-defined turn, forming an approximate 90 degrees bend, placing the other helices (residues 169-176 and 180-189), both of which are amphipathic, on the surface of the micelle. In this orientation, many hydrophilic residues of the receptor, including Glu177, Arg179, Arg181, Glu182, Asp185, and Arg186, are projecting toward the solvent available to form complementary Coulombic interactions with the polar residues of the principal binding domain of the ligand (e.g., Arg25, Lys26, Lys27, Asp30, and His32). Given that the binding domain of PTH adopts an amphipathic alpha-helix which lies on the membrane, we visualize ligand binding as a two stage process involving a nonspecific hydrophobic interaction of amphipathic helices with the membrane, followed by two-dimensional diffusion leading to highly specific, ligand-receptor interaction.",
"New protein parameters are reported for the all-atom empirical energy function in the CHARMM program. The parameter evaluation was based on a self-consistent approach designed to achieve a balance between the internal (bonding) and interaction (nonbonding) terms of the force field and among the solvent-solvent, solvent-solute, and solute-solute interactions. Optimization of the internal parameters used experimental gas-phase geometries, vibrational spectra, and torsional energy surfaces supplemented with ab initio results. The peptide backbone bonding parameters were optimized with respect to data for N-methylacetamide and the alanine dipeptide. The interaction parameters, particularly the atomic charges, were determined by fitting ab initio interaction energies and geometries of complexes between water and model compounds that represented the backbone and the various side chains. In addition, dipole moments, experimental heats and free energies of vaporization, solvation and sublimation, molecular volumes, and crystal pressures and structures were used in the optimization. The resulting protein parameters were tested by applying them to noncyclic tripeptide crystals, cyclic peptide crystals, and the proteins crambin, bovine pancreatic trypsin inhibitor, and carbonmonoxy myoglobin in vacuo and in crystals. A detailed analysis of the relationship between the alanine dipeptide potential energy surface and calculated protein φ, χ angles was made and used in optimizing the peptide group torsional parameters. The results demonstrate that use of ab initio structural and energetic data by themselves are not sufficient to obtain an adequate backbone representation for peptides and proteins in solution and in crystals. Extensive comparisons between molecular dynamics simulations and experimental data for polypeptides and proteins were performed for both structural and dynamic properties. Energy minimization and dynamics simulations for crystals demonstrate that the latter are needed to obtain meaningful comparisons with experimental crystal structures. The presented parameters, in combination with the previously published CHARMM all-atom parameters for nucleic acids and lipids, provide a consistent set for condensed-phase simulations of a wide variety of molecules of biological interest.",
"We describe a detailed protocol for heterologous expression of the human adenosine A2A G-protein coupled receptor (GPCR), using Pichia pastoris. Details are also provided for the reconstitution and functional purification steps. Yields of 2-6 mg/g membrane were obtained prior to functional purification (ligand column purification). Typically, functional purification reduced overall yields by a factor of 2-4, resulting in final functional production of 0.5-3 mg/L membrane. Yeast is an excellent protein expression system for NMR given its high tolerance for isotope-enriched solvents and its ability to grow in minimal media.",
"G-Protein-coupled receptors (GPCRs) belong to an important family of integral membrane receptor proteins that are essential for a variety of transmembrane signaling process, such as vision, olfaction, and hormone responses. They are also involved in many human diseases (Alzheimer's, heart diseases, etc.) and are therefore common drug targets. Thus, understanding the details of the GPCR activation process is a task of major importance. Various types of crystal structures of GPCRs have been solved either at stable end-point states or at possible intermediate states. However, the detailed mechanism of the activation process is still poorly understood. For example, it is not completely clear when the nucleotide release from the G protein occurs and how the key residues on α5 contribute to the coupling process and further affect the binding specificity. In this work we show by free energy analysis that the guanosine diphosphate (GDP) molecule could be released from the Gs protein when the binding cavity is half open. This occurs during the transition to the Gs open state, which is the rate-determining step in the system conformational change. We also account for the experimentally observed slow-down effects by the change of the reaction barriers after mutations. Furthermore, we identify potential key residues on α5 and validated their significance by site-directed mutagenesis, which illustrates that computational works have predictive value even for complex biophysical systems. The methodology of the current work may be applied to other biophysical systems of interest.",
"In the current standard procedure for preparation of mammalian rhodopsin mutants, transfected COS-1 cells expressing the mutant opsin genes are treated with 5 microM 11-cis-retinal before detergent solubilization for purification. We found that binding of 11-cis-retinal to opsin mutants with single amino acid changes at Trp-265 (W265F,Y,A) and a retinitis pigmentosa mutant (A164V) was far from complete and required much higher concentrations of 11-cis-retinal. By isolation of the expressed opsins in a stable form, kinetic studies of retinal binding to the opsins in vitro have been carried out by using defined phospholipid-detergent mixtures. The results show wide variation in the rates of 11-cis-retinal binding. Thus, the in vitro reconstitution procedure serves as a probe of the retinal-binding pocket in the opsins. Further, a method is described for purification and characterization of the rhodopsin mutants after retinal binding to the opsins in vitro.",
"Subunit c is the H+-translocating component of the F1F0 ATP synthase complex. H+ transport is coupled to conformational changes that ultimately lead to ATP synthesis by the enzyme. The properties of the monomeric subunit in a single-phase solution of chloroform-methanol-water (4:4:1) have been shown to mimic those of the protein in the native complex. Triple resonance NMR experiments were used to determine the complete structure of monomeric subunit c in this solvent mixture. The structure of the protein was defined by >2000 interproton distances, 64 (3)JN alpha, and 43 hydrogen-bonding NMR-derived restraints. The root mean squared deviation for the backbone atoms of the two transmembrane helices was 0.63 A. The protein folds as a hairpin of two antiparallel helical segments, connected by a short structured loop. The conserved Arg41-Gln42-Pro43 form the top of this loop. The essential H+-transporting Asp61 residue is located at a slight break in the middle of the C-terminal helix, just prior to Pro64. The C-terminal helix changes direction by 30 +/- 5 degrees at the conserved Pro64. In its protonated form, the Asp61 lies in a cavity created by the absence of side chains at Gly23 and Gly27 in the N-terminal helix. The shape and charge distribution of the molecular surface of the monomeric protein suggest a packing arrangement for the oligomeric protein in the F0 complex, with the front face of one monomer packing favorably against the back face of a second monomer. The packing suggests that the proton (cation) binding site lies between packed pairs of adjacent subunit c."
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Acute phase ceftazidime therapy in the murine model of inhalation melioidosis.
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Melioidosis is an endemic disease in numerous tropical regions. Additionally, the bacterium that causes melioidosis, Burkholderia pseudomallei, has potential to be used as a biological weapon. Therefore, development of effective and affordable medical countermeasures to serve regions affected by the disease and to have medical countermeasures available in the event of a bioterrorism attack remains critical. The current study evaluated the efficacy of eight distinct acute phase ceftazidime treatment regimens administered therapeutically in the murine model. At the conclusion of the treatment period, survival rates were significantly greater in several of the treated groups when compared to the control group. Pharmacokinetics of a single dose of ceftazidime were examined at 150 mg/kg, 300 mg/kg, and 600 mg/kg and were compared to an intravenous clinical dose administered at 2000 mg every eight hours. The clinical dose has an estimated 100% fT > 4*MIC which exceeded the highest murine dose of 300 mg/kg every six hours at 87.2% fT > 4*MIC. Based upon survival at the end of the treatment regimen and supplemented by pharmacokinetic modeling, a daily dose of 1200 mg/kg of ceftazidime, administered every 6 h at 300 mg/kg, provides protection in the acute phase of inhalation melioidosis in the murine model.
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[
"Although CpG oligodeoxynucleotides (CpG ODNs) are known to enhance resistance against infection in a number of animal models, little is known about the CpG-induced protection against acute fatal sepsis such as that associated with the highly virulent bacterium Burkholderia pseudomallei. We previously demonstrated in an in vitro study that immunostimulatory CpG ODN 1826 enhances phagocytosis of B. pseudomallei and induces nitric oxide synthase and nitric oxide production by mouse macrophages. In the present study, CpG ODN 1826 given intramuscularly to BALB/c mice 2 to 10 days prior to B. pseudomallei challenge conferred better than 90% protection. CpG ODN 1826 given 2 days before the bacterial challenge rapidly enhanced the innate immunity of these animals, judging from the elevated serum levels of interleukin-12 (IL-12)p70 and gamma interferon (IFN-gamma) over the baseline values. No bacteremia was detected on day 2 in 85 to 90% of the CpG-treated animals, whereas more than 80% of the untreated animals exhibited heavy bacterial loads. Although marked elevation of IFN-gamma was found consistently in the infected animals 2 days after the bacterial challenge, it was ameliorated by the CpG ODN 1826 pretreatment (P = 0.0002). Taken together, the kinetics of bacteremia and cytokine profiles presented are compatible with the possibility that protection by CpG ODN 1826 against acute fatal septicemic melioidosis in this animal model is associated with a reduction of bacterial load and interference with the potential detrimental effect of the robust production of proinflammatory cytokines associated with B. pseudomallei multiplication.",
"Melioidosis, caused by the intracellular pathogen Burkholderia pseudomallei, is endemic in northern Australia and Southeast Asia. Risk factors for this infection have also been associated with functional neutrophil defects. Because of this, granulocyte colony-stimulating factor (G-CSF) was adopted for use in patients with septic shock due to melioidosis in December 1998. We compared the mortality rates from before and after the introduction of G-CSF therapy at the Royal Darwin Hospital (Darwin, Australia) during the period of 1989-2002. The mortality rate decreased from 95% to 10% after the introduction of G-CSF. Risk factors, the duration of illness before presentation, and the severity of illness were similar in both groups. A smaller decrease in mortality among patients in the intensive care unit who did not have melioidosis was observed, suggesting that other changes in management did not account for the magnitude of the benefit seen. We conclude that G-CSF may have contributed to the reduction in the mortality rate among patients with septic shock due to melioidosis.",
"Melioidosis, caused by the gram-negative saprophyte Burkholderia pseudomallei, is a disease of public health importance in southeast Asia and northern Australia that is associated with high case-fatality rates in animals and humans. It has the potential for epidemic spread to areas where it is not endemic, and sporadic case reports elsewhere in the world suggest that as-yet-unrecognized foci of infection may exist. Environmental determinants of this infection, apart from a close association with rainfall, are yet to be elucidated. The sequencing of the genome of a strain of B. pseudomallei has recently been completed and will help in the further identification of virulence factors. The presence of specific risk factors for infection, such as diabetes, suggests that functional neutrophil defects are important in the pathogenesis of melioidosis; other studies have defined virulence factors (including a type III secretion system) that allow evasion of killing mechanisms by phagocytes. There is a possible role for cell-mediated immunity, but repeated environmental exposure does not elicit protective humoral or cellular immunity. A vaccine is under development, but economic constraints may make vaccination an unrealistic option for many regions of endemicity. Disease manifestations are protean, and no inexpensive, practical, and accurate rapid diagnostic tests are commercially available; diagnosis relies on culture of the organism. Despite the introduction of ceftazidime- and carbapenem-based intravenous treatments, melioidosis is still associated with a significant mortality attributable to severe sepsis and its complications. A long course of oral eradication therapy is required to prevent relapse. Studies exploring the role of preventative measures, earlier clinical identification, and better management of severe sepsis are required to reduce the burden of this disease.",
"Burkholderia pseudomallei (B. pseudomallei), the etiological agent of melioidosis, is a Gram-negative bacterium with additional concern as a biothreat pathogen. The mortality rate from B. pseudomallei varies depending on the type of infection and extent of available health care, but in the case of septicemia left untreated it can range from 50 - 90%. Current therapy for melioidosis is biphasic, consisting of parenteral acute-phase treatment for two weeks or longer, followed by oral eradication-phase treatment lasting several months. An effective oral therapeutic for outpatient treatment of acute-phase melioidosis is needed. GC-072 is a potent, 4-oxoquinolizine antibiotic with selective inhibitory activity against bacterial topoisomerases. GC-072 has demonstrated in vitro potency against susceptible and drug-resistant strains of B. pseudomallei and is also active against Burkholderia mallei, Bacillus anthracis, Yersinia pestis, and Francisella tularensis GC-072 is bactericidal both extra- and intracellularly, with rapid killing noted within a few hours and reduced development of resistance compared to ceftazidime. GC-072, delivered intragastrically to mimic oral administration, promoted dose-dependent survival in mice using lethal inhalational models of B. pseudomallei infection following exposure to a 24 or 339 LD50 challenge with B. pseudomallei strain 1026b. Overall, GC-072 appears to be a strong candidate for first-line, oral treatment of melioidosis.",
"Burkholderia pseudomallei is a soil bacterium that is endemic in southeast Asia and northern Australia and that can cause both acutely lethal pneumonia and chronic systemic infections in humans. The effective treatment of infection with B. pseudomallei requires rapid diagnosis and prolonged treatment with high doses of antimicrobials, and even with appropriate antibiotic therapy, patient relapses are common. Thus, new approaches to the treatment of B. pseudomallei infections are needed. In the present study, we asked whether active immunotherapy with gamma interferon (IFN-gamma), a key cytokine regulating the intracellular replication of B. pseudomallei, could increase the effectiveness of conventional antimicrobial therapy for B. pseudomallei infection. Macrophage infection assays and in vivo pulmonary challenge models were used to assess the inhibitory effects of combined treatment with IFN-gamma and ceftazidime on B. pseudomallei infection. We found that treatment with even very low doses of IFN-gamma and ceftazidime elicited strong synergistic inhibition of B. pseudomallei growth within infected macrophages. In vivo, active immunotherapy markedly potentiated the effectiveness of low-dose ceftazidime therapy for the treatment of infected mice in a pulmonary challenge model of B. pseudomallei. Combined treatment was associated with a significant reduction in the bacterial burden and a significant lessening of bacterial dissemination. We concluded, therefore, that immunotherapy with either endogenous or exogenous IFN-gamma could significantly increase the effectiveness of conventional antimicrobial therapy for the treatment of acute B. pseudomallei infection.",
"Introduction: Melioidosis is a significant health problem within endemic areas such as Southeast Asia and Northern Australia. The varied presentation of melioidosis and the intrinsic antibiotic resistance of Burkholderia pseudomallei, the causative organism, make melioidosis a difficult infection to manage. Often prolonged courses of antibiotic treatments are required with no guarantee of clinical success.Areas covered: B. pseudomallei is able to enter phagocytic cells, affect immune function, and replicate, via manipulation of the caspase system. An examination of this mechanism, and a look at other factors in the pathogenesis of melioidosis, shows that there are multiple potential points of therapeutic intervention, some of which may be complementary. These include the directed use of antimicrobial compounds, blocking virulence mechanisms, balancing or modulating cytokine responses, and ameliorating sepsis.Expert commentary: There may be therapeutic options derived from drugs in clinical use for unrelated conditions that may have benefit in melioidosis. Key compounds of interest primarily affect the disequilibrium of the cytokine response, and further preclinical work is needed to explore the utility of this approach and encourage the clinical research needed to bring these into beneficial use.",
"Previous studies have demonstrated that systemically administered immunotherapy can protect mice from systemic challenge with the bacterial pathogen Francisella tularensis. However, for protection from inhalational challenge with this bacterium, we wondered if mucosally administered immunotherapy might be more effective. Therefore, we administered cationic liposome-DNA complexes (CLDC), which are potent activators of innate immunity, intranasally (i.n.) and assessed the effectiveness of protection from lethal inhalational challenge with F. tularensis. We found that pretreatment by i.n. administration of CLDC 24h prior to bacterial challenge elicited nearly complete protection of BALB/c mice from lethal challenge with F. tularensis LVS strain. We also observed that mucosal CLDC immunotherapy provided a statistically significant increase in survival time in mice challenged with the highly virulent F. tularensis Schu4 strain. Protection was associated with a significant reduction in bacterial burden in the lungs, liver, and spleen. Mucosal administration of CLDC elicited significantly increased expression of IL-12, IFN-gamma, TNF-alpha, IFN-beta and IFN-alpha genes in the lung as detected by real-time quantitative PCR. In vitro treatment of F. tularensis infected macrophages with CLDC-elicited cytokines also significantly suppressed intracellular replication of F. tularensis in infected macrophages. In vivo, depletion of NK cells prior to administration of CLDC completely abolished the protective effects of CLDC immunotherapy. CLDC-elicited protection was also dependent on induction of IFN-gamma production in vivo. We conclude therefore that activation of local pulmonary innate immune responses is capable of eliciting significant protection from inhalational exposure to a virulent bacterial pathogen."
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Identification of Malate Dehydrogenase Genes in Chinese Fir
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Malate dehydrogenase (MDH) genes play vital roles in developmental control and environmental stress tolerance in sessile plants by modulating the organic acid-malic acid level. However, MDH genes have not yet been characterized in gymnosperm, and their roles in nutrient deficiency are largely unexplored. In this study, 12 MDH genes were identified in Chinese fir (
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"Sunflower occupies the fourth position among oilseed crops the around the world. Eceriferum (CER) is an important gene family that plays critical role in very-long-chain fatty acids elongation and biosynthesis of epicuticular waxes under both biotic and abiotic stress conditions. The aim of present study was to investigate the effect of sunflower CER genes during drought stress condition. Thus, comparative analysis was undertaken for sunflower CER genes with Arabidopsis genome to determine phylogenetic relationship, chromosomal mapping, gene structures, gene ontology and conserved motifs. Furthermore, we subjected the sunflower cultivars under drought stress and used qRT-PCR analysis to explore the expression pattern of CER genes during drought conditions. We identified thirty-seven unevenly distributed CER genes in the sunflower genome. The phylogenetic analysis revealed that CER genes were grouped into seven clades in Arabidopsis, Helianthus annuus, and Gossypium hirsutum. Expression analysis showed that genes CER10 and CER60 were upregulated in sunflower during drought conditions, indicating that these genes are activated during drought stress. The results obtained will serve to characterize the CER gene family in sunflower and exploit the role of these genes in wax biosynthesis under limited water conditions. Cuticular waxes protect the plants from drought stress, so we observed the expression of wax bio synthesis genes in recently sequences genome of Helianthus annuus. We observed that expression of wax biosynthesis genes CER10 and CER60 was upregulated when the plants were subjected to drought stress.",
"The MEME Suite is a powerful, integrated set of web-based tools for studying sequence motifs in proteins, DNA and RNA. Such motifs encode many biological functions, and their detection and characterization is important in the study of molecular interactions in the cell, including the regulation of gene expression. Since the previous description of the MEME Suite in the 2009 Nucleic Acids Research Web Server Issue, we have added six new tools. Here we describe the capabilities of all the tools within the suite, give advice on their best use and provide several case studies to illustrate how to combine the results of various MEME Suite tools for successful motif-based analyses. The MEME Suite is freely available for academic use at http://meme-suite.org, and source code is also available for download and local installation.",
"Centromeres direct the assembly of kinetochores, microtubule-attachment sites that allow chromosome segregation on the mitotic spindle. Fundamental differences in size and organization between evolutionarily distant eukaryotic centromeres have in many cases obscured general principles of their function. Here we demonstrate that centromere-binding proteins are highly conserved between budding yeast and humans. We identify the histone-fold protein Cnn1(CENP-T) as a direct centromere receptor of the microtubule-binding Ndc80 complex. The amino terminus of Cnn1 contains a conserved peptide motif that mediates stoichiometric binding to the Spc24-25 domain of the Ndc80 complex. Consistent with the critical role of this interaction, artificial tethering of the Ndc80 complex through Cnn1 allows mini-chromosomes to segregate in the absence of a natural centromere. Our results reveal the molecular function of CENP-T proteins and demonstrate how the Ndc80 complex is anchored to centromeres in a manner that couples chromosome movement to spindle dynamics.",
"In illuminated chloroplasts, one mechanism involved in reduction-oxidation (redox) homeostasis is the malate-oxaloacetate (OAA) shuttle. Excess electrons from photosynthetic electron transport in the form of nicotinamide adenine dinucleotide phosphate, reduced are used by NADP-dependent malate dehydrogenase (MDH) to reduce OAA to malate, thus regenerating the electron acceptor NADP. NADP-MDH is a strictly redox-regulated, light-activated enzyme that is inactive in the dark. In the dark or in nonphotosynthetic tissues, the malate-OAA shuttle was proposed to be mediated by the constitutively active plastidial NAD-specific MDH isoform (pdNAD-MDH), but evidence is scarce. Here, we reveal the critical role of pdNAD-MDH in Arabidopsis (Arabidopsis thaliana) plants. A pdnad-mdh null mutation is embryo lethal. Plants with reduced pdNAD-MDH levels by means of artificial microRNA (miR-mdh-1) are viable, but dark metabolism is altered as reflected by increased nighttime malate, starch, and glutathione levels and a reduced respiration rate. In addition, miR-mdh-1 plants exhibit strong pleiotropic effects, including dwarfism, reductions in chlorophyll levels, photosynthetic rate, and daytime carbohydrate levels, and disordered chloroplast ultrastructure, particularly in developing leaves, compared with the wild type. pdNAD-MDH deficiency in miR-mdh-1 can be functionally complemented by expression of a microRNA-insensitive pdNAD-MDH but not NADP-MDH, confirming distinct roles for NAD- and NADP-linked redox homeostasis.",
"Plants with C4 photosynthesis are efficient in carbon assimilation and have an advantage over C3 photosynthesis. In C4 photosynthesis, the primary CO2 fixation is catalyzed by phosphoenolpyruvate carboxylase (PEPC). Here, we show that overexpression of Zea mays PEPC cDNA, under the control of 35S promoter, in Arabidopsis thaliana resulted in ~7-10 fold higher protein abundance and ~7-10 fold increase in PEPC activity in the transgenic lines than that in the vector control. We suggest that overexpression of PEPC played an anaplerotic role to increase the supply of 4-carbon carboxylic acids, which provided carbon skeletons for increased amino acid and protein synthesis. Higher protein content must have been responsible for increased metabolic processes including chlorophyll biosynthesis, photosynthesis, and respiration. Consequently, the PEPC-overexpressed transgenic plants had higher chlorophyll content, enhanced electron transport rate (ETR), lower non-photochemical quenching (NPQ) of chlorophyll a fluorescence, and a higher performance index (PI) than the vector control. Consistent with these observations, the rate of CO2 assimilation, the starch content, and the dry weight of PEPC-overexpressed plants increased by 14-18 %, 10-18 %, and 6.5-16 %, respectively. Significantly, transgenics were tolerant to salt stress as they had increased ability to synthesize amino acids, including the osmolyte proline. NaCl (150 mM)-treated transgenic plants had higher variable to maximum Chl a fluorescence (F v/F m) ratio, higher PI, higher ETR, and lower NPQ than the salt-treated vector controls. These results suggest that expression of C4 photosynthesis enzyme(s) in a C3 plant can improve its photosynthetic capacity with enhanced tolerance to salinity stress.",
"Two different methods of presenting quantitative gene expression exist: absolute and relative quantification. Absolute quantification calculates the copy number of the gene usually by relating the PCR signal to a standard curve. Relative gene expression presents the data of the gene of interest relative to some calibrator or internal control gene. A widely used method to present relative gene expression is the comparative C(T) method also referred to as the 2 (-DeltaDeltaC(T)) method. This protocol provides an overview of the comparative C(T) method for quantitative gene expression studies. Also presented here are various examples to present quantitative gene expression data using this method.",
"Plant cis-elements play important roles in global regulation of gene expression. Based on microarray data from rice flag leaves during early senescence, we identified W-box and G-box cis-elements as positive regulators of senescence in the important rice variety Minghui 63. Both cis-elements were bound by leaf senescence-specific proteins in vitro and influenced senescence in vivo. Furthermore, combination of the two elements drove enhanced expression during leaf senescence, and copy numbers of the cis-elements significantly affected the levels of expression. The W-box is the cognate cis-element for WRKY proteins, while the G-box is the cognate cis-element for bZIP, bHLH and NAC proteins. Consistent with this, WRKY, bZIP, bHLH and NAC family members were overrepresented among transcription factor genes up-regulated according during senescence. Crosstalk between ABA, CTK, BR, auxin, GA and JA during senescence was uncovered by comparing expression patterns of senescence up-regulated transcription factors. Together, our results indicate that hormone-mediated signaling could converge on leaf senescence at the transcriptional level through W-box and G-box elements. Considering that there are very few documented early senescence-related cis-elements, our results significantly contribute to understanding the regulation of flag leaf senescence and provide prioritized targets for stay-green trait improvement."
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Role of Cluster of differentiation 47 in neointimal hyperplasia
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Cluster of differentiation 47 (CD47) plays an important role in the pathophysiology of various diseases including atherosclerosis but its role in neointimal hyperplasia which contributes to restenosis has not been studied. Using molecular approaches in combination with a mouse vascular endothelial denudation model, we studied the role of CD47 in injury-induced neointimal hyperplasia. We determined that thrombin-induced CD47 expression both in human aortic smooth muscle cells (HASMCs) and mouse aortic smooth muscle cells. In exploring the mechanisms, we found that the protease-activated receptor 1-Gα protein q/11 (Gαq/11)-phospholipase Cβ3-nuclear factor of activated T cells c1 signaling axis regulates thrombin-induced CD47 expression in HASMCs. Depletion of CD47 levels using its siRNA or interference of its function by its blocking antibody (bAb) blunted thrombin-induced migration and proliferation of HASMCs and mouse aortic smooth muscle cells. In addition, we found that thrombin-induced HASMC migration requires CD47 interaction with integrin β3. On the other hand, thrombin-induced HASMC proliferation was dependent on CD47's role in nuclear export and degradation of cyclin-dependent kinase-interacting protein 1. In addition, suppression of CD47 function by its bAb rescued HASMC efferocytosis from inhibition by thrombin. We also found that vascular injury induces CD47 expression in intimal SMCs and that inhibition of CD47 function by its bAb, while alleviating injury-induced inhibition of SMC efferocytosis, attenuated SMC migration, and proliferation resulting in reduced neointima formation. Thus, these findings reveal a pathological role for CD47 in neointimal hyperplasia.
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"We have characterized matrix metalloproteinase expression in the rat carotid artery after two forms of arterial injury, balloon catheter denudation and nylon filament denudation. Gelatinolytic enzymes with molecular masses of 70 and 62 kD were produced constitutively in the rat carotid. Production of an 88-kD gelatinase was induced after balloon catheter injury, and proteinase production continued during the period of migration of smooth muscle cells from the media to the intima, from 6 hours to 6 days after balloon catheter injury. In addition, a marked increase in 62-kD gelatinolytic activity was observed between 4 and 14 days after arterial injury. Gelatinase activities (88 and 62 kD) were also increased after nylon filament denudation but were markedly less after this injury than after balloon catheter injury. These results suggested a correlation between gelatinase activity and smooth muscle cell migration after arterial injury. Administration of a metalloproteinase inhibitor after balloon catheter injury resulted in a 97% reduction in the number of smooth muscle cells migrating into the intima. Therefore, we hypothesize that gelatinase expression directly facilitates smooth muscle cell migration within the media and into the intima. These results suggest that gelatinases are involved in the vascular smooth muscle cell activation and neointimal formation that characterize arterial tissue remodeling after injury.",
"We performed balloon injury in the rat carotid artery and identified intimal thickening after injury. Balloon-injured carotid arteries showed maximum thickness of the neointima on the 14th day before complete endothelial cell regeneration. In this lesion we identified apoptosis of vascular smooth muscle cells (VSMCs) by in situ DNA labelling and electron microscopy in the neointima on the 14th day after injury. mRNA expression levels of bcl-2, bax, bcl-x, p53 and caspase-1 were determined by the reverse transcriptase-polymerase chain reaction method both in injured and uninjured carotid arteries. Neither bcl-2 nor bcl-xl mRNA expression was detected in either injured or uninjured arteries, whereas bax and p53 mRNA expression was identified and their mRNA levels were not altered after balloon injury. In contrast, both bcl-xs and caspase-1 mRNA was detected and was markedly induced only in the injured carotid artery. Positive staining for immunoreactive Bcl-x was observed specifically in the injured arterial wall and co-localized with positive staining of nuclei identified by in situ DNA labelling. We conclude that two opposite cellular responses, VSMC proliferation and apoptosis, exist together in the neointima of the rat carotid artery after balloon injury, and selective induction of Bcl-xs expression is a key regulator of VSMC apoptosis in the process of vascular remodelling.",
"Despite the introduction of antiproliferative drug-eluting stents, coronary heart disease remains the leading cause of death in the United States. In-stent restenosis and bypass graft failure are characterized by excessive smooth muscle cell (SMC) proliferation and concomitant myointima formation with luminal obliteration. Here we show that during the development of myointimal hyperplasia in human arteries, SMCs show hyperpolarization of their mitochondrial membrane potential (ΔΨm) and acquire a temporary state with a high proliferative rate and resistance to apoptosis. Pyruvate dehydrogenase kinase isoform 2 (PDK2) was identified as a key regulatory protein, and its activation proved necessary for relevant myointima formation. Pharmacologic PDK2 blockade with dichloroacetate or lentiviral PDK2 knockdown prevented ΔΨm hyperpolarization, facilitated apoptosis and reduced myointima formation in injured human mammary and coronary arteries, rat aortas, rabbit iliac arteries and swine (pig) coronary arteries. In contrast to several commonly used antiproliferative drugs, dichloroacetate did not prevent vessel re-endothelialization. Targeting myointimal ΔΨm and alleviating apoptosis resistance is a novel strategy for the prevention of proliferative vascular diseases.",
"Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.",
"Intimal hyperplasia is the process by which the cell population increases within the innermost layer of the arterial wall, such as occurs physiologically during closure of the ductus arteriosus and during involution of the uterus. It also occurs pathologically in pulmonary hypertension, atherosclerosis, after angioplasty, in transplanted organs, and in vein grafts. The underlying causes of intimal hyperplasia are migration and proliferation of vascular smooth muscle cells provoked by injury, inflammation, and stretch. This review discusses, at a molecular level, both the final common pathways leading to smooth muscle migration and proliferation and their (patho)-physiological triggers. It emphasizes the key roles played by growth factors and extracellular matrix-degrading metalloproteinases, which act in concert to remodel the extracellular matrix and permit cell migration and proliferation.",
"ATP-binding cassette transporters A1 (ABCA1) and G1 (ABCG1) play a vital role in promoting cholesterol efflux. Although, the dysregulation of these transporters was attributed as one of the mechanisms of atherogenesis, what renders their dysfunction is not well explored. Previously, we have reported that thrombin without having any effect on ABCG1 levels depletes ABCA1 levels affecting cholesterol efflux. In this study, we explored the mechanisms underlying thrombin-induced depletion of ABCA1 levels both in macrophages and smooth muscle cells. Under normal physiological conditions, COP9 signalosome subunit 3 (CSN3) was found to exist in complex with ABCA1 and in the presence of proatherogenic stimulants such as thrombin, ABCA1 was phosphorylated and dissociated from CSN3, leading to its degradation. Forced expression of CSN3 inhibited thrombin-induced ABCA1 ubiquitination and degradation, restored cholesterol efflux and suppressed foam cell formation. In Western diet (WD)-fed ApoE-/- mice, CSN3 was also disassociated from ABCA1 otherwise remained as a complex in Chow diet (CD)-fed ApoE-/- mice. Interestingly, depletion of CSN3 levels in WD-fed ApoE-/- mice significantly lowered ABCA1 levels, inhibited cholesterol efflux and intensified foam cell formation exacerbating the lipid laden atherosclerotic plaque formation. Mechanistic studies have revealed the involvement of Par1-Gα12-Pyk2-Gab1-PKCθ signaling in triggering phosphorylation of ABCA1 and its disassociation from CSN3 curtailing cholesterol efflux and amplifying foam cell formation. In addition, although both CSN3 and ABCA1 were found to be colocalized in human non-lesion coronary arteries, their levels were decreased as well as dissociated from each other in advanced atherosclerotic lesions. Together, these observations reveal for the first time an anti-atherogenic role of CSN3 and hence, designing therapeutic drugs protecting its interactions with ABCA1 could be beneficial against atherosclerosis.",
"Proapoptotic proteins such as Bax, undergo translocation to the mitochondria during apoptosis, where they mediate the release of intermembrane space proteins including cytochrome c. Bax binds to the voltage-dependent anion channel (VDAC). VDAC is a beta-barrel protein located in the outer mitochondrial membrane. In planar lipid bilayers, Bax and VDAC form a channel through which cytochrome c can pass. Hexokinase II (HXK II) also binds to VDAC. HXK II catalyzes the first step of glycolysis and is highly expressed in transformed cells, where over 70% of it is bound to the mitochondria. The present study demonstrates that HXK II interferes with the ability of Bax to bind to mitochondria and release cytochrome c. Detachment of HXK II from the mitochondria-enriched fraction isolated from HeLa cells promoted the binding of recombinant Bax-Delta19 and subsequent cytochrome c release. Similarly, the addition of recombinant HXK II to the mitochondria-enriched fraction isolated from hepatocytes, cells that do not express HXK II endogenously, prevented the ability of recombinant Bax-Delta19 to bind to the mitochondria and promote cytochrome c release. Similar results were found in intact cells, in which the detachment of mitochondrial bound HXK II or its overexpression potentiated and inhibited, respectively, Bax-induced mitochondrial dysfunction and cell death."
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Automated extraction of features from candidemia and/or bacteremia episodes for the first phase of the AUTO-CAND project
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There is increasing interest in assessing whether machine learning (ML) techniques could further improve the early diagnosis of candidemia among patients with a consistent clinical picture. The objective of the present study is to validate the accuracy of a system for the automated extraction from a hospital laboratory software of a large number of features from candidemia and/or bacteremia episodes as the first phase of the AUTO-CAND project. The manual validation was performed on a representative and randomly extracted subset of episodes of candidemia and/or bacteremia. The manual validation of the random extraction of 381 episodes of candidemia and/or bacteremia, with automated organization in structured features of laboratory and microbiological data resulted in ≥99% correct extractions (with confidence interval < ±1%) for all variables. The final automatically extracted dataset consisted of 1338 episodes of candidemia (8%), 14,112 episodes of bacteremia (90%), and 302 episodes of mixed candidemia/bacteremia (2%). The final dataset will serve to assess the performance of different ML models for the early diagnosis of candidemia in the second phase of the AUTO-CAND project.
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"Nosocomial bloodstream infections (BSIs) are important causes of morbidity and mortality in the United States. Data from a nationwide, concurrent surveillance study (Surveillance and Control of Pathogens of Epidemiological Importance [SCOPE]) were used to examine the secular trends in the epidemiology and microbiology of nosocomial BSIs. Our study detected 24,179 cases of nosocomial BSI in 49 US hospitals over a 7-year period from March 1995 through September 2002 (60 cases per 10,000 hospital admissions). Eighty-seven percent of BSIs were monomicrobial. Gram-positive organisms caused 65% of these BSIs, gram-negative organisms caused 25%, and fungi caused 9.5%. The crude mortality rate was 27%. The most-common organisms causing BSIs were coagulase-negative staphylococci (CoNS) (31% of isolates), Staphylococcus aureus (20%), enterococci (9%), and Candida species (9%). The mean interval between admission and infection was 13 days for infection with Escherichia coli, 16 days for S. aureus, 22 days for Candida species and Klebsiella species, 23 days for enterococci, and 26 days for Acinetobacter species. CoNS, Pseudomonas species, Enterobacter species, Serratia species, and Acinetobacter species were more likely to cause infections in patients in intensive care units (P<.001). In neutropenic patients, infections with Candida species, enterococci, and viridans group streptococci were significantly more common. The proportion of S. aureus isolates with methicillin resistance increased from 22% in 1995 to 57% in 2001 (P<.001, trend analysis). Vancomycin resistance was seen in 2% of Enterococcus faecalis isolates and in 60% of Enterococcus faecium isolates. In this study, one of the largest multicenter studies performed to date, we found that the proportion of nosocomial BSIs due to antibiotic-resistant organisms is increasing in US hospitals.",
"As routine use of on-line progress notes in US Department of Veterans Affairs facilities grew rapidly in the past decade, health information managers and clinicians began to notice that authors sometimes copied text from old notes into new notes. Other sources of duplication were document templates that inserted boilerplate text or patient data into notes. Word-processing and templates aided the transition to electronic notes, but enabled author copying and sometimes led to lengthy, hard-to-read records stuffed with data already available on-line. Investigators at a VA center recognized for pioneering a fully electronic record system analyzed author copying and template-generated duplication with adapted plagiarism-detection software. Nine percent of progress notes studied contained copied or duplicated text. Most copying and duplication was benign, but some introduced misleading errors into the record and some seemed possibly unethical or potentially unsafe. High-risk author copying occurred once for every 720 notes, but one in ten electronic charts contained an instance of high-risk copying. Careless copying threatens the integrity of on-line records. Clear policies, practitioner consciousness-raising and development of effective monitoring procedures are recommended to protect the value of electronic patient records.",
"Invasive fungal diseases are important causes of morbidity and mortality. Clarity and uniformity in defining these infections are important factors in improving the quality of clinical studies. A standard set of definitions strengthens the consistency and reproducibility of such studies. After the introduction of the original European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions, advances in diagnostic technology and the recognition of areas in need of improvement led to a revision of this document. The revision process started with a meeting of participants in 2003, to decide on the process and to draft the proposal. This was followed by several rounds of consultation until a final draft was approved in 2005. This was made available for 6 months to allow public comment, and then the manuscript was prepared and approved. The revised definitions retain the original classifications of \"proven,\" \"probable,\" and \"possible\" invasive fungal disease, but the definition of \"probable\" has been expanded, whereas the scope of the category \"possible\" has been diminished. The category of proven invasive fungal disease can apply to any patient, regardless of whether the patient is immunocompromised, whereas the probable and possible categories are proposed for immunocompromised patients only. These revised definitions of invasive fungal disease are intended to advance clinical and epidemiological research and may serve as a useful model for defining other infections in high-risk patients.",
"Invasive candidiasis (IC) comprises candidemia and deep-seated candidiasis. Blood culture (BC) is the gold standard test, but sensitivity is low. T2Candida is a new diagnostic test. We investigated the performance of T2Candida, BC, and Candida mannan antigen (MAg) for detection of IC in a high-risk intensive care unit (ICU) population. One-hundred twenty-six ICU patients at high risk of IC with sepsis despite 3 days of broad-spectrum antibiotics were included. Paired BC, T2Candida, and MAg were obtained twice weekly (334 sets). Patients were classified into proven, likely, possible, or unlikely IC based on patient record review. At enrollment, 92 (77%) patients were receiving antifungal therapy (mainly fluconazole 66%). Fifteen (11.9%) patients were positive by BC (n = 4), T2Candida (n = 11), or MAg (n = 10). The T2Candida species distribution at inclusion (Candida albicans/Candida tropicalis: 8/11 [72.3%] and Candida glabrata/Candida krusei: 3/11 [27.3%]) was supported by the identification of BC or colonizing isolates in 10/11 cases. Patients were classified with proven (11), likely (6), possible (11), and unlikely (98) IC. Defining IC as proven/proven&likely/proven&likely&possible, respectively, the sensitivity was as follows: T2Candida (55%/59%/39%), BC (45%/29%/ 8%), and MAg (36%/41%/32%). The negative predictive value was similar across the tests for proven vs others and proven/likely vs others (94%-96% and 90%-95%, respectively). For test combinations including T2Candida, the sensitivity increased to 64%-65%, without hampering the positive predictive value. In conclusion, although the diagnostic performance was modest for all the tests, the combination of T2Candida and BC seemed to have the best diagnostic performance, and thus implementation of T2Candida may improve the diagnosis of IC.",
"As the mortality associated with invasive Candida infections remains high, it is important to make optimal use of available diagnostic tools to initiate antifungal therapy as early as possible and to select the most appropriate antifungal drug. A panel of experts of the European Fungal Infection Study Group (EFISG) of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) undertook a data review and compiled guidelines for the clinical utility and accuracy of different diagnostic tests and procedures for detection of Candida infections. Recommendations about the microbiological investigation and detection of candidaemia, invasive candidiasis, chronic disseminated candidiasis, and oropharyngeal, oesophageal, and vaginal candidiasis were included. In addition, remarks about antifungal susceptibility testing and therapeutic drug monitoring were made.",
"A concise invasive candidosis guideline (based on the ESCMID candidaemia guideline) utilizing an informative biomarker [serum β-1-3-d-glucan (BDG)] was developed in 2013 by an antifungal stewardship (AFS) team and implemented with the help of an AFS champion in 2014. The main aims of the AFS programme were to reduce inappropriate use of antifungals and improve patient outcomes. The aim of this project was to evaluate the compliance of the ICU teams with the invasive candidosis guideline and the impact of the AFS programme on mortality and antifungal consumption on the ICUs (total of 71 beds). All patients who were prescribed micafungin for suspected or proven invasive candidosis during 4 month audit periods in 2014 and 2016 were included. Prescriptions and patient records were reviewed against the guideline. Antifungal consumption and mortality data were analysed. The number of patients treated for invasive candidosis decreased from 39 in 2014 to 29 in 2016. This was mainly due to the reduction in patients initiated on antifungal therapy inappropriately: 18 in 2014 and 2 in 2016. Antifungal therapy was stopped following negative biomarker results in 12 patients in 2014 and 10 patients in 2016. Crude mortality due to proven or probable invasive candidosis decreased to 19% from 45% over the period 2003-07. Antifungal consumption reduced by 49% from 2014 to 2016. The AFS programme was successful in reducing the number of inappropriate initiations of antifungals by 90%. Concurrently, mortality due to invasive candidosis was reduced by 58%. BDG testing can guide safe cessation of antifungals in ICU patients at risk of invasive candidosis."
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Microglia in a Tri-Culture of Primary Rat Neurons, Astrocytes, and Microglia
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Neuroinflammation plays a central role in many neurological disorders, ranging from traumatic brain injuries to neurodegeneration. Electrophysiological activity is an essential measure of neuronal function, which is influenced by neuroinflammation. In order to study neuroinflammation and its electrophysiological fingerprints, there is a need for in vitro models that accurately capture the in vivo phenomena. In this study, we employed a new tri-culture of primary rat neurons, astrocytes, and microglia in combination with extracellular electrophysiological recording techniques using multiple electrode arrays (MEAs) to determine the effect of microglia on neural function and the response to neuroinflammatory stimuli. Specifically, we established the tri-culture and its corresponding neuron-astrocyte co-culture (lacking microglia) counterpart on custom MEAs and monitored their electrophysiological activity for 21 days to assess culture maturation and network formation. As a complementary assessment, we quantified synaptic puncta and averaged spike waveforms to determine the difference in excitatory to inhibitory neuron ratio (E/I ratio) of the neurons. The results demonstrate that the microglia in the tri-culture do not disrupt neural network formation and stability and may be a better representation of the in vivo rat cortex due to its more similar E/I ratio as compared to more traditional isolated neuron and neuron-astrocyte co-cultures. In addition, only the tri-culture displayed a significant decrease in both the number of active channels and spike frequency following pro-inflammatory lipopolysaccharide exposure, highlighting the critical role of microglia in capturing electrophysiological manifestations of a representative neuroinflammatory insult. We expect the demonstrated technology to assist in studying various brain disease mechanisms.
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"Brain in vitro models are critically important to developing our understanding of basic nervous system cellular physiology, potential neurotoxic effects of chemicals, and specific cellular mechanisms of many disease states. In this study, we sought to address key shortcomings of current brain in vitro models: the scarcity of comparative data for cells originating from distinct brain regions and the lack of multiregional brain in vitro models. We demonstrated that rat neurons from different brain regions exhibit unique profiles regarding their cell composition, protein expression, metabolism, and electrical activity in vitro. In vivo, the brain is unique in its structural and functional organization, and the interactions and communication between different brain areas are essential components of proper brain function. This fact and the observation that neurons from different areas of the brain exhibit unique behaviors in vitro underline the importance of establishing multiregional brain in vitro models. Therefore, we here developed a multiregional brain-on-a-chip and observed a reduction of overall firing activity, as well as altered amounts of astrocytes and specific neuronal cell types compared with separately cultured neurons. Furthermore, this multiregional model was used to study the effects of phencyclidine, a drug known to induce schizophrenia-like symptoms in vivo, on individual brain areas separately while monitoring downstream effects on interconnected regions. Overall, this work provides a comparison of cells from different brain regions in vitro and introduces a multiregional brain-on-a-chip that enables the development of unique disease models incorporating essential in vivo features.NEW & NOTEWORTHY Due to the scarcity of comparative data for cells from different brain regions in vitro, we demonstrated that neurons isolated from distinct brain areas exhibit unique behaviors in vitro. Moreover, in vivo proper brain function is dependent on the connection and communication of several brain regions, underlining the importance of developing multiregional brain in vitro models. We introduced a novel brain-on-a-chip model, implementing essential in vivo features, such as different brain areas and their functional connections.",
"Microglia and non-parenchymal macrophages in the brain are mononuclear phagocytes that are increasingly recognized to be essential players in the development, homeostasis and diseases of the central nervous system. With the availability of new genetic, molecular and pharmacological tools, considerable advances have been made towards our understanding of the embryonic origins, developmental programmes and functions of these cells. These exciting discoveries, some of which are still controversial, also raise many new questions, which makes brain macrophage biology a fast-growing field at the intersection of neuroscience and immunology. Here, we review the current knowledge of how and where brain macrophages are generated, with a focus on parenchymal microglia. We also discuss their normal functions during development and homeostasis, the disturbance of which may lead to various neurodegenerative and neuropsychiatric diseases.",
"Measurement of the activity of human pluripotent stem cell (hPSC)-derived neuronal networks with microelectrode arrays (MEAs) plays an important role in functional in vitro brain modelling and in neurotoxicological screening. The previously reported hPSC-derived neuronal networks do not, however, exhibit repeatable, stable functional network characteristics similar to rodent cortical cultures, making the interpretation of results difficult. In earlier studies, microtunnels have been used both to control and guide cell growth and amplify the axonal signals of rodent neurons. The aim of the current study was to develop tunnel devices that would facilitate signalling and/or signal detection in entire hPSC-derived neuronal networks containing not only axons, but also somata and dendrites. Therefore, MEA-compatible polydimethylsiloxane (PDMS) tunnel devices with 8 different dimensions were created. The hPSC-derived neurons were cultured in the tunnel devices on MEAs, and the spontaneous electrical activity of the networks was measured for 5 weeks. Although the tunnel devices improved the signal-to-noise ratio only by 1.3-fold at best, they significantly increased the percentage of electrodes detecting neuronal activity (52-100%) compared with the controls (27%). Significantly higher spike and burst counts were also obtained using the tunnel devices. Neuronal networks inside the tunnels were amenable to pharmacological manipulation. The results suggest that tunnel devices encompassing the entire neuronal network can increase the measured spontaneous activity in hPSC-derived neuronal networks on MEAs. Therefore, they can increase the efficiency of functional studies of hPSC-derived networks on MEAs.",
"Microglia are resident immune cells in the central nervous system (CNS) that are capable of carrying out prominent and various functions during development and adulthood under both homeostatic and disease conditions. Although microglia are traditionally thought to be heterogeneous populations, which potentially allows them to achieve a wide range of responses to environmental changes for the maintenance of CNS homeostasis, a lack of unbiased and high-throughput methods to assess microglia heterogeneity has prevented the study of spatially and temporally distributed microglia subsets. The recent emergence of novel single-cell techniques, such as cytometry by time-of-flight mass spectrometry (CyTOF) and single-cell RNA sequencing, enabled scientists to overcome such limitations and reveal the surprising context-dependent heterogeneity of microglia. In this review, we summarize the current knowledge about the spatial, temporal, and functional diversity of microglia during development, homeostasis, and disease in mice and humans.",
"Both epidemiological and genetic studies support a role of neuroinflammation in the pathophysiology of Parkinson's disease (PD). Furthermore, post mortem studies confirm the involvement of innate as well as adaptive immunity in the affected brain regions in patients with PD. Indeed, activated microglial cells and T lymphocytes have been detected in the substantia nigra of patients concomitantly with an increased expression of pro-inflammatory mediators. Preclinical investigations conducted in various animal models of PD indicate that inflammatory processes are instrumental in neuronal cell death even though they are unlikely to be a primary cause for neuronal loss. Neuroinflammatory processes in PD are rather involved in self-perpetuating deleterious events that lead to protracted neuronal degeneration. In line with this, recent data indicate that glucocorticoid receptors are important in curtailing microglial reactivity, and deregulation in their activity in PD could lead to sustained inflammation-mediated degeneration. Altogether, neuroinflammatory processes might represent a target for neuroprotection in PD.",
"Neuronal networks are capable of undergoing rapid structural and functional changes called plasticity, which are essential for shaping circuit function during nervous system development. These changes range from short-term modifications on the order of milliseconds, to long-term rearrangement of neural architecture that could last for the lifetime of the organism. Neural plasticity is most prominent during development, yet also plays a critical role during memory formation, behavior, and disease. Therefore, it is essential to define and characterize the mechanisms underlying the onset, duration, and form of plasticity. Astrocytes, the most numerous glial cell type in the human nervous system, are integral elements of synapses and are components of a glial network that can coordinate neural activity at a circuit-wide level. Moreover, their arrival to the CNS during late embryogenesis correlates to the onset of sensory-evoked activity, making them an interesting target for circuit plasticity studies. Technological advancements in the last decade have uncovered astrocytes as prominent regulators of circuit assembly and function. Here, we provide a brief historical perspective on our understanding of astrocytes in the nervous system, and review the latest advances on the role of astroglia in regulating circuit plasticity and function during nervous system development and homeostasis.",
"During the pre- and neonatal period, the cerebral cortex reveals distinct patterns of spontaneous synchronized activity, which is critically involved in the formation of early networks and in the regulation of neuronal survival and programmed cell death (apoptosis). During this period, the cortex is also highly vulnerable to inflammation and in humans prenatal infection may have a profound impact on neurodevelopment causing long-term neurological deficits. Using in vitro and in vivo multi-electrode array recordings and quantification of caspase-3 (casp-3)-dependent apoptosis, we demonstrate that lipopolysaccharide-induced inflammation causes rapid alterations in the pattern of spontaneous burst activities, which subsequently leads to an increase in apoptosis. We show that these inflammatory effects are specifically initiated by the microglia-derived pro-inflammatory cytokine tumor necrosis factor α and the chemokine macrophage inflammatory protein 2. Our data demonstrate that inflammation-induced modifications in spontaneous network activities influence casp-3-dependent cell death in the developing cerebral cortex."
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Intestinal microbiota and Huntington's disease
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The human intestinal microbiota is a diverse and dynamic microenvironment that forms a complex, bi-directional relationship with the host. The microbiome takes part in the digestion of food and the generation of crucial nutrients such as short chain fatty acids (SCFA), but is also impacts the host's metabolism, immune system, and even brain functions. Due to its indispensable role, microbiota has been implicated in both the maintenance of health and the pathogenesis of many diseases. Dysbiosis in the gut microbiota has already been implicated in many neurodegenerative diseases such as Parkinson's disease (PD) and Alzheimer's disease (AD). However, not much is known about the microbiome composition and its interactions in Huntington's disease (HD). This dominantly heritable, incurable neurodegenerative disease is caused by the expansion of CAG trinucleotide repeats in the huntingtin gene (
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"Huntington's disease is an inherited neurodegenerative disease described 150 years ago by George Huntington. The genetic defect was identified in 1993 to be an expanded CAG repeat on exon 1 of the huntingtin gene located on chromosome 4. In the following almost 30 years, a considerable amount of research, using mainly animal models or in vitro experiments, has tried to unravel the complex molecular cascades through which the transcription of the mutant protein leads to neuronal loss, especially in the medium spiny neurons of the striatum, and identified excitotoxicity, transcriptional dysregulation, mitochondrial dysfunction, oxidative stress, impaired proteostasis, altered axonal trafficking and reduced availability of trophic factors to be crucial contributors. This review discusses the pathogenic cascades described in the literature through which mutant huntingtin leads to neuronal demise. However, due to the ubiquitous presence of huntingtin, astrocytes are also dysfunctional, and neuroinflammation may additionally contribute to Huntington's disease pathology. The quest for therapies to delay the onset and reduce the rate of Huntington's disease progression is ongoing, but is based on findings from basic research.",
"Evidence of the gut microbiota influencing neurodegenerative diseases has been reported for several neural diseases. However, there is little insight regarding the relationship between the gut microbiota and prion disease. Here, using fecal samples of 12 prion-infected mice and 25 healthy controls, we analyzed the structure of the gut microbiota and metabolic changes by 16S rRNA sequencing and LC-MS-based metabolomics respectively as multi-omic analyses. Additionally, SCFAs and common amino acids were detected by GC-MS and UPLC respectively. Enteric changes induced by prion disease affected both structure and abundances of the gut microbiota. The gut microbiota of infected mice displayed greater numbers of Proteobacteria and less Saccharibacteria at the phylum level and more Lactobacillaceae and Helicobacteraceae and less Prevotellaceae and Ruminococcaceae at the family level. A total of 145 fecal metabolites were found to be significantly different in prion infection, and most (114) of these were lipid metabolites. Using KEGG pathway enrichment analysis, we found that 3 phosphatidylcholine (PC) compounds significantly decreased and 4 hydrophobic bile acids significantly increased. Decreases of 8 types of short-chain acids (SCFAs) and increases of Cys and Tyr and decreases of His, Trp, and Arg were observed in prion infection. Correlation analysis indicated that the gut microbiota changes observed in our study may have been the shared outcome of prion disease. These findings suggest that prion disease can cause significant shifts in the gut microbiota. Certain bacterial taxa can then respond to the resulting change to the enteric environment by causing dramatic shifts in metabolite levels. Our data highlight the health impact of the gut microbiota and related metabolites in prion disease.",
"There is accumulating evidence that physical fitness influences the gut microbiome and as a result, promotes health. Indeed, exercise-induced alterations in the gut microbiome can influence health parameters crucial to athletic performance, specifically, immune function, lower susceptibility to infection, inflammatory response and tissue repair. Consequently, maintenance of a healthy gut microbiome is essential for an athlete's health, training and performance. This review explores the effect of exercise on the microbiome while also investigating the effect of probiotics on various potential consequences associated with over-training in athletes, as well as their associated health benefits.",
"Huntington's disease (HD) is an inherited neurodegenerative disorder characterized by both neurological and systemic abnormalities. We examined the peripheral immune system and found widespread evidence of innate immune activation detectable in plasma throughout the course of HD. Interleukin 6 levels were increased in HD gene carriers with a mean of 16 years before the predicted onset of clinical symptoms. To our knowledge, this is the earliest plasma abnormality identified in HD. Monocytes from HD subjects expressed mutant huntingtin and were pathologically hyperactive in response to stimulation, suggesting that the mutant protein triggers a cell-autonomous immune activation. A similar pattern was seen in macrophages and microglia from HD mouse models, and the cerebrospinal fluid and striatum of HD patients exhibited abnormal immune activation, suggesting that immune dysfunction plays a role in brain pathology. Collectively, our data suggest parallel central nervous system and peripheral pathogenic pathways of immune activation in HD.",
"Huntington's disease (HD) is one of a class of inherited progressive neurodegenerative disorders that are caused by a CAG/polyglutamine repeat expansion. We have previously generated mice that are transgenic for exon 1 of the HD gene carrying highly expanded CAG repeats which develop a progressive movement disorder and weight loss with similarities to HD. Neuronal inclusions composed of the exon 1 protein and ubiquitin are present in specific brain regions prior to onset of the phenotype, which in turn occurs long before specific neurodegeneration can be detected. In this report we have extended the search for polyglutamine inclusions to non-neuronal tissues. Outside the central nervous system (CNS), inclusions were identified in a variety of post-mitotic cells. This is consistent with a concentration-dependent nucleation and aggregation model of inclusion formation and indicates that brain-specific factors are not necessary for this process. To possibly gain insights into the wasting that is observed in the human disease, we have conducted a detailed analysis of the timing and progression of inclusion formation in skeletal muscle and an investigation into the cause of the severe muscle atrophy that occurs in the mouse model. The formation of inclusions in non-CNS tissues will be particularly useful with respect to in vivo monitoring of pharmaceutical agents selected for their ability to prevent polyglutamine aggregation in vitro, without the requirement that the agent can cross the blood-brain barrier in the first instance.",
"Weight loss is the most important non-neurological complication of Huntington's disease (HD). It correlates with disease progression and affects the quality of life of HD patients, suggesting that it could be a valuable target for therapeutic intervention. The mechanism underlying weight loss in HD is unknown. Mutant huntingtin, the protein that causes the disease, is not only expressed in the brain, but also along the gastrointestinal (GI) tract. Here we demonstrate that the GI tract of HD mice is affected. At the anatomical level we observed loss of enteric neuropeptides, as well as decreased mucosal thickness and villus length. Exploring the functions of the GI system we found impaired gut motility, diarrhea, and malabsorption of food. The degree of malabsorption was inversely associated with body weight, suggesting that GI dysfunction plays an important role in weight loss in HD mice. In summary, these observations suggest that the GI tract is affected in HD mice and that GI dysfunction contributes to nutritional deficiencies and weight loss.",
"Interest in characterizing the role of impaired insulin actions in Alzheimer's disease (AD) and vascular dementia is growing exponentially. This review details what is currently known about insulin, insulin-like growth factor type I (IGF-I) and IGF-II proteins and their corresponding receptors in the brain, and delineates the major controversies pertaining to alterations in the expression and function of these molecules in AD. The various experimental animal models generated by over-expression, mutation, or depletion of genes that are critical to the insulin or IGF signaling cascades are summarized, noting the degrees to which they reproduce the histopathological, biochemical, molecular, or behavioral abnormalities associated with AD. Although no single model was determined to be truly representative of AD, depletion of the neuronal insulin receptor and intracerebroventricular injection of Streptozotocin reproduce a number of important aspects of AD-type neurodegeneration, and therefore provide supportive evidence that AD may be caused in part by neuronal insulin resistance, i.e. brain diabetes. The extant literature did not resolve whether the CNS insulin resistance in AD represents a local disease process, or complication/extension of peripheral insulin resistance, i.e. chronic hyperglycemia, hyperinsulinemia, and Type 2 diabetes mellitus. The available epidemiological data are largely inconclusive with regard to the contribution of Type 2 diabetes mellitus to cognitive impairment and AD-type neurodegeneration. A major conclusion drawn from this review is that there is a genuine need for thorough and comprehensive study of the neuropathological changes associated with diabetes mellitus, in the presence or absence of superimposed AD or vascular dementia. Strategies for intervention may depend entirely upon whether the CNS disease processes are mediated by peripheral, central, or both types of insulin resistance.",
"The gut microbiota is now recognized as a major contributor to the host's nutrition, metabolism, immunity, and neurological functions. Imbalanced microbiota (ie, dysbiosis) is linked to undernutrition-induced stunting, inflammatory and metabolic diseases, and cancers. Skeletal muscle also takes part in the interorgan crosstalk regulating substrate metabolism, immunity, and health. Here, we review the reciprocal influence of gut microbiota and skeletal muscle in relation to juvenile growth, performance, aging, and chronic diseases. Several routes involving the vascular system and organs such as the liver and adipose tissue connect the gut microbiota and skeletal muscle, with effects on fitness and health. Therapeutic perspectives arise from the health benefits observed with changes in gut microbiota and muscle activity, further encouraging multimodal therapeutic strategies.",
"C biosynthesis at extrahepatic sites remote from plasma C may be important in the protection of tissues against inflammation and infection but may also contribute to tissue injury. This latter possibility is particularly relevant in the central nervous system (CNS), where several cell types are susceptible to damage by C. We have previously shown that human astrocyte-derived tumor cell lines synthesize and secrete all of the components of the activation pathways of C. In this study, we demonstrate that these cells also produce the components (C6, C7, C8, and C9) and regulators (S-protein and clusterin) of the lytic terminal C pathway. The terminal components produced are hemolytically active, and secretion is markedly up-regulated by the inflammatory cytokine IFN-gamma. Primary human fetal astrocytes also expressed C6, C7, S-protein, and clusterin. The human monocyte/macrophage cell line, used here as a model for microglia, also produced all terminal components and regulators when appropriately stimulated. These studies raise the prospect of the intrathecal synthesis of a complete, functional C system and its regulators in the inflamed CNS. Intrathecal C synthesis may be important in the resolution of infection and inflammation but, given the C susceptibility of some CNS cell types, may also exacerbate damage in demyelination and neurodegeneration.",
"Obesity is a major risk factor for developing gallstone disease (GSD). Previous studies have shown that obesity is associated with an elevated Firmicutes/Bacteroidetes ratio in the gut microbiota. These findings suggest that the development of GSD may be related to gut dysbiosis. This review presents and summarizes the recent findings of studies on the gut microbiota in patients with GSD. Most of the studies on the gut microbiota in patients with GSD have shown a significant increase in the phyla Firmicutes (Lactobacillaceae family, genera Clostridium, Ruminococcus, Veillonella, Blautia, Dorea, Anaerostipes, and Oscillospira), Actinobacteria (Bifidobacterium genus), Proteobacteria, Bacteroidetes (genera Bacteroides, Prevotella, and Fusobacterium) and a significant decrease in the phyla Bacteroidetes (family Muribaculaceae, and genera Bacteroides, Prevotella, Alistipes, Paludibacter, Barnesiella), Firmicutes (genera Faecalibacterium, Eubacterium, Lachnospira, and Roseburia), Actinobacteria (Bifidobacterium genus), and Proteobacteria (Desulfovibrio genus). The influence of GSD on microbial diversity is not clear. Some studies report that GSD reduces microbial diversity in the bile, whereas others suggest the increase in microbial diversity in the bile of patients with GSD. The phyla Proteobacteria (especially family Enterobacteriaceae) and Firmicutes (Enterococcus genus) are most commonly detected in the bile of patients with GSD. On the other hand, the composition of bile microbiota in patients with GSD shows considerable inter-individual variability. The impact of GSD on the Firmicutes/Bacteroidetes ratio is unclear and reports are contradictory. For this reason, it should be stated that the results of reviewed studies do not allow for drawing unequivocal conclusions regarding the relationship between GSD and the Firmicutes/Bacteroidetes ratio in the microbiota."
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Strategies and mechanisms of induced pluripotent stem cell-derived small extracellular vesicles in the treatment of myocardial injury
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Induced pluripotent stem cell (iPSC) therapy brings great hope to the treatment of myocardial injuries, while extracellular vesicles may be one of the main mechanisms of its action. iPSC-derived small extracellular vesicles (iPSCs-sEVs) can carry genetic and proteinaceous substances and mediate the interaction between iPSCs and target cells. In recent years, more and more studies have focused on the therapeutic effect of iPSCs-sEVs in myocardial injury. IPSCs-sEVs may be a new cell-free-based treatment for myocardial injury, including myocardial infarction, myocardial ischemia-reperfusion injury, coronary heart disease, and heart failure. In the current research on myocardial injury, the extraction of sEVs from mesenchymal stem cells induced by iPSCs was widely used. Isolation methods of iPSCs-sEVs for the treatment of myocardial injury include ultracentrifugation, isodensity gradient centrifugation, and size exclusion chromatography. Tail vein injection and intraductal administration are the most widely used routes of iPSCs-sEV administration. The characteristics of sEVs derived from iPSCs which were induced from different species and organs, including fibroblasts and bone marrow, were further compared. In addition, the beneficial genes of iPSC can be regulated through CRISPR/Cas9 to change the composition of sEVs and improve the abundance and expression diversity of them. This review focused on the strategies and mechanisms of iPSCs-sEVs in the treatment of myocardial injury, which provides a reference for future research and the application of iPSCs-sEVs.
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"Bone defects caused by trauma, severe infection, tumor resection and skeletal abnormalities are common osteoporotic conditions and major challenges in orthopedic surgery, and there is still no effective solution to this problem. Consequently, new treatments are needed to develop regeneration procedures without side effects. Exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (hiPSCs, hiPSC-MSC-Exos) incorporate the advantages of both MSCs and iPSCs with no immunogenicity. However, there are no reports on the application of hiPSC-MSC-Exos to enhance angiogenesis and osteogenesis under osteoporotic conditions. HiPSC-MSC-Exos were isolated and identified before use. The effect of hiPSC-MSC-Exos on the proliferation and osteogenic differentiation of bone marrow MSCs derived from ovariectomized (OVX) rats (rBMSCs-OVX) in vitro were investigated. In vivo, hiPSC-MSC-Exos were implanted into critical size bone defects in ovariectomized rats, and bone regeneration and angiogenesis were examined by microcomputed tomography (micro-CT), sequential fluorescent labeling analysis, microfil perfusion and histological and immunohistochemical analysis. The results in vitro showed that hiPSC-MSC-Exos enhanced cell proliferation and alkaline phosphatase (ALP) activity, and up-regulated mRNA and protein expression of osteoblast-related genes in rBMSCs-OVX. In vivo experiments revealed that hiPSC-MSC-Exos dramatically stimulated bone regeneration and angiogenesis in critical-sized calvarial defects in ovariectomized rats. The effect of hiPSC-MSC-Exos increased with increasing concentration. In this study, we showed that hiPSC-MSC-Exos effectively stimulate the proliferation and osteogenic differentiation of rBMSCs-OVX, with the effect increasing with increasing exosome concentration. Further analysis demonstrated that the application of hiPSC-MSC-Exos+β-TCP scaffolds promoted bone regeneration in critical-sized calvarial defects by enhancing angiogenesis and osteogenesis in an ovariectomized rat model.",
"Therapeutic applications of tissue-derived mesenchymal stem cells (MSCs) are hindered by their limited expansion ability and variation across donors. Human induced pluripotent stem cell (iPSC)-derived MSCs show greater expandability and therefore offer potential for use in tissue repair therapies. Here we explored the regenerative effects of iPSC-MSCs and the mechanisms by which iPSC-MSCs promote mucosal healing via tumor necrosis factor-α-stimulated gene 6 (TSG-6) in mouse models of inflammatory bowel disease (IBD). Human iPSCs were induced to differentiate into MSCs following a clinically compliant protocol. The iPSC-MSC treatment promoted mucosal healing in colitic mice, accompanied by increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells. TSG-6 knockdown in iPSC-MSCs or blocking of hyaluronan-CD44 interactions by PEP-1 abrogated the therapeutic effects of iPSC-MSCs, whereas use of recombinant TSG-6 showed therapeutic effects similar to those of iPSC-MSCs. A mouse or patient-derived organoid culture system was developed. Organoids co-cultured with iPSC-MSCs showed increased epithelial cell proliferation, CD44-positive cells, and Lgr5-positive cells, which was abolished by TSG-6 knockdown. TSG-6-induced promoting effects in organoids were dependent on Akt activation and abrogated by the anti-CD44 antibody or MK2206. In conclusion, iPSC-MSCs promoted epithelial cell proliferation to accelerate mucosal healing in a murine colitis model via TSG-6 through hyaluronan-CD44 interactions in an Akt-dependent manner, demonstrating a patient-specific \"off-the-shelf\" format for IBD treatment.",
"Oral and craniofacial bone defects caused by congenital disease or trauma are widespread. In the case of severe alveolar bone defect, autologous bone grafting has been considered a \"gold standard\"; however, the procedure has several disadvantages, including limited supply, resorption, donor site morbidity, deformity, infection, and bone graft rejection. In the last few decades, bone tissue engineering combined with stem cell-based therapy may represent a possible alternative to current bone augmentation techniques. The number of studies investigating different cell-based bone tissue engineering methods to reconstruct alveolar bone damage is rapidly rising. As an interdisciplinary field, bone tissue engineering combines the use of osteogenic cells (stem cells/progenitor cells), bioactive molecules, and biocompatible scaffolds, whereas stem cells play a pivotal role. Therefore, our work highlights the osteogenic potential of various dental tissue-derived stem cells and induced pluripotent stem cells (iPSCs), the progress in differentiation techniques of iPSCs into osteoprogenitor cells, and the efforts that have been made to fabricate the most suitable and biocompatible scaffold material with osteoinductive properties for successful bone graft generation. Moreover, we discuss the application of stem cell-derived exosomes as a compelling new form of \"stem-cell free\" therapy.",
"The regeneration capacity of the osteoporotic bones is generally lower than that of the normal bones. Current methods of bone defect treatment for osteoporosis are not always satisfactory. Recent studies have shown that the silicate based biomaterials can stimulate osteogenesis and angiogenesis due to the silicon (Si) ions released from the materials, and enhance bone regeneration in vivo. Other studies showed that strontium (Sr) plays a distinct role on inhibiting bone resorption. Based on the hypothesis that the combination of Si and Sr may have synergetic effects on osteoporotic bone regeneration, the porous Sr-substituted calcium silicate (SrCS) ceramic scaffolds combining the functions of Sr and Si elements were developed with the goals to promote osteoporotic bone defect repair. The effects of the ionic extract from SrCS on osteogenic differentiation of bone marrow mesenchymal stem cells derived from ovariectomized rats (rBMSCs-OVX), angiogenic differentiation of human umbilical vein endothelial cells (HUVECs) were investigated. The in vitro results showed that Sr and Si ions released from SrCS enhanced cell viability, alkaline phosphatase (ALP) activity, and mRNA expression levels of osteoblast-related genes of rBMSCs-OVX and expression of vascular endothelial growth factor (VEGF) without addition of extra osteogenic and angiogenic reagents. The activation in extracellular signal-related kinases (ERK) and p38 signaling pathways were observed in rBMSCs-OVX cultured in the extract of SrCS, and these effects could be blocked by ERK inhibitor PD98059, and P38 inhibitor SB203580, respectively. Furthermore, the ionic extract of SrCS stimulated HUVECs proliferation, differentiation and angiogenesis process. The in vivo experiments revealed that SrCS dramatically stimulated bone regeneration and angiogenesis in a critical sized OVX calvarial defect model, and the enhanced bone regeneration might be attributed to the modulation of osteogenic differentiation of endogenous mesenchymal stem cells (MSCs) and the inhibition of osteoclastogenesis, accompanying with the promotion of the angiogenic activity of endothelial cells (ECs).",
"Induced pluripotent stem cells (iPSCs) have strong potential in regenerative medicine applications; however, immune rejection caused by HLA mismatching is a concern. B2M gene knockout and HLA-homozygous iPSC stocks can address this issue, but the former approach may induce NK cell activity and fail to present antigens, and it is challenging to recruit rare donors for the latter method. Here, we show two genome-editing strategies for making immunocompatible donor iPSCs. First, we generated HLA pseudo-homozygous iPSCs with allele-specific editing of HLA heterozygous iPSCs. Second, we generated HLA-C-retained iPSCs by disrupting both HLA-A and -B alleles to suppress the NK cell response while maintaining antigen presentation. HLA-C-retained iPSCs could evade T cells and NK cells in vitro and in vivo. We estimated that 12 lines of HLA-C-retained iPSCs combined with HLA-class II knockout are immunologically compatible with >90% of the world's population, greatly facilitating iPSC-based regenerative medicine applications.",
"The use of stem cells to generate replacement cells for damaged heart muscle, valves, vessels and conduction cells holds great potential. Recent identification of multipotent progenitor cells in the heart and improved understanding of developmental processes relevant to pluripotent embryonic stem cells may facilitate the generation of specific types of cell that can be used to treat human heart disease. Secreted factors from circulating progenitor cells that localize to sites of damage may also be useful for tissue protection or neovascularization. The exciting discoveries in basic science will require rigorous testing in animal models to determine those most worthy of future clinical trials.",
"Diagnostic methods that focus on the extracellular vesicles (EVs) present in saliva have been attracting great attention because of their non-invasiveness. EVs contain biomolecules such as proteins, messenger RNA (mRNA) and microRNA (miRNA), which originate from cells that release EVs, making them an ideal source for liquid biopsy. Although there have been many reports on density-based fractionation of EVs from blood and urine, the number of reports on EVs from saliva has been limited, most probably because of the difficulties in separating EVs from viscous saliva using density gradient centrifugation. This article establishes a protocol for the isolation of EVs from human saliva using density gradient centrifugation. The fractionated salivary EVs were characterized by atomic force microscopy, western blot and reverse transcription polymerase chain reaction. The results indicate that salivary EVs have a smaller diameter (47.8±12.3 nm) and higher density (1.11 g/ml) than EVs isolated from conditioned cell media (74.0±23.5 nm and 1.06 g/ml, respectively). Additionally, to improve the throughput of density-based fractionation of EVs, the original protocol was further modified by using a fixed angle rotor instead of a swinging rotor. It was also confirmed that several miRNAs were expressed strongly in the EV-marker-expressing fractions."
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Why addressing lifestyle factors within cancer care is so important
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A significant proportion of cancers could be prevented by adopting healthy lifestyle behaviours. In addition, healthy lifestyle factors can have a positive impact on cancer outcomes and survival. Yet, most physicians, including oncologists, do not dedicate a significant amount of time addressing these factors with their patients, who instead look to mainstream media and other non-medical sources for information. This has led to an increase in the number of 'influencers' in the wellness space who can accumulate a large and captive audience. At times, this has caused friction amongst healthcare professionals who feel that 'influencers' may overstate the potential benefits. The reality is that most people, physicians and the public alike, fail to recognise the immense power that lifestyle interventions hold. Rather than shy away from addressing these issues, we should be empowering our patients to take back control over their health. Here, we provide a personal perspective on why addressing lifestyle factors within cancer care is so important and that we can indeed work together with 'influencers' to amplify the message.
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"This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.",
"Both genetic and lifestyle factors play an etiologic role in colorectal cancer (CRC). We evaluated potential gene-environment interactions in CRC risk. We used data from 346,297 participants in the UK Biobank cohort. Healthy lifestyle scores (HLSs) were constructed using 8 lifestyle factors, primarily according to the American Cancer Society guidelines, and were categorized into unhealthy, intermediate, and healthy groups. A polygenic risk score (PRS) was created using 95 genetic risk variants identified by genome-wide association studies of CRC and was categorized by tertile. Cox models were used to estimate the HRs and 95% CIs of CRC risk associated with the HLS and PRS. During a median follow-up of 5.8 y, 2066 incident cases of CRC were identified. Healthier HLSs were associated with reduced risk of CRC in a dose-response manner. The risk reduction was more apparent among those with high PRS (HRhealthy vs. unhealthy HLS1: 0.58; 95% CI: 0.43, 0.79 for men and 0.71; 0.58, 0.85 for men and women combined) than those with low PRS. Although no multiplicative interactions were identified, the HLS1 and PRS showed a significant additive interaction (P = 0.02 for all participants combined, 0.04 for men). In analyses including all participants, the adjusted CRC cumulative risk from age 40 to 75 y was 6.40% for those with high PRS/unhealthy HLS1, with a relative excess risk due to interaction of 0.58 (95% CI: 0.06, 1.10), compared with 2.09% among those with low PRS/healthy HLS1. This pattern was more apparent among those who reported not having received any bowel screening before baseline. Although the observational nature of the study precludes proof of causality, our findings suggest that individuals with a high genetic susceptibility could benefit more substantially than those with a low genetic risk from lifestyle modification in reducing CRC risk.",
"UK Biobank is an open access prospective cohort of 500 000 men and women. Information on the frequency of consumption of main foods was collected at recruitment with a touchscreen questionnaire; prior to examining the associations between diet and disease, it is essential to evaluate the performance of the dietary touchscreen questionnaire. The objectives of the present paper are to: describe the repeatability of the touchscreen questionnaire in participants (n 20 348) who repeated the assessment centre visit approximately 4 years after recruitment, and compare the dietary touchscreen variables with mean intakes from participants (n 140 080) who completed at least one of the four web-based 24-h dietary assessments post-recruitment. For fish and meat items, 90 % or more of participants reported the same or adjacent category of intake at the repeat assessment visit; for vegetables and fruit, and for a derived partial fibre score (in fifths), 70 % or more of participants were classified into the same or adjacent category of intake (κweighted > 0·50 for all). Participants were also categorised based on their responses to the dietary touchscreen questionnaire at recruitment, and within each category the group mean intake of the same food group or nutrient from participants who had completed at least one web-based 24-h dietary assessment was calculated. The comparison showed that the dietary touchscreen variables, available on the full cohort, reliably rank participants according to intakes of the main food groups.",
"Epidemiologic studies have consistently reported positive associations between obesity and colon cancer risk for men, but the evidence is less consistent for women. Few studies have investigated effects of weight change on colon cancer risk. Using the Melbourne Collaborative Cohort Study, which recruited men and women mostly in 40 to 69 years of age, we investigated associations between weight and body mass index (BMI) at age 18 years and at study entry and weight change since age 18 years and colon cancer. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. During follow-up of 16,188 men and 23,438 women for 14 years on average, we ascertained 569 incident colon cancers. Weight and BMI at study entry were positively associated with colon cancer risk for men [HR, 1.12 (95% CI, 1.04-1.21) per 5-kg increment; HR, 1.39 (95% CI, 1.12-1.71) per 5 kg/m(2)], but not women. Risk of colon cancer was not associated with weight or BMI at age 18 years. Adult weight change was positively associated with colon cancer risk for men (HR, 1.11 per 5-kg increment; 95% CI, 1.03-1.20), but not women (HR, 1.00; 95% CI, 0.94-1.07). Men who gained ≥20 kg from age 18 had an increased risk of colon cancer compared with men whose weight was stable (HR, 1.47; 95% CI, 0.94-2.31). Weight gain during adult life increases men's risk of colon cancer. Avoiding excessive weight gain might help reduce colon cancer risk for men."
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Vitamin D receptor expression and insulin-like growth factor 1 receptor activation in breast cancer
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Vitamin D receptor (VDR) and insulin-like growth factor 1 receptor (IGF1R) are known to be involved in breast cancer (BC) progression. Our previous work reported a correlation of differential localization of IGF1R with hormone receptor status in BC. A recent report described VDR and IGF1R as potential indicators of BC prognosis, but their interplay was not discussed. The present study focused on understanding the association of VDR expression with IGF1R activation, different molecular markers, and subtypes of BC.
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[
"The nuclear receptor for 1α,25-dihydroxycholecalciferol (1,25D), the active form of vitamin D, has anti-tumor actions in many tissues. The vitamin D receptor (VDR) is expressed in normal mammary gland and in many human breast cancers suggesting it may represent an important tumor suppressor gene in this tissue. When activated by 1,25D, VDR modulates multiple cellular pathways including those related to energy metabolism, terminal differentiation and inflammation. There is compelling pre-clinical evidence that alterations in vitamin D status affect breast cancer development and progression, while clinical and epidemiological data are suggestive but not entirely consistent. The demonstration that breast cells express CYP27B1 (which converts the precursor vitamin D metabolite 25D to the active metabolite 1,25D) and CYP24A1 (which degrades both 25D and 1,25D) provides insight into the difficulties inherent in using dietary vitamin D, sun exposure and/or serum biomarkers of vitamin D status to predict disease outcomes. Emerging evidence suggests that the normally tight balance between CYP27B1 and CYP24A1 becomes deregulated during cancer development, leading to abrogation of the tumor suppressive effects triggered by VDR. Research aimed at understanding the mechanisms that govern uptake, storage, metabolism and actions of vitamin D steroids in normal and neoplastic breast tissue remain an urgent priority.",
"Vitamin D is a steroid hormone that exerts its actions through ligation of the vitamin D receptor (VDR), a transcription factor of the nuclear receptor family. VDR has not only physiologic actions in calcium metabolism but also several other cellular effects through extensive binding to the DNA and modification of genome expression. In cancer, it has neoplasia-suppressive effects and various mechanisms of action mediating cancer cell inhibition have been described. Vitamin D deficiency has been linked to increased risk of breast cancer. A role of the vitamin once the disease has been diagnosed is also probable. A systematic review and meta-analysis of studies that report on vitamin D levels (in the form of its main circulating metabolite, 25-hydroxyvitamin D [25-OHD]) in patients with newly diagnosed breast cancer was performed. Outcomes of interest included the levels of serum 25-OHD in patients with breast cancer, those of matched controlled, in studies that included controls, as well as respective percentages of patients and controls with deficient and insufficient 25-OHD levels. A total of 25 studies (10 with controls and 15 without controls) provided data on the outcomes of interest. Populations from all continents, besides Australia, were represented in the studies. The mean level of 25-OHD in patients with breast cancer was 26.88 ng/mL (95% CI 22.8-30.96 ng/mL) and the mean level of 25-OHD in control patients was 31.41 ng/mL (95% CI 19.31-43.5 ng/mL). In the patients with breast cancer group, 45.28% (95% CI 24.37%-53.51%) had levels of 25-OHD below 20 ng/mL, whereas this percentage was 33.71% (95% CI 21.61%-45.82%) in controls. Similarly, 67.44% (95% CI 48.32%-86.55%) of patients with breast cancer had a baseline level of 25-OHD below 30 ng/mL, whereas this percentage was 33.71% (95% CI 21.61%-45.82%) in controls. A high prevalence of vitamin D insufficiency is observed in patients with newly diagnosed breast cancer and may be linked pathophysiologically with breast cancer development or progression. Therapeutic benefits may be provided by manipulation of the vitamin D pathway in breast cancer.",
"Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation. We studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort (\"subcohort\"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort. Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 × 10-5), indicating a larger methylation-breast cancer hazard ratio in those with high serum 25(OH)D concentrations. We also observed statistically significant (p < 0.05) interactions for six other RXRA CpGs and CpGs in CYP24A1, CYP27B1, NADSYN1/DHCR7, and VDR. In the EWAS of the subcohort, 25(OH)D was associated (q < 0.05) with methylation at cg24350360 (EPHX1; p = 3.4 × 10-8), cg06177555 (SPN; p = 9.8 × 10-8), and cg13243168 (SMARCD2; p = 2.9 × 10-7). 25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer.",
"A higher vitamin D intake improves the prognosis of early stage breast cancer (BC) patients. We hypothesized that vitamin D intake should refer to vitamin D receptor (VDR) expression. In order to prove this hypothesis, we first intend to evaluate the correlation between VDR expression and prognosis of BC patients using meta-analysis. Literatures from PubMed, Embase, and the Cochrane Library (last update by May 20, 2020) were retrieved to find studies assessing the prognostic role of VDR in BC. The hazard ratios (HRs) for patients' survival were extracted for pooled analyses. Subgroup analysis, sensitivity analysis and meta-regression were performed to explore the sources of heterogeneity. Seven articles containing eight studies with 2503 patients were enrolled. The results from the pooled analyses showed that the VDR expression generally had no relationship with BC patients' overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and progression-free survival (PFS) (P > 0.05). Because only the number of studies exploring the relationship between VDR expression and OS is greater than five and there is heterogeneity, we explored the sources of heterogeneity of these studies. Subgroup analyses showed that the VDR expression in the nucleus had no relationship with OS, but high total VDR expression in the nucleus and cytoplasm was related to a better OS (pooled HR = 0.41; 95% CI = 0.18-0.95; P = 0.038). In addition, in subgroup of studies using cut-off values other than 'immunoreactive score (IRS)>5' and 'IRS > 25', high VDR expression was associated with a better OS (pooled HR = 0.47; 95% CI = 0.30-0.74; P = 0.001). Sensitivity analysis showed that the result pattern was not obviously affected by any single study. Meta-regression showed that the source of heterogeneity was not country (P = 0.657), pathological type (P = 0.614), molecular type (P = 0.423), staining location (P = 0.481), or cut-off value (P = 0.509). The protein expression level of VDR in entire BC cells evaluated by immunohistochemistry is related to the OS of BC patients. It is expected that a more individualized vitamin D intake and a more accurate prognosis assessment can be recommended for BC patients based on the VDR expression. Of course, more preclinical and clinical studies are needed.",
"This paper examines eight published reviews each reporting results from several related trials. Each review pools the results from the relevant trials in order to evaluate the efficacy of a certain treatment for a specified medical condition. These reviews lack consistent assessment of homogeneity of treatment effect before pooling. We discuss a random effects approach to combining evidence from a series of experiments comparing two treatments. This approach incorporates the heterogeneity of effects in the analysis of the overall treatment efficacy. The model can be extended to include relevant covariates which would reduce the heterogeneity and allow for more specific therapeutic recommendations. We suggest a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.",
"In systematic reviews and meta-analyses, time-to-event outcomes are most appropriately analysed using hazard ratios (HRs). In the absence of individual patient data (IPD), methods are available to obtain HRs and/or associated statistics by carefully manipulating published or other summary data. Awareness and adoption of these methods is somewhat limited, perhaps because they are published in the statistical literature using statistical notation. This paper aims to 'translate' the methods for estimating a HR and associated statistics from published time-to-event-analyses into less statistical and more practical guidance and provide a corresponding, easy-to-use calculations spreadsheet, to facilitate the computational aspects. A wider audience should be able to understand published time-to-event data in individual trial reports and use it more appropriately in meta-analysis. When faced with particular circumstances, readers can refer to the relevant sections of the paper. The spreadsheet can be used to assist them in carrying out the calculations. The methods cannot circumvent the potential biases associated with relying on published data for systematic reviews and meta-analysis. However, this practical guide should improve the quality of the analysis and subsequent interpretation of systematic reviews and meta-analyses that include time-to-event outcomes.",
"There is high interest in the discovery of early diagnostic biomarkers of Alzheimer's disease, for which metabolomics exhibits a great potential. In this work, a metabolomic approach based on ultrafiltration and analysis by CE-MS has been used to obtain representative fingerprints of polar metabolites from serum samples in order to distinguish between patients with Alzheimer's disease, mild cognitive impairment, and healthy controls. By the use of partial least squares discriminant analysis it was possible to classify patients according to the disease stage and then identify potential markers. Significant increase was observed with progression of disease in levels of choline, creatinine, asymmetric dimethyl-arginine, homocysteine-cysteine disulfide, phenylalanyl-phenylalanine, and different medium chain acylcarnitines. On the other hand, asparagine, methionine, histidine, carnitine, acetyl-spermidine, and C5-carnitine were reduced in these serum samples. In this way, multiple essential pathways were found implicated in the underlying pathology, such as oxidative stress or defects in energy metabolism. However, the most interesting results are related to the association of several vascular risk factors with Alzheimer's disease."
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Drosophila fibroblast growth factor receptor heartless signaling disrupts glial phagocytosis of apoptotic neurons
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Glial phagocytosis of apoptotic neurons is crucial for development and proper function of the central nervous system. Relying on transmembrane receptors located on their protrusions, phagocytic glia recognize and engulf apoptotic debris. Like vertebrate microglia, Drosophila phagocytic glial cells form an elaborate network in the developing brain to reach and remove apoptotic neurons. However, the mechanisms controlling creation of the branched morphology of these glial cells critical for their phagocytic ability remain unknown. Here, we demonstrate that during early embryogenesis, the Drosophila fibroblast growth factor receptor (FGFR) Heartless (Htl) and its ligand Pyramus are essential in glial cells for the formation of glial extensions, the presence of which strongly affects glial phagocytosis of apoptotic neurons during later stages of embryonic development. Reduction in Htl pathway activity results in shorter lengths and lower complexity of glial branches, thereby disrupting the glial network. Our work thus illuminates the important role Htl signaling plays in glial subcellular morphogenesis and in establishing glial phagocytic ability.
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"The glial cells missing (gcm) gene in Drosophila encodes a novel nuclear protein that is transiently expressed early in the development of nearly all glia. In loss-of-function gcm mutant alleles, nearly all glia fail to differentiate, and, where we can follow them in the PNS, are transformed into neurons. In gain-if-function gcm conditions using transgenic constructs that drive ectopic gcm expression, many presumptive neurons are transformed into glia. Thus, gcm appears to function as a binary genetic switch for glia versus neurons. In the presence of gcm protein, presumptive neurons become glia, while in its absence, presumptive glia become neurons.",
"Astrocytes are critically important for neuronal circuit assembly and function. Mammalian protoplasmic astrocytes develop a dense ramified meshwork of cellular processes to form intimate contacts with neuronal cell bodies, neurites, and synapses. This close neuron-glia morphological relationship is essential for astrocyte function, but it remains unclear how astrocytes establish their intricate morphology, organize spatial domains, and associate with neurons and synapses in vivo. Here we characterize a Drosophila glial subtype that shows striking morphological and functional similarities to mammalian astrocytes. We demonstrate that the Fibroblast growth factor (FGF) receptor Heartless autonomously controls astrocyte membrane growth, and the FGFs Pyramus and Thisbe direct astrocyte processes to ramify specifically in CNS synaptic regions. We further show that the shape and size of individual astrocytes are dynamically sculpted through inhibitory or competitive astrocyte-astrocyte interactions and Heartless FGF signaling. Our data identify FGF signaling through Heartless as a key regulator of astrocyte morphological elaboration in vivo.",
"Glia exhibit spontaneous and activity-dependent fluctuations in intracellular Ca(2+), yet it is unclear whether glial Ca(2+) oscillations are required during neuronal signaling. Somatic glial Ca(2+) waves are primarily mediated by the release of intracellular Ca(2+) stores, and their relative importance in normal brain physiology has been disputed. Recently, near-membrane microdomain Ca(2+) transients were identified in fine astrocytic processes and found to arise via an intracellular store-independent process. Here, we describe the identification of rapid, near-membrane Ca(2+) oscillations in Drosophila cortex glia of the CNS. In a screen for temperature-sensitive conditional seizure mutants, we identified a glial-specific Na(+)/Ca(2+), K(+) exchanger (zydeco) that is required for microdomain Ca(2+) oscillatory activity. We found that zydeco mutant animals exhibit increased susceptibility to seizures in response to a variety of environmental stimuli, and that zydeco is required acutely in cortex glia to regulate seizure susceptibility. We also found that glial expression of calmodulin is required for stress-induced seizures in zydeco mutants, suggesting a Ca(2+)/calmodulin-dependent glial signaling pathway underlies glial-neuronal communication. These studies demonstrate that microdomain glial Ca(2+) oscillations require NCKX-mediated plasma membrane Ca(2+) flux, and that acute dysregulation of glial Ca(2+) signaling triggers seizures.",
"Fibroblast growth factors (FGFs) have been implicated in numerous cellular processes, including proliferation, migration, differentiation, and survival. Whereas FGF-2, the prototypic ligand in a family of 22 members, activates all four tyrosine kinase FGF receptors (FGFR1-FGFR4), other members demonstrate a higher degree of selectivity. Oligodendrocytes (OLs), the myelin-producing cells of the CNS, are highly influenced by FGF-2 at all stages of their development. However, how other FGFs and their cognate receptors orchestrate the development of OLs is essentially undefined. Using a combination of specific FGF ligands and receptor blocking antibodies, we now show that FGF-8 and FGF-17 target OL progenitors, inhibiting their terminal differentiation via the activation of FGFR3, whereas FGF-9 specifically targets differentiated OLs, triggering increases in process growth via FGFR2 signaling; FGF-18 targets both OL progenitors and OLs via activation of both FGFR2 and FGFR3. These events are highly correlated with changes in FGF receptor expression from FGFR3 to FGFR2 as OL progenitors differentiate into mature OLs. In addition, we demonstrate that, although activation of FGFR1 by FGF-2 leads to proliferation of OL progenitors, it produces deleterious effects on differentiated OLs (i.e., aberrant reentry into cell cycle and down-regulation of myelin proteins with a loss of myelin membrane). These data suggest that ligand availability, coupled with changes in FGF receptor expression, yield a changing repertoire of ligand-receptor signaling complexes that contribute critically to the regulation of both normal OL development and potential OL/myelin pathogenesis.",
"Precise neural circuit assembly is achieved by initial overproduction of neurons and synapses, followed by refinement through elimination of exuberant neurons and synapses. Glial cells are the primary cells responsible for clearing neuronal debris, but the cellular and molecular basis of glial pruning is poorly defined. Here we show that Drosophila larval astrocytes transform into phagocytes through activation of a cell-autonomous, steroid-dependent program at the initiation of metamorphosis and are the primary phagocytic cell type in the pupal neuropil. We examined the developmental elimination of two neuron populations-mushroom body (MB) γ neurons and vCrz⁺ neurons (expressing Corazonin [Crz] neuropeptide in the ventral nerve cord [VNC])-where only neurites are pruned or entire cells are eliminated, respectively. We found that MB γ axons are engulfed by astrocytes using the Draper and Crk/Mbc/dCed-12 signaling pathways in a partially redundant manner. In contrast, while elimination of vCrz⁺ cell bodies requires Draper, elimination of vCrz⁺ neurites is mediated by Crk/Mbc/dCed-12 but not Draper. Intriguingly, we also found that elimination of Draper delayed vCrz⁺ neurite degeneration, suggesting that glia promote neurite destruction through engulfment signaling. This study identifies a novel role for astrocytes in the clearance of synaptic and neuronal debris and for Crk/Mbc/dCed-12 as a new glial pathway mediating pruning and reveals, unexpectedly, that the engulfment signaling pathways engaged by glia depend on whether neuronal debris was generated through cell death or local pruning.",
"We describe the cloning, expression and phenotypic characterisation of repo, a gene from Drosophila melanogaster that is essential for the differentiation and maintenance of glia function. It is not, however, required for the initial determination of glial cells. In the embryo, the gene, which encodes a homeodomain protein, is expressed exclusively in all developing glia and closely related cells in both the central and peripheral nervous systems. The only observed exceptions in the CNS are the midline glia derived from the mesectoderm and two of three segmental nerve root glial cells. Using a polyclonal antibody we traced the spatial and temporal pattern of the protein expression in detail. Embryos homozygous for null alleles of the protein exhibit late developmental defects in the nervous system, including a reduction in the number of glial cells, disrupted fasciculation of axons, and the inhibition of ventral nerve cord condensation. The expression of an early glial-specific marker is unaffected in such homozygotes. By contrast, the expression of late glial-specific markers is either substantially reduced or absent. The specificity of expression is also observed in the locust Schistocerca gregaria and is thus evolutionarily conserved.",
"A conventional view of development is that cells cooperate to build an organism. However, based on studies of Drosophila, it has been known for years that viable cells can be eliminated by their neighbours through a process termed cell competition. New studies in mammals have revealed that this process is universal and that many factors and mechanisms are conserved. During cell competition, cells with lower translation rates or those with lower levels of proteins involved in signal transduction, polarity and cellular growth can survive in a homogenous environment but are killed when surrounded by cells of higher fitness. Here, we discuss recent advances in the field as well as the mechanistic steps involved in this phenomenon, which have shed light on how and why cell competition exists in developing and adult organisms."
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Expression of epithelial-to-mesenchymal transition-associated markers in mammary tumors of humans, dogs, and cats
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Epithelial-to-mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal properties. EMT has been closely associated with cancer cell aggressiveness. The aim of this study was to evaluate the mRNA and protein expression of EMT-associated markers in mammary tumors of humans (HBC), dogs (CMT), and cats (FMT). Real-time qPCR for
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"Downregulation of E-cadherin is a crucial event for epithelial to mesenchymal transition (EMT) in embryonic development and cancer progression. Using the EpFosER mammary tumour model we show that during EMT, upregulation of the transcriptional regulator deltaEF1 coincided with transcriptional repression of E-cadherin. Ectopic expression of deltaEF1 in epithelial cells was sufficient to downregulate E-cadherin and to induce EMT. Analysis of E-cadherin promoter activity and chromatin immunoprecipitation identified deltaEF1 as direct transcriptional repressor of E-cadherin. In human cancer cells, transcript levels of deltaEF1 correlated directly with the extent of E-cadherin repression and loss of the epithelial phenotype. The protein was enriched in nuclei of human cancer cells and physically associated with the E-cadherin promoter. RNA interference-mediated downregulation of deltaEF1 in cancer cells was sufficient to derepress E-cadherin expression and restore cell to cell adhesion, suggesting that deltaEF1 is a key player in late stage carcinogenesis.",
"The TWIST family of basic helix-loop-helix transcription factors, Twist-1 and Dermo-1 are known mediators of mesodermal tissue development and contribute to correct patterning of the skeleton. In this study, we demonstrate that freshly purified human bone marrow-derived mesenchymal stromal/stem cells (MSC) express high levels of Twist-1 and Dermo-1 which are downregulated following ex vivo expansion. Enforced expression of Twist-1 or Dermo-1 in human MSC cultures increased expression of the MSC marker, STRO-1, and the early osteogenic transcription factors, Runx2 and Msx2. Conversely, overexpression of Twist-1 and Dermo-1 was associated with a decrease in the gene expression of osteoblast-associated markers, bone morphogenic protein-2, bone sialoprotein, osteopontin, alkaline phosphatase and osteocalcin. High expressing Twist-1 or Dermo-1 MSC lines exhibited an enhanced proliferative potential of approximately 2.5-fold compared with control MSC populations that were associated with elevated levels of Id-1 and Id-2 gene expression. Functional studies demonstrated that high expressing Twist-1 and Dermo-1 MSC displayed a decreased capacity for osteo/chondrogenic differentiation and an enhanced capacity to undergo adipogenesis. These findings implicate the TWIST gene family members as potential mediators of MSC self-renewal and lineage commitment in postnatal skeletal tissues by exerting their effects on genes involved in the early stages of bone development.",
"Among breast cancer patients who develop distant metastases, there is marked variability in the clinical course, including metastasis pattern. Here, we present a retrospective study of breast cancer patients who all developed distant metastases focusing on the association between breast cancer subtype and clinical course, including organ-specific metastasis. Tissue microarrays (TMAs) were assembled and stained for ER, PR, HER2, EGFR, CK5/6, CK14, E-Cadherin, TP53 and Ki67 for 263 breast cancer patients with metastatic disease. Tumours were classified into ER+/HER2-/Ki67high, ER+/HER2-/Ki67low, ER+/HER2+, ER-/HER2+ and ER-/HER2- groups. Relevant data related to metastasis pattern, metastasis timeline, systemic treatment and survival were retrieved. Associations between site-specific relapse and patient/tumour characteristics were assessed with multivariate models using logistic regression. Median time for development of distant metastasis was 30 months (range 0-15.3 years); 75.8 % of the distance metastases developed in the first 5 years after treatment of the primary tumour. Patients with ER-/HER2- tumours had a median overall survival of 27 months; those with HER2+ tumours of 52 months; those with ER+/HER2-/Ki67high of 76 months and those with ER+/HER2-/Ki67low of 79 months. Bone was the most common site for distant metastasis (70.6 %) followed by liver (54.5 %) and lung (31.4 %), respectively. Visceral metastasis was found in 76.8 % of the patients. Patients with ER-/HER2- tumours developed visceral metastases in 81 % and bone metastases in 55.2 %; those with HER2+ tumours developed visceral metastases in 77.4 % and bone metastases in 69.8 %; those with ER+/HER2-/Ki67high developed visceral metastases in 75.7 % and bone metastases in 87.8 % and those with ER+/HER2-/Ki67low developed visceral metastases in 76.9 % and bone metastases in 73.1 %. In metastatic breast cancer patients, tumour subtypes are associated with survival and pattern of distant metastases. These associations are of help in choices for surveillance and therapy in individual patients.",
"Mammary tumors are a very common neoplasm in the dog and show histological features and biological behaviour similar to human mammary carcinomas. Recently, a pathway named Wnt-1, involving beta-catenin and APC protein, has emerged as an important player in many human tumor types, including mammary neoplasms. Thirty-five samples of canine mammary tumors (10 benign and 25 malignant) were studied in order to evaluate the co-expression of beta-catenin, APC protein and E cadherin with confocal laser microscopical observation, by western blot analysis and by correlating data obtained with the histological grade of tumours. A progressive decrease of E-cadherin together with disruption of beta-catenin expression was observed in less differentiated malignant tumors. In addition, a loss of beta-catenin membranous distribution and a cytoplasmic accumulation was often coexpressed with disrupted expression of APC protein. Western blot analysis showed a progressive increase of beta-catenin in malignant tumors, which could be the expression of disrupted /-catenin catabolism leading to cytoplasmic accumulation. In some less differentiated malignant tumors, a marked beta-catenin decrease was also observed. This feature could be linked to mutations in beta-catenin gene coding for a truncated and lighter protein. These results may indicate the multifunctional role played by beta-catenin in canine mammary oncogenesis.",
"Cytokeratin 5/6 and Cytokeratin 8/18 are basal and luminal markers of breast cancer and they have pathological and prognostic significance in breast cancer. We performed Cytokeratin 5/6 and CK8/18 immunohistochemistry on 150 cases of triple negative breast cancers and association with various clinicopathological features was evaluated. Positive CK5/6 expression was noted in 8% (12 cases) of TNBC while 2.4% (4 cases) showed focal positive (< 10%) and 89.3% (134) were negative with CK5/6. Complete loss of CK8/18 expression was seen in 4.7% (7 cases) while 32.7% (49 cases) revealed focal loss of CK8/18 and 62.7% (94 cases) showed intact normal expression of CK8/18. No significant association of CK5/6 and CK8/18 with various clinicopathological parameters was observed. We found a low expression of basal cytokeratin (CK5/6) in TNBC our studied population, while loss/altered expression of CK8/18 in approximately 38% of TNBC. Although no prognostic relevance of these finding was noted in our study, however these findings are different from those reported in literature in other parts of the world. Therefore we suggest a more through immunohistochemical and genomic profiling of TNBC in our population for better understanding of this disease in this part of the world.",
"This retrospective study and meta-analysis was designed to explore the relationship between E-cadherin (E-cad) expression and the molecular subtypes of invasive non-lobular breast cancer, especially in early-stage invasive ductal carcinoma (IDC). A total of 156 post-operative cases of early-stage IDCs were retrospectively collected for the immunohistochemistry (IHC) detection of E-cad expression. The association of E-cad expression with molecular subtypes of early-stage IDCs was analyzed. A literature search was conducted in March 2016 to retrieve publications on E-cad expression in association with molecular subtypes of invasive non-lobular breast cancer, and a meta-analysis was performed to estimate the relational statistics. E-cad was expressed in 82.7% (129/156) of early-stage IDCs. E-cad expression was closely associated with the molecular types of early-stage IDCs (P < 0.050); moreover, the molecular subtypes were an independent factor influencing E-cad expression in early-stage IDCs. A total of 12 observational studies (including our study) were included in the meta-analysis. The meta-analytical results show a significantly greater risk of E-cad expression loss in triple-negative breast cancer (TNBC) than in other molecular subtypes (TNBC vs. luminal A: RR = 3.45, 95% CI = 2.79-4.26; TNBC vs. luminal B: RR = 2.41, 95% CI = 1.49-3.90; TNBC vs. HER2-enriched: RR = 1.95, 95% CI = 1.24-3.07). Early-stage IDCs or invasive non-lobular breast cancers with the TNBC molecular phenotype have a higher risk for the loss of E-cad expression than do tumors with non-TNBC molecular phenotypes, suggesting that E-cad expression phenotypes were closely related to molecular subtypes and further studies are needed to clarify the underlying mechanism."
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Pathophysiological mechanism of 7,25-dihydroxycholesterol in osteoarthritis pathogenesis
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This study aimed to exploring the pathophysiological mechanism of 7α,25-dihydroxycholesterol (7α,25-DHC) in osteoarthritis (OA) pathogenesis. 7α,25-DHC accelerated the proteoglycan loss in
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"Cholesterol plays an important role in cellular homeostasis by maintaining the rigidity of cell membranes, providing a medium for signaling transduction, and being converted into other vital macromolecules, such as sterol hormones and bile acids. Epidemiological studies have shown the correlation between cholesterol content and cancer incidence worldwide. Accumulating evidence has shown the emerging roles of the dysregulation of cholesterol metabolism in cancer development. More specifically, recent reports have shown the distinct role of cholesterol in the suppression of immune cells, regulation of cell survival, and modulation of cancer stem cells in cancer. Here, we provide a comprehensive review of the epidemiological analysis, functional roles, and mechanistic action of cholesterol homeostasis in regard to its contribution to cancer development. Based on the existing data, cholesterol homeostasis is identified to be a new key player in cancer pathogenesis. Lastly, we also discuss the therapeutic implications of natural compounds and cholesterol-lowering drugs in cancer prevention and treatment. In conclusion, intervention in cholesterol metabolism may offer a new therapeutic avenue for cancer treatment.",
"The specific role of dietary fat in breast cancer progression is unclear, although a low-fat diet was associated with decreased recurrence of estrogen receptor alpha negative (ER(-)) breast cancer. ER(-) basal-like MDA-MB-231 and MDA-MB-436 breast cancer cell lines contained a greater number of cytoplasmic lipid droplets compared to luminal ER(+) MCF-7 cells. Therefore, we studied lipid storage functions in these cells. Both triacylglycerol and cholesteryl ester (CE) concentrations were higher in the ER(-) cells, but the ability to synthesize CE distinguished the two types of breast cancer cells. Higher baseline, oleic acid- and LDL-stimulated CE concentrations were found in ER(-) compared to ER(+) cells. The differences corresponded to greater mRNA and protein levels of acyl-CoA:cholesterol acyltransferase 1 (ACAT1), higher ACAT activity, higher caveolin-1 protein levels, greater LDL uptake, and lower de novo cholesterol synthesis in ER(-) cells. Human LDL stimulated proliferation of ER(-) MDA-MB-231 cells, but had little effect on proliferation of ER(+) MCF-7 cells. The functional significance of these findings was demonstrated by the observation that the ACAT inhibitor CP-113,818 reduced proliferation of breast cancer cells, and specifically reduced LDL-induced proliferation of ER(-) cells. Taken together, our studies show that a greater ability to take up, store and utilize exogenous cholesterol confers a proliferative advantage to basal-like ER(-) breast cancer cells. Differences in lipid uptake and storage capability may at least partially explain the differential effect of a low-fat diet on human breast cancer recurrence.",
"Cholesterol is one of the major components of membrane lipids. Adjustment of the membrane cholesterol balance is, therefore, pivotal in the maintenance of cellular homeostasis. Cholesterol biosynthesis and uptake are tightly regulated at the transcriptional level through a negative feedback control. The transcription factor family known as sterol regulatory element-binding proteins (SREBPs) is in charge of this feedback control. In particular, SREBP-2 is activated in a cholesterol-dependent manner, and hence is deeply involved in regulation of the expression of genes closely related to cholesterol metabolism. Sterol metabolites, including cholesterol, 24,25-dihydrolanosterol and oxysterols, strongly participate in the regulation of sterol metabolism via binding to its particular proteins.",
"Oxysterols are oxidized forms of cholesterol generated from cholesterol by auto-oxidation, enzymatic processes, or both. Some of them (7-ketocholesterol, 7β-hydroxycholesterol and 24(S)-hydroxycholesterol), when used at cytotoxic concentrations on different cell types from different species (mesenchymal bone marrow cells, monocytic cells and nerve cells), induce a type of cell death associated with OXIdative stress and several characteristics of APOPTOsis and autoPHAGY, defined as oxiapoptophagy. Oxidative stress is associated with overproduction of ROS, increased antioxidant enzyme activities, lipid peroxidation and protein carbonylation. Apoptosis is associated with activation of the mitochondrial pathway, opening of the mitochondrial permeability pore, loss of mitochondrial membrane potential, caspase-3 activation, PARP degradation, nuclear condensation and/or fragmentation. Autophagy is characterized by autophagic vacuoles revealed by monodansylcadaverine staining and transmission electron microscopy, plus increased ratio of LC-3II/LC-3I. In addition, morphological, topographical and functional changes of the peroxisome are observed. LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.",
"The relationship between serum cholesterol level and development of hepatocellular carcinoma (HCC) remains unclear. We investigated the effects of serum cholesterol level on development of liver tumors in mice. We performed studies with C57BL/6J mice, mice with disruption of the low-density lipoprotein receptor gene (Ldlr-/-mice), and mice with conditional deletion of nature killer (NK) cells (NKdele mice). Some C57BL/6J and NKdele mice were given injections of diethylinitrosamine to induce liver tumor formation. Mice were placed on a normal diet (ND) or high-cholesterol diet (HCD) to induce high serum levels of cholesterol. We also studied mice with homozygous disruption of ApoE (ApoE-/- mice), which spontaneously develop high serum cholesterol. C57BL/6J and NKdele mice on the ND or HCD were implanted with Hep1-6 (mouse hepatoma) cells and growth of xenograft tumors and lung metastases were monitored. Blood samples were collected from mice and analyzed by biochemistry and flow cytometry; liver and tumor tissues were collected and analyzed by histology, immunohistochemistry, and RNA-sequencing analysis. NK cells were isolated from mice and analyzed for cholesterol content, lipid raft formation, immune signaling, and changes in functions. We obtained matched tumor tissues and blood samples from 30 patients with HCC and blood samples from 40 healthy volunteers; levels of cholesterol and cytotoxicity of NK cells were measured. C57BL/6J mice on HCD and ApoE-/- mice with high serum levels of cholesterol developed fewer and smaller liver tumors and lung metastases after diethylinitrosamine injection or implantation of Hep1-6 cells than mice on ND. Liver tumors from HCD-fed mice and ApoE-/- mice had increased numbers of NK cells compared to tumors from ND-fed mice. NKdele mice or mice with antibody-based depletion for NK cells showed similar tumor number and size in ND and HCD groups after diethylinitrosamine injection or implantation of Hep1-6 cells. NK cells isolated from C57BL/6J mice fed with HCD had increased expression of NK cell-activating receptors (natural cytotoxicity triggering receptor 1 and natural killer group 2, member D), markers of effector function (granzyme B and perforin), and cytokines and chemokines compared with NK cells from mice on ND; these NK cells also had enhanced cytotoxic activity against mouse hepatoma cells, accumulated cholesterol, increased lipid raft formation, and immune signaling activation. NK cells isolated from HCD-fed Ldlr-/- mice did not have increased cholesterol content or cytotoxic activity against mouse hepatoma cells compared with ND-fed Ldlr-/- mice. Serum levels of cholesterol correlated with number and activity of NK cells isolated from human HCCs. Mice with increased serum levels of cholesterol due to an HCD or genetic disruption of ApoE develop fewer and smaller tumors after injection of hepatoma cells or a chemical carcinogen. We found cholesterol to accumulate in NK cells and activate their effector functions against hepatoma cells. Strategies to increase cholesterol uptake by NK cells can be developed for treatment of HCC.",
"Cholesterol is an essential lipid primarily synthesized in the liver through the mevalonate pathway. Besides being a precursor of steroid hormones, bile acid, and vitamin D, it is an essential structural component of cell membranes, is enriched in membrane lipid rafts, and plays a key role in intracellular signal transduction. The lipid homeostasis is finely regulated end appears to be impaired in several types of tumors, including breast cancer. In this review, we will analyse the multifaceted roles of cholesterol and its derivatives in breast cancer progression. As an example of the bivalent role of cholesterol in the cell membrane of cancer cells, on the one hand, it reduces membrane fluidity, which has been associated with a more aggressive tumor phenotype in terms of cell motility and migration, leading to metastasis formation. On the other hand, it makes the membrane less permeable to small water-soluble molecules that would otherwise freely cross, resulting in a loss of chemotherapeutics permeability. Regarding cholesterol derivatives, a lower vitamin D is associated with an increased risk of breast cancer, while steroid hormones, coupled with the overexpression of their receptors, play a crucial role in breast cancer progression. Despite the role of cholesterol and derivatives molecules in breast cancer development is still controversial, the use of cholesterol targeting drugs like statins and zoledronic acid appears as a challenging promising tool for breast cancer treatment.",
"Prostate cancer risk can be modified by environmental factors, however the molecular mechanisms affecting susceptibility to this disease are not well understood. As a result of a series of recently published studies, the steroidal lipid, cholesterol, has emerged as a clinically relevant therapeutic target in prostate cancer. This review summarizes the findings from human studies as well as animal and cell biology models, which suggest that high circulating cholesterol increases risk of aggressive prostate cancer, while cholesterol lowering strategies may confer protective benefit. Relevant molecular processes that have been experimentally tested and might explain these associations are described. We suggest that these promising results now could be applied prospectively to attempt to lower risk of prostate cancer in select populations."
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Complete Genome Sequence and Comparative Genotypic Analysis of Burkholderia contaminans SK875
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The Burkholderia cepacia complex (BCC) is a Gram-negative bacterial, including Burkholderia contaminans species. Although the plain Burkholderia is pervasive from taxonomic and genetic perspectives, a common characteristic is that they may use the quorum-sensing (QS) system. In our previous study, we generated the complete genome sequence of Burkholderia contaminans SK875 isolated from the respiratory tract. To our knowledge, this is the first study to report functional genomic features of B. contaminans SK875 for understanding the pathogenic characteristics. In addition, comparative genomic analysis for five B. contaminans genomes was performed to provide comprehensive information on the disease potential of B. contaminans species. Analysis of average nucleotide identity (ANI) showed that the genome has high similarity (> 96%) with other B. contaminans strains. Five B. contaminans genomes yielded a pangenome of 8832 coding genes, a core genome of 5452 genes, the accessory genome of 2128 genes, and a unique genome of 1252 genes. The 186 genes were specific to B. contaminans SK875, including toxin higB-2, oxygen-dependent choline dehydrogenase, and hypothetical proteins. Genotypic analysis of the antimicrobial resistance of B. contaminans SK875 verified resistance to tetracycline, fluoroquinolone, and aminoglycoside. Compared with the virulence factor database, we identified 79 promising virulence genes such as adhesion system, invasions, antiphagocytic, and secretion systems. Moreover, 45 genes of 57 QS-related genes that were identified in B. contaminans SK875 indicated high sequence homology with other B. contaminans strains. Our results will help to gain insight into virulence, antibiotic resistance, and quorum sensing for B. contaminans species.
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"Burkholderia sp. is a gram-negative bacterium that commonly exists in the environment, and can cause diseases in plants, animals, and humans. Here, a transposon mutant library of a Burkholderia lata isolate from a pig with swine respiratory disease in Korea was screened for strains showing attenuated virulence in Caenorhabditis elegans. One such mutant was obtained, and the Tn5 insertion junction was mapped to rpfR, a gene encoding a cyclic di-GMP phosphodiesterase that functions as a receptor. Mutation of rpfR caused a reduction in growth on CPG agar and swimming motility as well as a rough colony morphology on Congo red agar. TLC analysis showed reduced AHL secretion, which was in agreement with the results from plate-based and bioluminescence assays. The mutant strain produced significantly more biofilm detected by crystal violet staining than the parent strain. SEM of the mutant strain clearly showed that the overproduced biofilm contained a filamentous structure. These results suggest that the cyclic di-GMP phosphodiesterase RpfR plays an important role in quorum sensing modulation of the bacterial virulence and biofilm formation.",
"Quorum sensing (QS), a type of chemical communication, allows bacteria to sense and coordinate activities in natural biofilm communities using N-acyl homoserine lactones (AHLs) as one type of signaling molecule. For AHL-based communication to occur, bacteria must produce and recognize the same signals, which activate similar genes in different species. Our current understanding of AHL-QS suggests that signaling between species would arise randomly, which is not probable. We propose that AHL-QS signaling is a mutable and adaptable process, within limits. AHLs are highly-conserved signals, however, their corresponding receptor proteins (LuxR) are highly variable. We suggest that both flexibility and adaptation occur among receptor proteins, allowing for complex signaling networks to develop in biofilms over time.",
"Bacteria use quorum sensing to orchestrate gene expression programmes that underlie collective behaviours. Quorum sensing relies on the production, release, detection and group-level response to extracellular signalling molecules, which are called autoinducers. Recent work has discovered new autoinducers in Gram-negative bacteria, shown how these molecules are recognized by cognate receptors, revealed new regulatory components that are embedded in canonical signalling circuits and identified novel regulatory network designs. In this Review we examine how, together, these features of quorum sensing signal-response systems combine to control collective behaviours in Gram-negative bacteria and we discuss the implications for host-microbial associations and antibacterial therapy.",
"Pseudomonas syringae pv. actinidiae (Psa) is an emerging phytopathogen causing bacterial canker disease in kiwifruit plants worldwide. Quorum sensing (QS) gene regulation plays important roles in many different bacterial plant pathogens. In this study we analyzed the presence and possible role of N-acyl homoserine lactone (AHL) quorum sensing in Psa. It was established that Psa does not produce AHLs and that a typical complete LuxI/R QS system is absent in Psa strains. Psa however possesses three putative luxR solos designated here as PsaR1, PsaR2 and PsaR3. PsaR2 belongs to the sub-family of LuxR solos present in many plant associated bacteria (PAB) that binds and responds to yet unknown plant signal molecules. PsaR1 and PsaR3 are highly similar to LuxRs which bind AHLs and are part of the canonical LuxI/R AHL QS systems. Mutation in all the three luxR solos of Psa showed reduction of in planta survival and also showed additive effect if more than one solo was inactivated in double mutants. Gene promoter analysis revealed that the three solos are not auto-regulated and investigated their possible role in several bacterial phenotypes."
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Incidence and predictors of mortality among adult trauma patients admitted to intensive care units in Ethiopia
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Trauma is the leading cause of morbidity and mortality among adult population in the world. Despite many improvements in technology and care, mortality among trauma patients in the intensive care unit is still high particularly in Ethiopia. However, there is limited evidence on the incidence and predictors of mortality among trauma patients in Ethiopia. Therefore, this study aimed to assess the incidence and predictors of mortality among adult trauma patients admitted to intensive care units.
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"Surgical critical care is crucial to the care of trauma and surgical patients. This study was designed to provide a contemporary assessment of patient types, injuries, and conditions in intensive care units (ICU) caring for trauma patients. This was a multicenter prevalence study of the American Association for the Surgery of Trauma; data were collected on all patients present in participating centers' trauma ICU (TICU) on November 2, 2017 and April 10, 2018. Forty-nine centers submitted data on 1416 patients. Median age was 58 years (IQR 41-70). Patient types included trauma (n=665, 46.9%), non-trauma surgical (n=536, 37.8%), medical (n=204, 14.4% overall), or unspecified (n=11). Surgical intensivists managed 73.1% of patients. Of ICU-specific diagnoses, 57% were pulmonary related. Multiple high-intensity diagnoses were represented (septic shock, 10.2%; multiple organ failure, 5.58%; adult respiratory distress syndrome, 4.38%). Hemorrhagic shock was seen in 11.6% of trauma patients and 6.55% of all patients. The most common traumatic injuries were rib fractures (41.6%), brain (38.8%), hemothorax/pneumothorax (30.8%), and facial fractures (23.7%). Forty-four percent were on mechanical ventilation, and 17.6% had a tracheostomy. One-third (33%) had an infection, and over half (54.3%) were on antibiotics. Operations were performed in 70.2%, with 23.7% having abdominal surgery. At 30 days, 5.4% were still in the ICU. Median ICU length of stay was 9 days (IQR 4-20). 30-day mortality was 11.2%. Patient acuity in TICUs in the USA is very high, as is the breadth of pathology and the interventions provided. Non-trauma patients constitute a significant proportion of TICU care. Further assessment of the global predictors of outcome is needed to inform the education, research, clinical practice, and staffing of surgical critical care providers. IV, prospective observational study.",
"Traumatic injury is a leading cause of morbidity and mortality worldwide, but epidemiologic data about trauma patients who require intensive care unit (ICU) admission are scant. This study aimed to describe the annual incidence of ICU admission for adult trauma patients, including an assessment of risk factors for hospital complications and mortality in this population. This was a retrospective study of adults hospitalized at Level 1 and Level 2 trauma centers after trauma and recorded in the National Trauma Data Bank in 2013. Multiple logistic regression analyses were performed to determine predictors of hospital complications and hospital mortality for those who required ICU admission. There were an estimated total of 1.03 million ICU admissions for trauma at Level 1 and Level 2 trauma centers in the United States in 2013, yielding an annual incidence of 3.3 per 1000 population. The annual incidence was highest in men (4.6 versus 1.9 per 100,000 for women), those aged 80 years or older (7.8 versus 3.6-4.3 per 100,000 in other age groups), and residents in the Western US Census region (3.9 versus 2.7 to 3.6 per 100,000 in other regions). The most common complications in patients admitted to the ICU were pneumonia (10.9 %), urinary tract infection (4.7 %), and acute respiratory distress syndrome (4.4 %). Hospital mortality was significantly higher for ICU patients who developed one or more complications (16.9 % versus 10.7 % for those who did not develop any complications, p < 0.001). Admission to the ICU after traumatic injury is common, and almost a quarter of these patients experience hospital complications. Hospital complications are associated with significantly increased risk of mortality.",
"Traumatic brain injury is a major global public health problem causing substantial mortality among the adult population. Hence, this study aimed to determine the predictors of mortality among adult traumatic brain injury patients in Felegehiwot Comprehensive Specialized Hospital in Northwest Ethiopia during 2020. A retrospective cohort study was conducted at Felegehiwot Comprehensive Specialized Hospital using anonymized patient data obtained from chart review. Descriptive statistics were used to summarise the patient characteristics. The Kaplan-Meier survival curve and log-rank test were used to test for differences in survival status among groups. The Cox proportional hazards regression model was used at the 5% level of significance to determine the net effect of each explanatory variable on time to death. In total, 338 patients aged ≥15 years and diagnosed with traumatic brain injury were included in the analysis. Among these patients, 103 (30.45%) died, giving a crude death rate of 25.53 per 1000 (95% CI: 21.05-30.98) person-days of follow-up. The overall median survival time was 44 days. The independent predictors of mortality after diagnosis of traumatic brain injury were admission Glasgow coma scale score ≤ 8 (adjusted hazard ratio (AHR): 4.85; 95% confidence interval (CI): 1.73-13.62), bilateral non-reactive pupils at admission (AHR: 2.00 (95% CI: 1.10-3.71), elevated systolic blood pressure at admission (AHR: 0.31; 95% CI:0.11-0.86), elevated diastolic blood pressure at admission (AHR: 3.54; 95% CI: 1.33-9.43), and haematoma evacuation (AHR: 0.42; 95% CI: 0.16-0.90). The Survival status of traumatic brain injury patients was relatively low in this study. Glasgow coma scale score, bilateral non-reactive pupils, and elevated blood pressure were significant predictors of mortality. Further prospective follow-up studies that include residence and occupation are recommended.",
"The epidemiology of traumatic deaths was periodically described during the development of the American trauma system between 1977 and 1995. Recognizing the impact of aging populations and the potential changes in injury mechanisms, the purpose of this work was to provide a comprehensive, prospective, population-based study of Australian trauma-related deaths and compare the results with those of landmark studies. All prehospitalization and in-hospital trauma deaths occurring in an inclusive trauma system at a single Level 1 trauma center [400 patients with an injury severity score (ISS) >15/year] underwent autopsy and were prospectively evaluated during 2005. High-energy (HE) and low-energy (LE) deaths were categorized based on the mechanism of the injury, time frame (prehospitalization, <48 hours, 2-7 days, >7 days), and cause [which was determined by an expert panel and included central nervous system-related (CNS), exsanguination, CNS + exsanguination, airway, multiple organ failure (MOF)]. Data are presented as a percent or the mean +/- SEM. There were 175 deaths during the 12-month period. For the 103 HE fatalities (age 43 +/- 2 years, ISS 49 +/- 2, male 63%), the predominant mechanisms were motor vehicle related (72%), falls (4%), gunshots (8%), stabs (6%), and burns (5%). In all, 66% of the patients died during the prehospital phase, 27% died after <48 hours in hospital, 5% died after 3 to 7 days in hospital, and 2% died after >7 days. CNS (33%) and exsanguination (33%) were the most common causes of deaths, followed by CNS + exsanguination (17%) and airway compromise 8%; MOF occurred in only 3%. Six percent of the deaths were undetermined. All LE deaths (n = 72, age 83 +/- 1 years, ISS 14 +/- 1, male 45%) were due to low falls. All LE patients died in hospital (20% <48 hours, 32% after 3-7 days, 48% after 7 days). The causes of deaths were head injury (26%) and complications of skeletal injuries (74%). The HE injury mechanisms, time frames, and causes in our study are different from those in the earlier, seminal reports. The classic trimodal death distribution is much more skewed to early death. Exsanguination became as frequent as lethal head injuries, but the incidence of fatal MOF is lower than reported earlier. LE trauma is responsible for 41% of the postinjury mortality, with distinct epidemiology. The LE group deserves more attention and further investigation."
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Serum electrolytes and acute kidney injury: a review
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Acute kidney injury (AKI) affects up to 30% of all hospitalized patients in Central Europe and the USA. New biomarker molecules have been identified in recent years; most studies performed so far however aimed to identify markers for diagnostic purposes. Serum electrolytes such as sodium and potassium are quantified in more or less all hospitalized patients. Aim of the article is to review the literature on the AKI predictive role of four distinct serum electrolytes in evolving/progressing AKI. The following databases were searched for references: PubMed, Web of Science, Cochrane Library, and Scopus. The period lasted from 2010 until 2022. The following terms were utilized: "AKI" AND "sodium" OR "potassium" OR "calcium" OR "phosphate" AND "risk" OR "dialysis" OR "recovery of kidney function" OR "renal recovery" OR "kidney recovery" OR "outcome". Finally, 17 references were selected. The included studies were mostly retrospective in nature. Particularly, hyponatremia has been shown to be associated with an overall poor clinical outcome. The association between dysnatremia and AKI is anything but consistent. Hyperkalemia and potassium variability are most likely AKI predictive. Serum calcium and AKI risk are associated in a U-shaped manner. Higher phosphate levels potentially predict AKI in non-coronavirus disease 2019 (COVID-19) patients. The literature suggests that admission electrolytes can offer valuable information about AKI onset during follow-up. Limited data are however available on follow-up characteristics such as the need for dialysis or the chance of renal recovery. These aspects are of particular interest from the nephrologist's perspective.
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"The burden of AKI around the globe has not been systematically examined. A systematic review (2004-2012) of large cohort studies was conducted to estimate the world incidence of AKI and its stages of severity and associated mortality, and to describe geographic variations according to countries, regions, and their economies. AKI definitions were reclassified according to the Kidney Disease Improving Global Outcomes (KDIGO) staging system. Random-effects model meta-analyses and meta-regressions were used to generate summary estimates and explore sources of heterogeneity. There were 312 studies identified (n=49,147,878) , primarily in hospital settings. Most studies originated from North America, Northern Europe, and Eastern Asia, from high-income countries, and from nations that spent ≥5% of the gross domestic product on total health expenditure. Among the 154 studies (n=3,585,911) that adopted a KDIGO-equivalent AKI definition, the pooled incidence rates of AKI were 21.6% in adults (95% confidence interval [95% CI], 19.3 to 24.1) and 33.7% in children (95% CI, 26.9 to 41.3). The pooled AKI-associated mortality rates were 23.9% in adults (95% CI, 22.1 to 25.7) and 13.8% in children (95% CI, 8.8 to 21.0). The AKI-associated mortality rate declined over time, and was inversely related to income of countries and percentage of gross domestic product spent on total health expenditure. Using the KDIGO definition, 1 in 5 adults and 1 in 3 children worldwide experience AKI during a hospital episode of care. This analysis provides a platform to raise awareness of AKI with the public, government officials, and health care professionals.",
"Achieving \"adequacy of dialysis\" includes the maintenance of normal serum phosphate concentrations and is an important therapeutic goal in the treatment of acute renal failure (ARF). It is unknown whether this goal is best achieved with intermittent or continuous renal replacement therapy. We compared the effects of continuous veno-venous hemodiafiltration (CVVHDF) and intermittent hemodialysis (IHD) on serum phosphate concentrations using daily morning blood tests in 88 consecutive intensive care patients half of which were treated with IHD and half with CRRT RESULTS: Mean patient age was 54+/-14 years for IHD and 60+/-14 years for CVVHDF (NS). However, patients who received CVVHDF were more critically ill (mean APACHE II scores: 24.4+/-5.1 for IHD vs. 29.2+/-5.7 for CVVHDF, p<0.003). Before treatment, the serum phosphate concentration was 2.04+/-0.16 mmoll L for IHD and 1.96+/-0.17 mmoll L for CVVHDF (NS), with abnormal values in 79.4% of IHD patients and in 64.8% of CVVHDF patients (NS). During treatment, CVVHDF induced a greater reduction in serum phosphate (p=0.02) during the first 48 hours and conferred superior subsequent control of hyperphosphatemia (achieved in 64.6% of observations during CVVHDF vs. 41.8% during IHD; p<0.0001). The serum phosphate concentration was also more likely to be within the normal range during CVVHDF (55.3% vs.36.2%; p<0.0001). There was a trend toward more frequent hypophosphatemia (9.3% vs. 5.6%; P<0.1) during CVVHDF CONCLUSIONS: Abnormal serum phosphate concentrations are frequent in ARF patients before and during renal replacement, however, normalization of phosphatemia is achieved more frequently with CVVHDF.",
"Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of >90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD.",
"Hypophosphatemia during renal replacement therapy (RRT) is common in critically ill patients with acute kidney injury (AKI). The clinical consequences of RRT-induced phosphate depletion are not well defined in this patient population, and there is no evidence that intravenous sodium phosphate supplementation (PS) prevents the clinical sequelae of acute hypophosphatemia. The purpose of this retrospective analysis of the Acute Renal Support Registry of the University of Munich was to examine the association between severe hypophosphatemia and severity of and recovery from AKI. 289 ICU patients with AKI on intermittent hemodialysis (IHD) were included in the study. One hundred and forty-nine patients received PS during IHD. Outcomes were short-term (at discharge) and long-term (at 1 year) recovery of renal function and mortality. The two patient groups did not differ in demographics, clinical features, renal characteristics, and frequency of hypophosphatemia at initiation of IHD. Without PS, the frequency of hypophosphatemia increased from 20 to 35%. Severe hypophosphatemia was found in 50% of these patients. By comparison, PS was not associated with an increased frequency of hypophosphatemia. Compared with patients with acute phosphate depletion, patients receiving PS developed less oliguria during IHD, had shorter duration of AKI, higher incidence of complete renal recovery at discharge, and a lower risk of de novo chronic kidney disease. Hypophosphatemia was associated with higher all-cause in-hospital mortality and higher risk of long-term mortality. This multicenter study indicates for the first time that hypophosphatemia during IHD adversely affects short- and long-term outcome of critically-ill patients with AKI. The clinical consequences of the acute hypophosphatemic syndrome may be prevented by PS."
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The Repair Effects of the Repair Efficacy of a Multi-Agent System in a Multi-Agent System
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This study evaluated the repair effects of
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[
"Gut microbiota and their major metabolites, short-chain fatty acids (SCFAs), are recognized as important players in gut homeostasis and metabolic disease occurance. A convenient and sensitive detection method is needed to profile SCFAs in limited and complex biological samples. The gas chromatography/mass spectrometry (GC/MS) is the most common method for SCFAs profiling in biological samples. Trimethylsilyl (TMS) derivatization reagents such as N, O-bis(trimethyl-silyl)-trifluoroacetamide (BSTFA) are commonly used in GC/MS analysis to improve sensitivity and accuracy, but they were barely used in SCFA analysis due to their sensitivity to moisture and the volatility of SCFAs. Here, we developed a rapid, convenient and reliable method for SCFAs profiling in small amounts of fecal and serum samples by GC/MS using BSTFA in combination with sodium sulfate dehydration pretreatment. SCFAs were extracted with anhydrous ether from acidified fecal water extract or serum samples, followed by dehydration with sodium sulfate and BSTFA derivatization at a reduced temperature. Select ion monitoring mode was used for highly sensitive quantification of SCFAs by GC/MS. The derivation with BSTFA at 37 °C or 22 °C showed an excellent linearity (R2 > 0.999), good recoveries (81.27-128.42%), high repeatability (RSD < 2%) and low limit of detections (LODs) of different SCFAs ranging from 0.064 to 0.067 µM. All major SCFAs including acetic acid, propionic acid, isobutyric acid, butyric acid, isovaleric acid and valeric acid were identified and quantified accurately in fecal and serum samples. In conclusions, a reliable, convenient and sensitive method wasdeveloped for the measurement of SCFA and other volatile compounds in small biological samples using sodium sulfate dehydration pretreatment and BSTFA derivatization-based GC/MS analyses.",
"Antibiotic-associated diarrhea (AAD) is a common complication of antibiotics and recent findings on the epidemiology, etiologies and treatment strategies are reviewed. Rates of AAD vary from 5 to 39% depending upon the specific type of antibiotic. The severity of AAD may include uncomplicated diarrhea, colitis or pseudomembranous colitis. The pathogenesis of AAD may be mediated through the disruption of the normal flora and overgrowth of pathogens or through metabolic imbalances. The impact of AAD is reflected by increased hospital stays, higher medical costs and increased rates of comorbidity. The key to decreasing these consequences is prompt diagnosis followed by effective treatment and institution of control measures.",
"Antibiotic-associated diarrhea (AAD) is one of the most common complications of most types of antibiotics. Our aim was to determine the efficacy of Clostridium butyricum, Bifidobacterium infantis, and their mixture for AAD treatment in mice. AAD models were administered with single probiotic strain and probiotic mixture for short term and long term to evaluate the changes of the composition and diversity of intestinal microbiota, histopathology of the colon, and the systemic inflammation. Our data indicated that long-term probiotic therapy, but not short-term course, exerted beneficial effects on the restoration of the intestinal microbiota, the recovery of the tissue architecture, and attenuation of systemic inflammation. All predominant fecal bacteria reached normal level after the long-term probiotic mixture treatment, while IL-10, IFN-γ, and TNF-α also returned to normal level. However, the efficacy for AAD was time dependent and probiotic strain specific. Short-term administration of probiotic strains or mixture showed no apparent positive effects for AAD. In addition, the beneficial effects of C. butyricum combined with B. infantis probiotic mixture were superior to their single strain. This research showed that supplementation with C. butyricum combined with B. infantis probiotic mixture may be a simple and effective method for AAD treatment.",
"Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here, we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5+) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5+ cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5+ cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.",
"Early-life antibiotic use is associated with increased risk for metabolic and immunological diseases, and mouse studies indicate a causal role of the disrupted microbiome. However, little is known about the impacts of antibiotics on the developing microbiome of children. Here we use phylogenetics, metagenomics and individual antibiotic purchase records to show that macrolide use in 2-7 year-old Finnish children (N=142; sampled at two time points) is associated with a long-lasting shift in microbiota composition and metabolism. The shift includes depletion of Actinobacteria, increase in Bacteroidetes and Proteobacteria, decrease in bile-salt hydrolase and increase in macrolide resistance. Furthermore, macrolide use in early life is associated with increased risk of asthma and predisposes to antibiotic-associated weight gain. Overweight and asthmatic children have distinct microbiota compositions. Penicillins leave a weaker mark on the microbiota than macrolides. Our results support the idea that, without compromising clinical practice, the impact on the intestinal microbiota should be considered when prescribing antibiotics."
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Shigellosis in Low- and Middle-Income Countries (LMICs)
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Shigellosis causes more than 200,000 deaths worldwide and most of this burden falls on Low- and Middle-Income Countries (LMICs), with a particular incidence in children under 5 years of age. In the last decades,
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"The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.",
"The burden of dysentery due to shigellosis among children in the developing world is still a major concern. A safe and efficacious vaccine against this disease is a priority, since no licensed vaccine is available. This review provides an update of vaccine achievements focusing on subunit vaccine strategies and the forthcoming strategies surrounding this approach. In particular, this review explores several aspects of the pathogenesis of shigellosis and the elicited immune response as being the basis of vaccine requirements. The use of appropriate Shigella antigens, together with the right adjuvants, may offer safety, efficacy and more convenient delivery methods for massive worldwide vaccination campaigns.",
"Shigellosis is a leading cause of diarrhea worldwide prompting vaccine development. The Shigella flexneri Invaplex 50 is a macromolecular complex containing IpaB, IpaC, and LPS, formulated from an aqueous extract of virulent Shigella delivered via nasal administration. Preclinical vaccine testing demonstrated safety, immunogenicity and efficacy. An open-label dose-escalating phase 1 study evaluated a 3-dose (2-week intervals) regimen via nasal pipette delivery. Thirty-two subjects were enrolled into one of four vaccine dose groups (10, 50, 240, or 480 microg). The vaccine was well tolerated with minor short-lived nasal symptoms without evidence of dose effect. Antibody-secreting cell (ASC) responses were elicited at doses > or =50 microg with the highest IgG ASC, Invaplex 50 (100%) and S. flexneri 2a LPS (71%), as well as, serologic responses (43%) occurring with the 240 microg dose. Fecal IgA responses, Invaplex 50 (38.5%) and LPS (30.8%), were observed at doses > or =240 microg. The Invaplex 50 nasal vaccine was safe with encouraging mucosal immune responses. Follow-on studies will optimize dose, delivery mechanism and assess efficacy in a S. flexneri 2a challenge study.",
"Shigella remains the primary cause of diarrhoea in paediatric patients worldwide and accounts for up to 40,000 deaths per year. Current guidelines for the treatment of shigellosis are based on data which are over a decade old. In an era of increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for shigellosis in children is necessary, taking into account susceptibility patterns, cost and the risk of adverse events. A systematic review of the current published literature on the treatment of shigella dysentery was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The initial search produced 131 results, of which nine studies met the inclusion criteria. The quality of the studies was assessed as per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. International guidelines were also reviewed. There is a lack of current research regarding the clinical treatment of shigellosis in paediatric and adult patients, despite rising antimicrobial resistance worldwide. In particular, there is a lack of studies assessing the non-susceptibility of community-acquired strains, with almost all published research pertaining to microbiological data from hospital-based settings. Current WHO guidelines support the use of fluoroquinolones (first-line), β-lactams (second-line) and cephalosporins (second-line) which accords with currently available evidence and other international guidelines, and there is no strong evidence for changing this guidance. Azithromycin is appropriate as a second-line therapy in regions where the rate of non-susceptibility of ciprofloxacin is known to be high, and research suggests that, from a cardiac point of view, azithromycin is safer than other macrolide antibiotics. Cefixime is also a reasonable alternative, although its use must be weighed against the risk of dissemination of extended-spectrum β-lactamase-producing organisms.",
"Shigella is a highly prevalent bacterium causing acute diarrhea and dysentery in developing countries. Shigella infections are treated with antibiotics but Shigellae are increasingly resistant to these drugs. Vaccination can be a countermeasure against emerging antibiotic-resistant shigellosis. Because of the structural variability in Shigellae O-antigen polysaccharides (Oag), cross-protective Shigella vaccines cannot be derived from single serotype-specific Oag. We created an attenuated Shigella flexneri 2a strain with one rather than multiple Oag units by disrupting the Oag polymerase gene (Δwzy), which broadened protective immunogenicity by exposing conserved surface proteins. Inactivated Δwzy mutant cells combined with Escherichia coli double mutant LT(R192G/L211A) as adjuvant, induced potent antibody responses to outer membrane protein PSSP-1, and type III secretion system proteins IpaB and IpaC. Intranasal immunization with the vaccine preparation elicited cross-protective immunity against S. flexneri 2a, S. flexneri 3a, S. flexneri 6, and Shigella sonnei in a mouse pneumonia model. Thus, S. flexneri 2a Δwzy represents a promising candidate strain for a universal Shigella vaccine.",
"We are at an exciting moment in time with the advancement of many vaccines, including a shigella vaccine for the world. It is instructive to look at the long road that some vaccines have traveled to recognize the remarkable accomplishments of those who were pioneers, appreciate the evolution of scientific and applied technology, and inform the future history of a vaccine that would have great potential for global health. To achieve this valuable retrospective, a narrative historical literature review was undertaken utilizing PubMed and Embase databases with relevant search terms. Retrieved articles were reviewed and information was organized into historical themes, landmark discoveries, and important vaccine development parallels. The literature reviewed was synthesized into major eras of shigella vaccine development from pathogen discovery and first attempts to empirical approaches of killed whole-cell and live-attenuated approaches, and a modern era that applied recombinant DNA engineering and structural vaccinology. The history of shigella vaccine development has largely followed the evolutionary path of vaccine development over the last 120 years, but with important lessons learned that should be considered as we embark on the future chapters of bringing to the world a safe and effective vaccine for global health.",
"Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death. We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score-matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions). During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin. During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.)."
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Radiomics analysis as an adjuvant tool in the prognosis of disability after stroke
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Stroke is a leading cause of disability and mortality, resulting in substantial socio-economic burden for healthcare systems. With advances in artificial intelligence, visual image information can be processed into numerous quantitative features in an objective, repeatable and high-throughput fashion, in a process known as radiomics analysis (RA). Recently, investigators have attempted to apply RA to stroke neuroimaging in the hope of promoting personalized precision medicine. This review aimed to evaluate the role of RA as an adjuvant tool in the prognosis of disability after stroke. We conducted a systematic review following the PRISMA guidelines, searching PubMed and Embase using the keywords: 'magnetic resonance imaging (MRI)', 'radiomics', and 'stroke'. The PROBAST tool was used to assess the risk of bias. Radiomics quality score (RQS) was also applied to evaluate the methodological quality of radiomics studies. Of the 150 abstracts returned by electronic literature research, 6 studies fulfilled the inclusion criteria. Five studies evaluated predictive value for different predictive models (PMs). In all studies, the combined PMs consisting of clinical and radiomics features have achieved the best predictive performance compared to PMs based only on clinical or radiomics features, the results varying from an area under the ROC curve (AUC) of 0.80 (95% CI, 0.75-0.86) to an AUC of 0.92 (95% CI, 0.87-0.97). The median RQS of the included studies was 15, reflecting a moderate methodological quality. Assessing the risk of bias using PROBAST, potential high risk of bias in participants selection was identified. Our findings suggest that combined models integrating both clinical and advanced imaging variables seem to better predict the patients' disability outcome group (favorable outcome: modified Rankin scale (mRS) ≤ 2 and unfavorable outcome: mRS > 2) at three and six months after stroke. Although radiomics studies' findings are significant in research field, these results should be validated in multiple clinical settings in order to help clinicians to provide individual patients with optimal tailor-made treatment.
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[
"Accumulating evidence suggests that characteristics of pre-treatment FDG-PET could be used as prognostic factors to predict outcomes in different cancer sites. Current risk analyses are limited to visual assessment or direct uptake value measurements. We are investigating intensity-volume histogram metrics and shape and texture features extracted from PET images to predict patient's response to treatment. These approaches were demonstrated using datasets from cervix and head and neck cancers, where AUC of 0.76 and 1.0 were achieved, respectively. The preliminary results suggest that the proposed approaches could potentially provide better tools and discriminant power for utilizing functional imaging in clinical prognosis.",
"To test the hypothesis that texture analysis of postcontrast T1-weighted MR images will predict hemorrhagic transformation (HT) in patients with acute ischemic stroke (AIS) with better accuracy than visual evidence of contrast-enhancement (VE). Thirty-four AIS patients were examined within 3.5 +/- 1.5 h after stroke. T1-weighted MR images were acquired 19 +/- 7 min postcontrast injection. HT was determined by follow-up imaging at 24-72 h. Postcontrast images were evaluated for VE. Four second-order textural features were extracted (f1, f2, f3, and f9) for each patient. Receiver operating characteristic (ROC) curves were constructed for VE and for textural features, with HT as the outcome measure. The f2 for HT patients (n = 12) was significantly lower than in non-HT patients (1058 +/- 356 versus 1568 +/- 527; P = 0.005); the converse was true for f3 (0.67 +/- 0.12 versus 0.54 +/- 0.13; P = 0.007). ROC analysis indicated that the f2 and f3 textural features were the only two significant predictors of HT (P = 0.0018 and P = 0.0042). The addition of VE to either f2 or f3 did not result in a significant improvement in accuracy. Texture analysis of postcontrast T1-weighted images may be superior to visual evidence of enhancement for the prediction of HT.",
"To determine whether mean and entropy apparent diffusion coefficient (ADC) values obtained at diffusion-weighted (DW) magnetic resonance (MR) imaging can help detect and stage histopathologic liver fibrosis and grade inflammation activity in patients with chronic hepatitis C. This retrospective study was approved by the institutional review board, and the requirement for informed consent was waived. The study included 55 patients with focal hepatic lesions and either chronic hepatitis C (n = 43) or normal hepatic function (control subjects) (n = 12). Mean and entropy of volume histograms were generated in four cubic regions of interest placed in the right hepatic lobe of ADC map images, which were obtained at echo-planar DW MR imaging (gradient factor b values of 0 and 1000 sec/mm(2)). These two parameters (mean and entropy ADC) were compared by using METAVIR histopathologic liver fibrosis and inflammatory activity scores. Statistical analysis was performed with the Kruskal-Wallis test and receiver operating characteristic curves. The mean ADC decreased with an increase in the fibrosis stage or inflammatory activity grade, and the entropy ADC increased with an increase in the fibrosis stage or inflammatory activity grade (P < .001 for all comparisons, Kruskal-Wallis test). The area under the receiver operating characteristic curve (A(z)) for the mean ADC was statistically significant in the differentiation of fibrosis stage or inflammatory activity grade (A(z), 0.807-0.926; P < .001 for all comparisons). Entropy of ADC was helpful for classifying normal from abnormal fibrosis stage or inflammatory activity grade (A(z) for both parameters, 0.937; P < .001). Assessment of a combination of mean ADC and entropy ADC in patients with chronic hepatitis C is more accurate for predicting pathologic hepatic fibrosis stage and inflammatory activity grade and helpful for detecting early fibrotic or inflammatory activity when compared with assessment of mean ADC alone.",
"The discrimination of tumor boundaries from normal tissue, as well as the evaluation of tissue heterogeneity and tumor grading often continue to pose a challenge in MRI. Although yielding promising results in various fields of medical imaging, two- dimensional (2D) texture analysis in MRI has, until now, demonstrated a lack of specificity in brain tumor classification. A new three-dimensional (3D) approach using Cooccurrence Matrix analysis is proposed to increase the sensitivity and specificity of brain tumor characterization. A preliminary comparative evaluation of 2D and 3D texture analysis was performed on T(1)-weighted MRI of seven gliomas for characterization of solid tumor, necrosis, edema and surrounding white matter. With 3D compared to 2D method, a better discrimination is obtained between necrosis and solid tumor as well as between edema and solid tumor. Using both methods, peritumoral white matter overlaps with edema, but is completely separated from far homo-lateral matter. This latter shows a complete overlapping with contra-lateral matter. The 3D texture analysis approach could provide a new tool for tumor grading and treatment follow-up, as well as for surgery or radiation therapy planning.",
"Diffusion tensor imaging (DTI) is shown to reveal changes caused by cerebral infarction. The aim of this study is to reveal those changes also in the conventional magnetic resonance (MR) images using a quantitative image analysis method, texture analysis (TA). Thirty patients who had suffered their first ever infarction located on the right hemisphere underwent DTI and conventional MRI studies in the chronic phase. DTI parameters fractional anisotropy and mean diffusivity, as well as four second-order texture parameters were calculated. Interhemispheric differences and correlations between DTI and TA parameters were evaluated. Our DTI findings supported earlier studies as fractional anisotropy values were lowered and mean diffusivity values elevated in the lesion site, and ipsilateral cerebral peduncle, thalamus, and centrum semiovale compared to the unaffected side. Textural homogeneity parameters showed lower and complexity parameters higher values in the lesion site and ipsilateral centrum semiovale compared to the contralateral hemisphere. Correlation between the two methods was found in ipsilateral mesencephalon. In addition to DTI method, TA could assist in revealing the changes caused by infarction, also outside the lesion site. Damaged areas were found more heterogeneous and random in texture compared to unaffected sites.",
"The increasing use of biomarkers in cancer have led to the concept of personalized medicine for patients. Personalized medicine provides better diagnosis and treatment options available to clinicians. Radiological imaging techniques provide an opportunity to deliver unique data on different types of tissue. However, obtaining useful information from all radiological data is challenging in the era of \"big data\". Recent advances in computational power and the use of genomics have generated a new area of research termed Radiomics. Radiomics is defined as the high throughput extraction of quantitative imaging features or texture (radiomics) from imaging to decode tissue pathology and creating a high dimensional data set for feature extraction. Radiomic features provide information about the gray-scale patterns, inter-pixel relationships. In addition, shape and spectral properties can be extracted within the same regions of interest on radiological images. Moreover, these features can be further used to develop computational models using advanced machine learning algorithms that may serve as a tool for personalized diagnosis and treatment guidance.",
"Dynamic contrast-enhanced MRI (DCE-MRI) is widely used in the diagnosis and staging of cancer and is emerging as a promising method for monitoring tumour response to treatment. However, DCE-MR imaging techniques are still evolving and methods of image analysis remain variable and non-standard, and range from relative changes in the pattern of enhancement to pharmacokinetic modelling of contrast agent uptake. The combination of results from different institutions is therefore difficult and the sensitivities of different methods have not been compared. The purpose of this study is to investigate correlations between qualitative and quantitative methods of analysis for DCE-MR images from breast cancer patients undergoing neo-adjuvant chemotherapy. Fifteen patients underwent DCE-MRI examinations before and after one course of chemotherapy. Changes in the temporal pattern of signal enhancement, the rate and amplitude of enhancement and the volume transfer constant of contrast agent between the blood plasma and the extravascular extracellular space (EES), K(trans), and the EES fractional volume, nu(e), were determined. In addition, whole tumour region-of-interest analysis was compared with histogram analysis to investigate the extent of tumour heterogeneity. It was found that changes in the rate of enhancement correlated strongly with changes in K(trans) values (Kendall's tau = 0.68, P < 0.001). Furthermore, it was found that the shape of the signal enhancement curve only changed when the K(trans) values changed by 50% or more. Median K(trans) values determined following histogram analysis of pixel maps of K(trans) were approximately equal to those determined by whole tumour region-of-interest analysis. The absolute change in the K(trans) values correlated negatively with the pre-treatment values, particularly for responding patients. Thus, for higher pre-treatment K(trans) values, a greater decrease was observed. Greater changes were observed in the upper extremes of the K(trans) histogram than in the median values after one course of treatment."
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Prevalence, indications, and outcome of operative vaginal delivery in sub-Saharan Africa
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This systematic review and meta-analysis is intended to assess the prevalence, indications, and fetal outcome of operative vaginal delivery in sub-Saharan Africa.
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"Operative vaginal delivery refers to the use of measures to accomplish vaginal delivery through the use of instruments, mainly obstetric forceps and vacuum cups. In developed countries, the rate of cesarean section is increasing for fear of vaginal delivery complications, including instrumental delivery. This study was done to explore trends of operative vaginal deliveries and their characteristics. A cross-sectional, facility-based retrospective study was conducted over a period of five years July 1, 2011, to June 30, 2016, using data collected from the labor ward logbook, patient charts. Data were coded, entered, using SPSS version 20 statistical software. Descriptive statistical analysis was used to describe and analyze the data into graphs and tables. The rates of operative vaginal delivery and cesarean section over the five-year study period were 11.9% and 30.4%, respectively. The trend in the operative vaginal delivery rate declined from 15.8% in July 2011 to 9.9% in June 2016, while it shows a noticeable rise in cesarean section rate 25.4% to 33.8%. The trend in the use of vacuum has shown a sharp decrease from 58% in the 1st year to 10.5% in the fifth year of the study period. There is a rise in the use of forceps from 42% of all operative vaginal delivery in the first year to 89.5% in the fifth year. This study shows that the rate of operative vaginal delivery has declined. The use of vacuum-assisted delivery has especially decreased compared to that of forceps-assisted delivery.",
"Neonatal cephalohematoma and hyperbilirubinemia are often encountered after vacuum-assisted delivery. For safe obstetric practice, guidelines for vacuum procedure were published in 2014 in Japan. We aimed to identify the risk of mild neonatal complications since guideline introduction. This retrospective observational study included singleton deliveries at term gestation from 2015 to 2019 at a single perinatal center in Japan. Incidences of neonatal jaundice requiring phototherapy, cephalohematoma, and umbilical artery pH <7.10 were determined and risk factors relevant to the development of hyperbilirubinemia were evaluated. Of 1010 deliveries during the study period, vacuum procedures were attempted in 183 (18%). Guideline recommendations were fully adhered to in over 98% of vacuum procedures. Phototherapy for neonatal hyperbilirubinemia was performed in 75 (41%) of 183 deliveries with vacuum procedure, cephalohematoma occurred in 35 (19%), and umbilical artery pH <7.10 was observed in 10 (5.5%), all of which were significantly higher than without vacuum procedure, such as hyperbilirubinemia (11%, risk ratio [RR] = 3.8, 95% confidence interval [CI] = 2.9 - 4.9, p < .0001), cephalohematoma (1.0%, RR = 19.8, 95%CI = 9.3 - 41.9, p < .0001), and umbilical artery pH <7.10 (0.6%, RR = 9.0, 95%CI = 3.1 - 26.1, p < .0001). Multiple logistic regression analysis demonstrated that vacuum procedure was the factor most strongly associated with neonatal hyperbilirubinemia (odds ratio = 3.5, 95%CI = 2.2 - 5.5, p < .0001). Vacuum procedure is an important option for the safe vaginal delivery. However, neonates should be observed for development of jaundice to prevent kernicterus even after optimally performed vacuum-assisted delivery.",
"To identify potential risk or mishap in the system of intrapartum care, relating to the deployment of midwives. Prospective semistructured observational study. Labour wards of seven maternity units in the north west of England. All midwives working on the labour ward during the observation period in 2000. \"Latent failures\" within the system relating to midwifery staffing levels, deployment, and training or updating opportunities. Despite the exemplary dedication of midwives, potential risk of mishap due to their deployment occurred within the system of care. A shortfall of midwives existed in all seven maternity units and was most acute in the largest units. Six units relied on bank midwives to maintain minimum staffing levels. High risk practices (oxytocin administration and epidural blockades) continued during midwifery shortfalls in all units. Some adverse events and \"near misses\" were attributable to midwifery shortages in all units, and near misses remained unreported in all units. Uptake of opportunities for training or updating in interpretation of cardiotocographs and obstetric emergency management remained low owing to midwifery shortages in all units. A poor skill mix of midwives occurred at times in all units. In six units midwives spent time away from clinical areas performing clerical duties. In three units team midwifery systems were reported to erode labour ward skills and confidence. Midwives are fundamental components in the system of intrapartum care, and the system cannot operate safely and effectively when the number of midwives is inadequate, midwives are poorly deployed, and they are unable to engage in opportunities for training and updating.",
"The objective of this study was to assess the prevalence and sociodemographic characteristics of cesarean section in Ethiopia. We used data collected for Ethiopia Demographic and Health Surveys (DHS) conducted in 2000, 2005, 2011, and 2016. A two-stage, stratified, clustered random sampling design was used to gather information from women who gave birth within the 5-year period before each of the surveys. We analyzed the data to identify sociodemographic characteristics associated with cesarean section using log-Poisson regression models. The national cesarean section rate increased from 0.7% in 2000 to 1.9% in 2016, with increases across seven of the eleven administrative regions of Ethiopia. Addis Ababa had the highest cesarean section rate (21.4%) in 2016 and the greatest increase since 2000. In the adjusted analysis, women who gave birth in private health facility had a 78.0% higher risk of cesarean section (adjusted prevalence ratio (aPR) (95% CI) 1.78 (1.22, 2.58)) compared with women who gave birth in public health facility. Having four or more births was associated with a lower risk of cesarean section compared with first births (aPR (95% CI) 0.36 (0.16, 0.79)). The Ethiopian national cesarean section rate is about 2%, but the rate varies widely among administrative regions, suggesting unequal access. Cesarean sections were highest among urban mothers, first births, births to women with higher education, and births to women from the richest quintile of household wealth."
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Memory-guided decision-making in rat medial prefrontal cortex and dorsal hippocampal CA1
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Short-term memory enables incorporation of recent experience into subsequent decision-making. This processing recruits both the prefrontal cortex and hippocampus, where neurons encode task cues, rules, and outcomes. However, precisely which information is carried when, and by which neurons, remains unclear. Using population decoding of activity in rat medial prefrontal cortex (mPFC) and dorsal hippocampal CA1, we confirm that mPFC populations lead in maintaining sample information across delays of an operant non-match to sample task, despite individual neurons firing only transiently. During sample encoding, distinct mPFC subpopulations joined distributed CA1-mPFC cell assemblies hallmarked by 4-5 Hz rhythmic modulation; CA1-mPFC assemblies re-emerged during choice episodes but were not 4-5 Hz modulated. Delay-dependent errors arose when attenuated rhythmic assembly activity heralded collapse of sustained mPFC encoding. Our results map component processes of memory-guided decisions onto heterogeneous CA1-mPFC subpopulations and the dynamics of physiologically distinct, distributed cell assemblies.
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[
"Correlated activity in cortico-basal ganglia circuits plays a key role in the encoding of movement, associative learning and procedural memory. How correlated activity is assembled by striatal microcircuits is not understood. Calcium imaging of striatal neuronal populations, with single-cell resolution, reveals sporadic and asynchronous activity under control conditions. However, N-methyl-d-aspartate (NMDA) application induces bistability and correlated activity in striatal neurons. Widespread neurons within the field of observation present burst firing. Sets of neurons exhibit episodes of recurrent and synchronized bursting. Dimensionality reduction of network dynamics reveals functional states defined by cell assemblies that alternate their activity and display spatiotemporal pattern generation. Recurrent synchronous activity travels from one cell assembly to the other often returning to the original assembly; suggesting a robust structure. An initial search into the factors that sustain correlated activity of neuronal assemblies showed a critical dependence on both intrinsic and synaptic mechanisms: blockage of fast glutamatergic transmission annihilates all correlated firing, whereas blockage of GABAergic transmission locked the network into a single dominant state that eliminates assembly diversity. Reduction of L-type Ca(2+)-current restrains synchronization. Each cell assembly comprised different cells, but a small set of neurons was shared by different assemblies. A great proportion of the shared neurons was local interneurons with pacemaking properties. The network dynamics set into action by NMDA in the striatal network may reveal important properties of striatal microcircuits under normal and pathological conditions.",
"When making a decision it is often necessary to consider the available alternatives in order to choose the most appropriate option. This deliberative process, where the pros and cons of each option are considered, relies on memories of past actions and outcomes. The hippocampus and prefrontal cortex are required for memory encoding, memory retrieval and decision making, but it is unclear how these areas support deliberation. Here we examine the potential neural substrates of these processes in the rat. The rat is a powerful model to investigate the network mechanisms underlying deliberation in the mammalian brain given the anatomical and functional conservation of its hippocampus and prefrontal cortex to other mammalian systems. Importantly, it is amenable to large scale neural recording while performing laboratory tasks that exploit its natural decision-making behavior. Focusing on findings in the rat, we discuss how hippocampal-cortical interactions could provide a neural substrate for deliberative decision making.",
"Persistent activity underlying short-term memory encodes sensory information or instructs specific future movement and, consequently, has a crucial role in cognition. Despite extensive study, how the same set of neurons respond differentially to form selective persistent activity remains unknown. Here, we report that the cortico-basal ganglia-thalamo-cortical (CBTC) circuit supports the formation of selective persistent activity in mice. Optogenetic activation or inactivation of the basal ganglia output nucleus substantia nigra pars reticulata (SNr)-to-thalamus pathway biased future licking choice, without affecting licking execution. This perturbation differentially affected persistent activity in the frontal cortex and selectively modulated neural trajectory that encodes one choice but not the other. Recording showed that SNr neurons had selective persistent activity distributed across SNr, but with a hotspot in the mediolateral region. Optogenetic inactivation of the frontal cortex also differentially affected persistent activity in the SNr. Together, these results reveal a CBTC channel functioning to produce selective persistent activity underlying short-term memory.",
"The hippocampus, the prefrontal cortex, and the ventral striatum form interconnected neural circuits that may underlie aspects of spatial cognition and memory. In the present series of experiments, we investigated functional interactions between these areas in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. The two-phase delayed task consisted of a training phase that provided rats with information about where food would be located on the maze 30 min later during a test phase. The single-phase nondelayed task was identical to the test phase of the delayed task, but in the absence of a training phase rats lacked previous knowledge of the location of food on the maze. Transient inactivation of the ventral CA1/subiculum (vSub) by a bilateral injection of lidocaine disrupted performance on both tasks. Lidocaine injections into the vSub on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task but not the nondelayed task. Transient disconnections between the vSub and the nucleus accumbens produced the opposite effect, disrupting foraging during the nondelayed task but not during the delayed task. These data suggest that serial transmission of information between the vSub and the prefrontal cortex is required when trial-unique, short-term memory is used to guide prospective search behavior. In contrast, exploratory goal-directed locomotion in a novel situation not requiring previously acquired information about the location of food is dependent on serial transmission between the hippocampus and the nucleus accumbens. These results indicate that different aspects of spatially mediated behavior are subserved by separate, distributed limbic-cortical-striatal networks.",
"The hippocampus (HPC) and prefrontal cortex (PFC) are both necessary for learning and memory-guided behavior. Multiple direct and indirect anatomical projections connect the two regions, and HPC - PFC functional interactions are mediated by diverse physiological network patterns, thought to sub serve various memory processes. Disconnection experiments using contralateral inactivation approaches have established the role of direct, ipsilateral projections from ventral and intermediate HPC (vHPC and iHPC) to PFC in spatial memory. However, numerous studies have also prominently implicated physiological interactions between dorsal HPC (dHPC) and PFC regions in spatial memory tasks, and recent reports have identified direct dHPC - PFC connections. Whether dHPC - PFC interactions are necessary for spatial learning and memory has yet to be tested. Here, we used a chemogenetic inactivation approach using virally-expressed DREADDs (designer receptors exclusively activated by designer drugs) in rats to investigate the role of dHPC - PFC interactions in learning a hippocampal - dependent spatial alternation task. We implemented a rapid learning paradigm for a continuous W-track spatial alternation task comprising two components: an outbound, working memory component, and an inbound, spatial reference memory component. We investigated the effect of contralateral inactivation of dHPC and PFC on learning this task as compared with naïve and vehicle injection controls, as well as ipsilateral inactivation of the same regions. Contralateral dHPC - PFC inactivation selectively led to a significant impairment in learning the spatial working memory task compared to control groups, but did not impair learning of the spatial reference memory task. Ipsilateral inactivation animals showed similar learning rates as animals in the control groups. In a separate experiment, we confirmed that bilateral inactivation of PFC also leads to an impairment in learning the spatial working memory task. Our results thus demonstrate that dHPC - PFC interactions are necessary for spatial alternation learning in novel tasks. In addition, they provide crucial evidence to support the view that physiological interactions between dHPC and PFC play a key role in spatial learning and memory.",
"Competing accounts propose that working memory (WM) is subserved either by persistent activity in single neurons or by dynamic (time-varying) activity across a neural population. Here, we compare these hypotheses across four regions of prefrontal cortex (PFC) in an oculomotor-delayed-response task, where an intervening cue indicated the reward available for a correct saccade. WM representations were strongest in ventrolateral PFC neurons with higher intrinsic temporal stability (time-constant). At the population-level, although a stable mnemonic state was reached during the delay, this tuning geometry was reversed relative to cue-period selectivity, and was disrupted by the reward cue. Single-neuron analysis revealed many neurons switched to coding reward, rather than maintaining task-relevant spatial selectivity until saccade. These results imply WM is fulfilled by dynamic, population-level activity within high time-constant neurons. Rather than persistent activity supporting stable mnemonic representations that bridge subsequent salient stimuli, PFC neurons may stabilise a dynamic population-level process supporting WM.",
"Cortical neurons in vivo had been regarded as Poisson spike generators that convey no information other than the rate of random firing. Recently, using a metric for analyzing local variation of interspike intervals, researchers have found that individual neurons express specific patterns in generating spikes, which may symbolically be termed regular, random, or bursty, rather invariantly in time. In order to study the dynamics of firing patterns in greater detail, we propose here a Bayesian method for estimating firing irregularity and the firing rate simultaneously for a given spike sequence, and we implement an algorithm that may render the empirical Bayesian estimation practicable for data comprising a large number of spikes. Application of this method to electrophysiological data revealed a subtle correlation between the degree of firing irregularity and the firing rate for individual neurons. Irregularity of firing did not deviate greatly around the low degree of dependence on the firing rate and remained practically unchanged for individual neurons in the cortical areas V1 and MT, whereas it fluctuated greatly in the lateral geniculate nucleus of the thalamus. This indicates the presence and absence of autocontrolling mechanisms for maintaining patterns of firing in the cortex and thalamus, respectively.",
"Working memory (WM) provides the stability necessary for high-level cognition. Influential theories typically assume that WM depends on the persistence of stable neural representations, yet increasing evidence suggests that neural states are highly dynamic. Here we apply multivariate pattern analysis to explore the population dynamics in primate lateral prefrontal cortex (PFC) during three variants of the classic memory-guided saccade task (recorded in four animals). We observed the hallmark of dynamic population coding across key phases of a working memory task: sensory processing, memory encoding, and response execution. Throughout both these dynamic epochs and the memory delay period, however, the neural representational geometry remained stable. We identified two characteristics that jointly explain these dynamics: (1) time-varying changes in the subpopulation of neurons coding for task variables (i.e., dynamic subpopulations); and (2) time-varying selectivity within neurons (i.e., dynamic selectivity). These results indicate that even in a very simple memory-guided saccade task, PFC neurons display complex dynamics to support stable representations for WM.SIGNIFICANCE STATEMENT Flexible, intelligent behavior requires the maintenance and manipulation of incoming information over various time spans. For short time spans, this faculty is labeled \"working memory\" (WM). Dominant models propose that WM is maintained by stable, persistent patterns of neural activity in prefrontal cortex (PFC). However, recent evidence suggests that neural activity in PFC is dynamic, even while the contents of WM remain stably represented. Here, we explored the neural dynamics in PFC during a memory-guided saccade task. We found evidence for dynamic population coding in various task epochs, despite striking stability in the neural representational geometry of WM. Furthermore, we identified two distinct cellular mechanisms that contribute to dynamic population coding.",
"We consider the problem of extracting smooth, low-dimensional neural trajectories that summarize the activity recorded simultaneously from many neurons on individual experimental trials. Beyond the benefit of visualizing the high-dimensional, noisy spiking activity in a compact form, such trajectories can offer insight into the dynamics of the neural circuitry underlying the recorded activity. Current methods for extracting neural trajectories involve a two-stage process: the spike trains are first smoothed over time, then a static dimensionality-reduction technique is applied. We first describe extensions of the two-stage methods that allow the degree of smoothing to be chosen in a principled way and that account for spiking variability, which may vary both across neurons and across time. We then present a novel method for extracting neural trajectories-Gaussian-process factor analysis (GPFA)-which unifies the smoothing and dimensionality-reduction operations in a common probabilistic framework. We applied these methods to the activity of 61 neurons recorded simultaneously in macaque premotor and motor cortices during reach planning and execution. By adopting a goodness-of-fit metric that measures how well the activity of each neuron can be predicted by all other recorded neurons, we found that the proposed extensions improved the predictive ability of the two-stage methods. The predictive ability was further improved by going to GPFA. From the extracted trajectories, we directly observed a convergence in neural state during motor planning, an effect that was shown indirectly by previous studies. We then show how such methods can be a powerful tool for relating the spiking activity across a neural population to the subject's behavior on a single-trial basis. Finally, to assess how well the proposed methods characterize neural population activity when the underlying time course is known, we performed simulations that revealed that GPFA performed tens of percent better than the best two-stage method.",
"Most sensory, cognitive and motor functions depend on the interactions of many neurons. In recent years, there has been rapid development and increasing use of technologies for recording from large numbers of neurons, either sequentially or simultaneously. A key question is what scientific insight can be gained by studying a population of recorded neurons beyond studying each neuron individually. Here, we examine three important motivations for population studies: single-trial hypotheses requiring statistical power, hypotheses of population response structure and exploratory analyses of large data sets. Many recent studies have adopted dimensionality reduction to analyze these populations and to find features that are not apparent at the level of individual neurons. We describe the dimensionality reduction methods commonly applied to population activity and offer practical advice about selecting methods and interpreting their outputs. This review is intended for experimental and computational researchers who seek to understand the role dimensionality reduction has had and can have in systems neuroscience, and who seek to apply these methods to their own data."
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DNA alkylation adducts and DNA translesion synthesis
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Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.
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[
"N3-Methyladenine (3-MeA) is formed in DNA by reaction with S-adenosylmethionine, the reactive methyl donor, and by reaction with alkylating agents. 3-MeA protrudes into the DNA minor groove and strongly blocks synthesis by replicative DNA polymerases (Pols). However, the mechanisms for replicating through this lesion in human cells remain unidentified. Here we analyzed the roles of translesion synthesis (TLS) Pols in the replication of 3-MeA-damaged DNA in human cells. Because 3-MeA has a short half-life in vitro, we used the stable 3-deaza analog, 3-deaza-3-methyladenine (3-dMeA), which blocks the DNA minor groove similarly to 3-MeA. We found that replication through the 3-dMeA adduct is mediated via three different pathways, dependent upon Polι/Polκ, Polθ, and Polζ. As inferred from biochemical studies, in the Polι/Polκ pathway, Polι inserts a nucleotide (nt) opposite 3-dMeA and Polκ extends synthesis from the inserted nt. In the Polθ pathway, Polθ carries out both the insertion and extension steps of TLS opposite 3-dMeA, and in the Polζ pathway, Polζ extends synthesis following nt insertion by an as yet unidentified Pol. Steady-state kinetic analyses indicated that Polι and Polθ insert the correct nt T opposite 3-dMeA with a much reduced catalytic efficiency and that both Pols exhibit a high propensity for inserting a wrong nt opposite this adduct. However, despite their low fidelity of synthesis opposite 3-dMeA, TLS opposite this lesion replicates DNA in a highly error-free manner in human cells. We discuss the implications of these observations for TLS mechanisms in human cells.",
"Chloroethylating nitrosoureas (CNU), such as lomustine, nimustine, semustine, carmustine and fotemustine are used for the treatment of malignant gliomas, brain metastases of different origin, melanomas and Hodgkin disease. They alkylate the DNA bases and give rise to the formation of monoadducts and subsequently interstrand crosslinks (ICL). ICL are critical cytotoxic DNA lesions that link the DNA strands covalently and block DNA replication and transcription. As a result, S phase progression is inhibited and cells are triggered to undergo apoptosis and necrosis, which both contribute to the effectiveness of CNU-based cancer therapy. However, tumor cells resist chemotherapy through the repair of CNU-induced DNA damage. The suicide enzyme O6-methylguanine-DNA methyltransferase (MGMT) removes the precursor DNA lesion O6-chloroethylguanine prior to its conversion into ICL. In cells lacking MGMT, the formed ICL evoke complex enzymatic networks to accomplish their removal. Here we discuss the mechanism of ICL repair as a survival strategy of healthy and cancer cells and DNA damage signaling as a mechanism contributing to CNU-induced cell death. We also discuss therapeutic implications and strategies based on sequential and simultaneous treatment with CNU and the methylating drug temozolomide.",
"Quantitative measurement of DNA adducts in carcinogen-exposed cells provides the information about the frequency of formation and the rate of removal of DNA lesions in vivo, which yields insights into the initial events of mutagenesis. Metabolic activation of tobacco-specific nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its reduction product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), leads to pyridyloxobutylation and pyridylhydroxybutylation of DNA. In this study, we employed a highly robust nanoflow liquid chromatography-nanoelectrospray ionization-tandem mass spectrometry (nLC-nESI-MS/MS) coupled with the isotope-dilution method for simultaneous quantification of O6-[4-(3-pyridyl)-4-hydroxylbut-1-yl]-2'-deoxyguanosine ( O6-PHBdG) and O2- and O4-[4-(3-pyridyl)-4-hydroxylbut-1-yl]-thymidine ( O2-PHBdT and O4-PHBdT). Cultured mammalian cells were exposed to a model pyridylhydroxybutylating agent, 4-(acetoxymethylnitrosamino)-1-(3-pyridyl)-1-butanol (NNALOAc), followed by DNA extraction, enzymatic digestion, and sample enrichment prior to nLC-nESI-MS/MS quantification. Our results demonstrate, for the first time, that O4-PHBdT is quantifiable in cellular DNA and naked DNA upon NNALOAc exposure. We also show that nucleotide excision repair (NER) machinery may counteract the formation of O2-PHBdT and O4-PHBdT, and O6-alkylguanine DNA alkyltransferase (AGT) may be responsible for the repair of O6-PHBdG and O4-PHBdT in mammalian cells. Together, our study provides new knowledge about the occurrence and repair of NNAL-induced DNA lesions in mammalian cells.",
"1,N(6)-ethanoadenine (EA) forms through the reaction of adenine in DNA with the antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic used to combat various brain, head, and neck tumors. Previous studies of the toxic and mutagenic properties of the DNA adduct EA have been limited to in vitro experiments using mammalian polymerases and have revealed the lesion to be both miscoding and genotoxic. This work explores lesion bypass and mutagenicity of EA replicated in vivo and demonstrates that EA is neither toxic nor mutagenic in wild-type Escherichia coli. Although the base excision repair glycosylase enzymes of both humans and E. coli possess a weak ability to act on the lesion in vitro, an in vivo repair pathway has not yet been demonstrated. Here we show that an enzyme mechanistically unrelated to DNA glycosylases, the adaptive response protein AlkB, is capable of acting on EA via its canonical mechanism of oxidative dealkylation. The reaction alleviates the unrepaired adduct's potent toxicity through metabolism at the C8 position (attached to N1 of adenine), producing a nontoxic and weakly mutagenic N(6) adduct. AlkB is shown here to be a geno-protective agent that reduces the toxicity of DNA damage by converting the primary adduct to a less toxic secondary product.",
"Adducts of O6-alkylguanine in DNA that are induced by cytotoxic, carcinogenic or mutagenic alkylating agents can be removed by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). Human tumor cell lines that do not express this enzyme (Mer-) are hypersensitive to the effects of such alkylating agents, although the molecular basis of MGMT gene suppression is not yet understood. Previous studies suggested that Mer- cells deficient in this enzyme lack neither the gene nor the trans-acting factors necessary for normal transcription. Methylation of CpG dinucleotides is an attractive mechanism to account for suppression of the MGMT gene; however, there have been reports of both direct and inverse correlations between methylation and MGMT expression. We previously demonstrated an inverse correlation between methylation at a single SmaI site in the human MGMT promoter and gene expression. To substantiate this observation, we examined additional CpGs in the promoters of three Mer+ and three Mer- cell lines, using rare methylation-sensitive restriction sites, and then sought to identify the region where methylation correlated with gene expression. Six CpGs in the region from -245 bp to +225 bp (relative to the transcription start site) were completely unmethylated in all Mer+ cells, whereas in Mer- cells were at least partially methylated. The methylation status of CpGs further upstream did not correlate with MGMT expression. We conclude, therefore, that the association between CpG methylation and suppressed MGMT gene activity extends to sites other than SmaI but is limited to a core region of the promoter.",
"O(6)-Methylguanine ((Me)G) is a highly cytotoxic DNA modification generated by S(N)1-type methylating agents. Despite numerous studies implicating DNA replication, mismatch repair (MMR), and homologous recombination (HR) in (Me)G toxicity, its mode of action has remained elusive. We studied the molecular transactions in the DNA of yeast and mammalian cells treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Although replication fork progression was unaffected in the first cell cycle after treatment, electron microscopic analysis revealed an accumulation of (Me)G- and MMR-dependent single-stranded DNA (ssDNA) gaps in newly replicated DNA. Progression into the second cell cycle required HR, while the following G(2) arrest required the continued presence of (Me)G. Yeast cells overcame this block, while mammalian cells generally failed to recover, and those that did contained multiple sister chromatid exchanges. Notably, the arrest could be abolished by removal of (Me)G after the first S phase. These new data provide compelling support for the hypothesis that MMR attempts to correct (Me)G/C or (Me)G/T mispairs arising during replication. Due to the persistence of (Me)G in the exposed template strand, repair synthesis cannot take place, which leaves single-stranded gaps behind the replication fork. During the subsequent S phase, these gaps cause replication fork collapse and elicit recombination and cell cycle arrest.",
"Elevated levels of luminal nitrite and a lowered luminal pH were found in 77 percent of patients with acute ulcerative colitis. No luminal nitrite was found in healthy control subjects. Nitrites are a secretory product of activated macrophages and neutrophils of the lamina propria, whereas the lowered luminal pH is due to diminished bicarbonate formation by impaired colonocytes. A hypothesis is put forward that nitrites, lowered pH, and bacterial amines are conducive to formation of carcinogenic n-nitroso compounds, which reflect a cancer risk in patients with ulcerative colitis dependent on the type and extent of inflammatory cell activation as well as metabolic impairment of colonic epithelial cells."
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Prevalence of vitamin D deficiency/insufficiency in hospitalized patients in Romania
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Vitamin D deficiency is one of the most common medical conditions, with approximately one billion people having low vitamin D levels. Vitamin D is associated with a pleiotropic effect (immunomodulatory, anti-inflammatory and antiviral), which can be essential for a better immune response. The aim of this research was to evaluate the prevalence of vitamin D deficiency/insufficiency in hospitalized patients focusing on demographic parameters as well as assessing the possibility of its associations with different comorbidities. Of 11,182 Romanian patients evaluated in the study over 2 years, 28.83% had vitamin D deficiency, 32.11% insufficiency and 39.05% had optimal vitamin D levels. The vitamin D deficiency was associated with cardiovascular disorders, malignancies, dysmetabolic disorders and SARS-CoV2 infection, older age and the male sex. Vitamin D deficiency was prevalent and showed pathology association, while insufficiency of vitamin D (20-30 ng/mL) had lower statistical relevance and represents a grey zone in vitamin D status. Guidelines and recommendations are necessary for homogeneity of the monitoring and management of inadequately vitamin D status in the risk categories.
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[
"To heighten awareness of the problems related to the high prevalence of suboptimal vitamin D status in hospitalized patients and the general population, including an overview of vitamin D biology, how vitamin D status is defined, the negative health issues associated with suboptimal vitamin D status, indications for treatment, treatment strategies, and controversies in the field. (a) Literature review was performed using PubMed and CINAHL databases to locate and review medical, nursing, and nutritional journals. (b) Authors' recent prospective studies of 100 patients in a general tertiary hospital rehabilitation unit and 51 nonhospitalized volunteers. Poor vitamin D status (ranging from suboptimal to overt deficiency) is common in both hospitalized patients and ostensibly healthy individuals of all ages and geographic latitude. Suboptimal vitamin D status is associated with muscle weakness, functional deficits, and perhaps longer length of stay of hospitalized patients. Predictors of vitamin D status include race, poor nutrition, advanced age, use of multivitamins, ultraviolet light exposure, and grip strength. Fortunately, treatment with 50,000 IU of vitamin D(2) for several weeks is a very inexpensive and safe yet effective treatment to replete vitamin D status. NPs should be aware of the indications for monitoring vitamin D status and the appropriate treatment for suboptimal vitamin D status. Improving vitamin D status may improve a patient's functional ability, therefore decreasing falls and preventing fractures, decreasing length of stay in the hospital, and decreasing the cost of health care. Providers can potentially improve the life of older adults by educating patients on the importance of vitamin D supplementation.",
"Vitamin D deficiency is present even in sunny regions. Ageing decreases pre-vitamin D production in the skin and is associated with altered cytokine profile. We performed a multivariate analysis considering lifestyle factors, anthropometric, and inflammatory markers according to seasonal variation in Mexican healthy older adults. The same cohort was followed during 12 months. Vitamin D deficiency/insufficiency was found in 91.3% of the subjects despite living in appropriate latitude (25°40'0″N). 25(OH)D levels remained below <30 ng/mL through all seasons. Vitamin D deficiency did not correlate to sun exposure or dietary intake. Gender was the strongest associated factor, explaining a variance of 20%. Waist circumference (WC) greater than 88 cm was a risk factor for vitamin D deficiency. Age (>74 years) combined with WC (>88 cm) and BMI (>32.7) showed a high probability (90%) of vitamin D deficiency. Remarkably, an increase in one centimeter in WC decreased 25(OH)D by 0.176 ng/mL, while an increase in one point BMI decreased 25(OH)D by 0.534 ng/mL. A cutoff point of 74 years of age determined probability of vitamin D hipovitaminosis. Vitamin D deficiency was correlated with TNF-α serum levels, possibly increasing the susceptibility of older adults to a proinflammatory state and its related diseases.",
"Beyond its critical function in calcium homeostasis, vitamin D has recently been found to play an important role in the modulation of the immune/inflammation system via regulating the production of inflammatory cytokines and inhibiting the proliferation of proinflammatory cells, both of which are crucial for the pathogenesis of inflammatory diseases. Several studies have associated lower vitamin D status with increased risk and unfavorable outcome of acute infections. Vitamin D supplementation bolsters clinical responses to acute infection. Moreover, chronic inflammatory diseases, such as atherosclerosis-related cardiovascular disease, asthma, inflammatory bowel disease, chronic kidney disease, nonalcoholic fatty liver disease, and others, tend to have lower vitamin D status, which may play a pleiotropic role in the pathogenesis of the diseases. In this article, we review recent epidemiological and interventional studies of vitamin D in various inflammatory diseases. The potential mechanisms of vitamin D in regulating immune/inflammatory responses in inflammatory diseases are also discussed.",
"Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory autoimmune disease. Vitamin D has potent immunomodulatory properties that support its use in the treatment of autoimmune conditions, including SLE. We assessed vitamin D status in patients with SLE and determined alterations in inflammatory and hemostatic markers and disease activity before and after vitamin D supplementation. Patients with SLE (n = 267) were randomized 2:1 to receive either oral cholecalciferol 2000 IU/day or placebo for 12 months. Outcome measures included assessment of alterations in levels of proinflammatory cytokines and hemostatic markers, and improvement in disease activity before and after 12 months of supplementation. Disease activity was measured by the SLE Disease Activity Index. Vitamin D levels were measured by Liaison immunoassay (normal 30-100 ng/ml). Serum levels between 10 and 30 ng/ml were classified as vitamin D insufficiency and levels < 10 ng/ml as vitamin D deficiency. The mean 25(OH)D level at baseline was 19.8 ng/ml in patients compared to 28.7 ng/ml in controls. The overall prevalence of suboptimal and deficient 25(OH)D serum levels among patients with SLE at baseline was 69% and 39%, respectively. Lower 25(OH)D levels correlated significantly with higher SLE disease activity. At 12 months of therapy, there was a significant improvement in levels of inflammatory and hemostatic markers as well as disease activity in the treatment group compared to the placebo group. Vitamin D supplementation in patients with SLE is recommended because increased vitamin D levels seem to ameliorate inflammatory and hemostatic markers and show a tendency toward subsequent clinical improvement. Clinical Trial Registry NCT01425775.",
"Vitamin D deficiency has a high worldwide prevalence, but actions to improve this public health problem are challenged by the heterogeneity of nutritional and clinical vitamin D guidelines, with respect to the diagnosis and treatment of vitamin D deficiency. We aimed to address this issue by providing respective recommendations for adults, developed by a European expert panel, using the Delphi method to reach consensus. Increasing the awareness of vitamin D deficiency and efforts to harmonize vitamin D guidelines should be pursued. We argue against a general screening for vitamin D deficiency but suggest 25-hydroxyvitamin D (25(OH)D) testing in certain risk groups. We recommend a vitamin D supplementation dose of 800 to 2000 international units (IU) per day for adults who want to ensure a sufficient vitamin D status. These doses are also recommended for the treatment of vitamin D deficiency, but higher vitamin D doses (e.g., 6000 IU per day) may be used for the first 4 to 12 weeks of treatment if a rapid correction of vitamin D deficiency is clinically indicated before continuing, with a maintenance dose of 800 to 2000 IU per day. Treatment success may be evaluated after at least 6 to 12 weeks in certain risk groups (e.g., patients with malabsorption syndromes) by measurement of serum 25(OH)D, with the aim to target concentrations of 30 to 50 ng/mL (75 to 125 nmol/L).",
"Vitamin D has immune-regulatory functions in experimental colitis, and low vitamin D levels are present in Crohn's disease. To assess the effectiveness of vitamin D3 treatment in Crohn's disease with regard to improved disease course. We performed a randomized double-blind placebo-controlled trial to assess the benefits of oral vitamin D3 treatment in Crohn's disease. We included 108 patients with Crohn's disease in remission, of which fourteen were excluded later. Patients were randomized to receive either 1200 IU vitamin D3 (n = 46) or placebo (n = 48) once daily during 12 months. The primary endpoint was clinical relapse. Oral vitamin D3 treatment with 1200 IU daily increased serum 25OHD from mean 69 nmol/L [standard deviation (s.d.) 31 nmol/L] to mean 96 nmol/L (s.d. 27 nmol/L) after 3 months (P < 0.001). The relapse rate was lower among patients treated with vitamin D3 (6/46 or 13%) than among patients treated with placebo (14/48 or 29%), (P = 0.06). Oral supplementation with 1200 IE vitamin D3 significantly increased serum vitamin D levels and insignificantly reduced the risk of relapse from 29% to 13%, (P = 0.06). Given that vitamin D3 treatment might be effective in Crohn's disease, we suggest larger studies to elucidate this matter further. ClinicalTrial.gov(NCT00122184).",
"Vitamin D insufficiency [serum 25-hydroxyvitamin D (25OHD) concentration less than 20 ng/ml] is prevalent among children with inflammatory bowel disease (IBD), and its treatment has not been studied. The aim of this study was to compare the efficacy and safety of three vitamin D repletion regimens. We conducted a randomized, controlled clinical trial from November 2007 to June 2010 at the Clinical and Translational Study Unit of Children's Hospital Boston. The study was not blinded to participants and investigators. Eligibility criteria included diagnosis of IBD, age 5-21, and serum 25OHD concentration below 20 ng/ml. Seventy-one patients enrolled, 61 completed the trial, and two withdrew due to adverse events. Patients received orally for 6 wk: vitamin D(2), 2,000 IU daily (arm A, control); vitamin D(3), 2,000 IU daily (arm B); vitamin D(2), 50,000 IU weekly (arm C); and an age-appropriate calcium supplement. We measured the change in serum 25OHD concentration (Δ25OHD) (ng/ml). Secondary outcomes included change in serum intact PTH concentration (ΔPTH) (pg/ml) and the adverse event occurrence rate. After 6 wk, Δ25OHD ± se was: 9.3 ± 1.8 (arm A); 16.4 ± 2.0 (arm B); 25.4 ± 2.5 (arm C); P (A vs. C) = 0.0004; P (A vs. B) = 0.03. ΔPTH ± SE was -5.6 ± 5.5 (arm A); -0.1 ± 4.2 (arm B); -4.4 ± 3.9 (arm C); P = 0.57. No participant experienced hypercalcemia or hyperphosphatemia, and the prevalence of hypercalciuria did not differ among arms at follow-up. Oral doses of 2,000 IU vitamin D(3) daily and 50,000 IU vitamin D(2) weekly for 6 wk are superior to 2,000 IU vitamin D(2) daily for 6 wk in raising serum 25OHD concentration and are well-tolerated among children and adolescents with IBD. The change in serum PTH concentration did not differ among arms.",
"Vitamin D is well known to exert multiple functions in bone biology, autoimmune diseases, cell growth, inflammation or neuromuscular and other immune functions. It is a fat-soluble vitamin present in many foods. It can be endogenously produced by ultraviolet rays from sunlight when the skin is exposed to initiate vitamin D synthesis. However, since vitamin D is biologically inert when obtained from sun exposure or diet, it must first be activated in human beings before functioning. The kidney and the liver play here a crucial role by hydroxylation of vitamin D to 25-hydroxyvitamin D in the liver and to 1,25-dihydroxyvitamin D in the kidney. In the past decades, it has been proven that vitamin D deficiency is involved in many diseases. Due to vitamin D's central role in the musculoskeletal system and consequently the strong negative impact on bone health in cases of vitamin D deficiency, our aim was to underline its importance in bone physiology by summarizing recent findings on the correlation of vitamin D status and rickets, osteomalacia, osteopenia, primary and secondary osteoporosis as well as sarcopenia and musculoskeletal pain. While these diseases all positively correlate with a vitamin D deficiency, there is a great controversy regarding the appropriate vitamin D supplementation as both positive and negative effects on bone mineral density, musculoskeletal pain and incidence of falls are reported.",
"The impact of vitamin D deficiency on the recovery of patients with malnutrition remains undefined. Our aim was to study the prevalence of vitamin D deficiency in a well-characterized cohort of patients with malnutrition and its association with outcomes.Within this secondary analysis of a randomized controlled trial, we examined the association of vitamin D deficiency and adverse clinical outcomes over a follow-up of 180 days in hospitalized patients at risk for malnutrition. We measured 25-hydroxyvitamin D levels upon admission and defined Vitamin D deficiency when levels were <50nmol/l. The primary endpoint was 180-day mortality.The prevalence of vitamin D deficiency in our cohort of 828 patients was 58.2% (n = 482). Patients with vitamin D deficiency had increased 180-day mortality rates from 23.1% to 29.9% (odds ratio 1.42, 95% confidence interval [CI] 1.03-1.94, P = .03). When adjusting the analysis for demographics, comorbidities, and randomization, this association remained significant for the subgroup of patients not receiving vitamin D treatment (adjusted odds ratio 1.63, 95% CI 1.01-2.62, P = .04). There was no significantly lower risk for mortality in the subgroup of vitamin D deficient patients receiving vitamin D treatment compared to not receiving treatment (adjusted odds ratio 0.74, 95% CI 0.48-1.13, P = .15).Vitamin D deficiency is highly prevalent in the population of malnourished inpatients and is negatively associated with long-term mortality particularly when patients are not receiving vitamin D treatment. Our findings suggest that malnourished patients might benefit from vitamin D screening and treatment in case of deficiency.",
"Vitamin D has cardiovascular protective effects besides regulating calcium homeostasis. To examine the chronic in vivo effect of a physiological dose of 1,25-dihydroxyvitamin D(3) on the occurrence of endothelium-dependent contractions, spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were treated with the vitamin D derivative for 6 wk. The serum 1,25-dihydroxyvitamin D(3) level of both treated WKY and SHR was significantly higher than in untreated rats while the mean arterial blood pressure of the treated SHR was significantly lower than that of control SHR. Aortic rings with or without endothelium were studied in conventional organ chambers for isometric force measurement. Confocal microscopy was used to measure the cytosolic free calcium concentration (with the fluorescent dye fluo 4) and reactive oxygen species (ROS; with dichlorodihydrofluorescein diacetate). Reverse transcription PCR and Western blotting were used to determine the mRNA and protein expression level of cyclooxygenase-1 (COX-1), prostacyclin synthase, and thromboxane synthase. The endothelium-dependent concentration-contraction curves to both acetylcholine- and A-23187-induced contractions were shifted to the right in aortas from treated SHR but not from treated WKY. The chronic treatment normalized the relaxations of contracted preparations to acetylcholine. There were no significant differences in the increases in cytosolic free calcium concentration evoked by acetylcholine and A-23187 between control and treated groups. The endothelial ROS level was higher in SHR than WKY aortas and reduced by the chronic treatment. The gene and protein expression studies indicated that the overexpression of COX-1 observed in SHR aorta was reduced by the chronic treatment. These results demonstrate that chronic treatment with 1,25-dihydroxyvitamin D(3) modulates vascular tone and this modulation is accompanied by a lowered blood pressure, reduced expression of COX-1 mRNA and protein, and reduced ROS level in SHR. The reduction in endothelium-dependent contractions does not involve the surge in endothelial cytosolic calcium concentration that initiates the contractions."
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Effect of silicon on Cd accumulation and its physiological characteristics
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Soil Cadmium (Cd) pollution has become a serious environmental problem. Silicon (Si) plays key roles in alleviating Cd toxicity in plants. However, the effects of Si on mitigation of Cd toxicity and accumulation of Cd by hyperaccumulators are largely unknown. This study was conducted to investigate the effect of Si on Cd accumulation and the physiological characteristics of Cd hyperaccumulator
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"Silicon (Si), although not considered as an essential element for plants in general, can ameliorate the phytotoxicity induced by excess metal(loid)s whether non-essential (e.g. Cd, Pb, Cr, Al, As, and Sb) or essential (e.g. Cu, Ni, and Zn). The Si-enhanced resistance allowing plants to cope with this type of abiotic stress has been developed at multiple levels in plants. Restriction of root uptake and immobilization of metal(loid)s in the rhizosphere by Si is probably one of the first defence mechanism. Further, retention of elements in the root apoplasm might enhance the resistance and vigour of plants. At the cellular level, the formation of insoluble complexes between Si and metal(loid)s and their storage within cell walls help plants to decrease available element concentration and restrict symplasmic uptake. Moreover, Si influences the oxidative status of plants by modifying the activity of various antioxidants, improves membrane stability, and acts on gene expression, although its exact role in these processes is still not well understood. This review focuses on all currently known plant-based mechanisms related to Si supply and involved in amelioration of stress caused by excess metal(loid)s.",
"The remediation efficiency of phytoextraction on heavy metal could be influenced by metal bioavailability and plant growth. Hence, we applied a synergistic intensification system with plant hormone (24-Epibrassinolide, EBR) and metal-resistant bacterium (Serratia sp. CTZ4) to enhance Cd extraction of Amaranthus hypochondriacus L. in contaminated soil. Results demonstrated that the combination of CTZ4 and EBR promoted soil microecology through decreasing soil pH, improving soil enzymatic activity (dehydrogenase, invertase, acid phosphate, urease). Besides, microbial community structure was evaluated to understand the diversity and relative abundance of microbe in soil after remediation. Moreover, the maximum extraction of Cd was 5.91 mg kg-1 and increased about 60.16 % to CK. Meanwhile, the antioxidant system (SOD, CAT activities) of plant was improved significantly as well as plants biomass increasing by 46.02 % with the combination of EBR and CTZ4. Thus, our results proved that the utilization of EBR and CTZ4 is an alternated method to enhance phytoextraction efficiency of A. hypochondriacus in Cd-contaminated soil.",
"Soil contamination with toxic heavy metals [such as cadmium (Cd)] is becoming a serious global problem due to rapid development of social economy. Silicon (Si), being an important fertilizer element, has been found effective in enhancing plant tolerance against biotic and abiotic stresses. The present study investigated the extent to which different levels of Si modulated the Cd tolerance of Ajwain (Trachyspermum ammi L.) seedlings when maintained in artificially Cd spiked regimes. A pot experiment was conducted under controlled conditions for four weeks, by using sand, mixed with different levels of Cd i.e., 0, 1.5 and 3 mM together with the application of Si at 0, 1.5 and 3 mM levels to monitor different growth, gaseous exchange, oxidative stress, antioxidative responses, minerals accumulation, organic acid exudation patterns of T. ammi seedlings. Our results depicted that Cd addition to growth medium significantly decreased plant growth and biomass, gaseous exchange attributes and minerals uptake by T. ammi seedlings as compared to the plants grown without addition of Cd. However, Cd toxicity boosted the production of reactive oxygen species (ROS) by increasing the contents of malondialdehyde (MDA), which is the indication of oxidative stress in T. ammi seedlings and was also manifested by hydrogen peroxide (H2O2) contents and electrolyte leakage to the membrane bounded organelles. Although, activities of various antioxidative enzymes like superoxidase dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) initially increased up to a Cd level of 1.5 mM but were significantly diminished at the highest Cd level of 3 mM. Results revealed that the anthocyanin and soluble proteins contents were decreased in seedlings grown under elevating Cd levels but increased the Cd accumulation of T. ammi roots and shoots. The negative impacts of Cd injury were reduced by the application of Si which increased plant growth and biomass, improved photosynthetic apparatus, antioxidant enzymes, minerals uptake together with diminished exudation of organic acids as well as oxidative stress indicators in roots and shoots of T. ammi by decreasing Cd retention in different plant parts. Research findings, therefore, suggested that Si application can ameliorate Cd toxicity in T. ammi seedlings and resulted in improved plant growth and composition under metal stress as depicted by balanced exudation of organic acids.",
"Metallothioneins are cysteine-rich metal-binding proteins. In the present study, SaMT2, a type 2 metallothionein gene, was isolated from Cd/Zn co-hyperaccumulator Sedum alfredii Hance. SaMT2 encodes a putative peptide of 79 amino acid residues including two cysteine-rich domains. The transcript level of SaMT2 was higher in shoots than in roots of S. alfredii, and was significantly induced by Cd and Zn treatments. Yeast expression assay showed SaMT2 significantly enhanced Cd tolerance and accumulation in yeast. Ectopic expression of SaMT2 in tobacco enhanced Cd and Zn tolerance and accumulation in both shoots and roots of the transgenic plants. The transgenic plants had higher antioxidant enzyme activities and accumulated less H2O2 than wild-type plants under Cd and Zn treatment. Thus, SaMT2 could significantly enhance Cd and Zn tolerance and accumulation in transgenic tobacco plants by chelating metals and improving antioxidant system.",
"Expression of plant metallothionein genes has been reported in a variety of senescing tissues, such as leaves and stems, ripening fruits, and wounded tissues, and has been proposed to function in both metal chaperoning and scavenging of reactive oxygen species. In this work, it is shown that MT is also associated with suberization, after identifying a gene actively transcribed in Quercus suber cork cells as a novel MT. This cDNA, isolated from a phellem cDNA library, encodes a MT that belongs to type 2 plant MTs (QsMT). Expression of the QsMT cDNA in E. coli grown in media supplemented with Zn, Cd, or Cu has yielded recombinant QsMT. Characterization of the respective metal aggregates agrees well with a copper-related biological role, consistent with the capacity of QsMT to restore copper tolerance to a MT-deficient, copper-sensitive yeast mutant. Furthermore, in situ hybridization results demonstrate that RNA expression of QsMT is mainly observed under conditions related to oxidative stress, either endogenous, as found in cork or in actively proliferating tissues, or exogenous, for example, in response to H(2)O(2) or paraquat treatments. The putative role of QsMT in oxidative stress, both as a free radical scavenger via its sulphydryl groups or as a copper chelator is discussed.",
"Silicon (Si) is a beneficial macronutrient for plants. The Si supplementation to growth media mitigates abiotic and biotic stresses by regulating several physiological, biochemical and molecular mechanisms. The uptake of Si from the soil by root cells and subsequent transport are facilitated by Lsi1 (Low silicon1) belonging to nodulin 26-like major intrinsic protein (NIP) subfamily of aquaporin protein family, and Lsi2 (Low silicon 2) belonging to putative anion transporters, respectively. The soluble Si in the cytosol enhances the production of jasmonic acid, enzymatic and non-enzymatic antioxidants, secondary metabolites and induces expression of genes in plants under stress conditions. Silicon has been found beneficial in conferring tolerance against biotic and abiotic stresses by scavenging the reactive oxygen species (ROS) and regulation of different metabolic pathways. In the present review, Si transporters identified in various plant species and mechanisms of Si-mediated abiotic and biotic stress tolerance have been presented. In addition, role of Si in regulating gene expression under various abiotic and biotic stresses as revealed by transcriptome level studies has been discussed. This provides a deeper understanding of various mechanisms of Si-mediated stress tolerance in plants and may help in devising strategies for stress resilient agriculture.",
"Silicon (Si) is known to alleviate the adverse impact of different abiotic and biotic stresses by different mechanisms including morphological, physiological, and genetic changes. Photosynthesis, one of the most important physiological processes in the plant is sensitive to different stress factors. Several studies have shown that Si ameliorates the stress effects on photosynthesis by protecting photosynthetic machinery and its function. In stressed plants, several photosynthesis-related processes including PSII maximum photochemical quantum yield (Fv/Fm), the yield of photosystem II (φPSII), electron transport rates (ETR), and photochemical quenching (qP) were observed to be regulated when supplemented with Si, which indicates that Si effectively protects the photosynthetic machinery. In addition, studies also suggested that Si is capable enough to maintain the uneven swelling, disintegrated, and missing thylakoid membranes caused during stress. Furthermore, several photosynthesis-related genes were also regulated by Si supplementation. Taking into account the key impact of Si on the evolutionarily conserved process of photosynthesis in plants, this review article is focused on the aspects of silicon and photosynthesis interrelationships during stress and signaling pathways. The assemblages of this discussion shall fulfill the lack of constructive literature related to the influence of Si on one of the most dynamic and important processes of plant life i.e. photosynthesis."
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Effects of air pollution on metabolic dysfunction in mice
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Air pollution has emerged as an unexpected risk factor for diabetes. However, the mechanism behind remains ill-defined. So far, the lung has been considered as the main target organ of air pollution. In contrast, the gut has received little scientific attention. Since air pollution particles can reach the gut after mucociliary clearance from the lungs and through contaminated food, our aim was to assess whether exposure deposition of air pollution particles in the lung or the gut drive metabolic dysfunction in mice.
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"Large population cohort studies have indicated an association between exposure to particulate matter and cardiopulmonary morbidity and mortality. The inhalation of toxic environmental particles and gases impacts the innate and adaptive defense systems of the lung. Lung macrophages play a critically important role in the recognition and processing of any inhaled foreign material such as pathogens or particulate matter. Alveolar macrophages and lung epithelial cells are the predominant cells that process and remove inhaled particulate matter from the lung. Cooperatively, they produce proinflammatory mediators when exposed to atmospheric particles. These mediators produce integrated local (lung, controlled predominantly by epithelial cells) and systemic (bone marrow and vascular system, controlled predominantly by macrophages) inflammatory responses. The systemic response results in an increase in the release of leukocytes from the bone marrow and an increased production of acute phase proteins from the liver, with both factors impacting blood vessels and leading to destabilization of existing atherosclerotic plaques. This review focuses on lung macrophages and their role in orchestrating the inflammatory responses induced by exposure to air pollutants.",
"Emerging evidence indicates that exposure to fine particulate matter contributes to the onset of diabetes. The present study aimed to investigate the mechanism of particulate matters (PM)2.5 affecting glucose homeostasis in mice with type 1 diabetes mellitus. Male C57BL/6 mice were housed under filtered air (FA) or PM2.5 for 12 weeks and then received intraperitoneal injection of streptozotocin (STZ; 40 mg/kg) or acetic buffer daily for 5 days. At 4 weeks after the last injection, fasting glucose was tested. In the plasma and liver, cholesterol levels were determined by cholesterol oxidase-peroxidase and triglyceride levels were determined by triglycerophosphate oxidase-peroxidase. Homeostasis model assessment of β cell function (Homa-β) was computed based on fasting insulin and glucose levels. Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNFα) levels in plasma, visceral adipose tissues, RAW264.7 macrophages and MIN6 pancreatic β cells treated with PM2.5 (0-50 µg/ml) were quantified via ELISA. Before STZ injection, fasting blood glucose (FBG) levels were similar between FA and PM2.5 groups. After STZ injection, FBG levels were higher in mice pre-exposed to PM2.5 compared with those pre-exposed to FA. When taking FBG levels ≥7 mmol/l as the criteria for impaired glucose level, its incidence was 53.3% and 77.8% in FA and PM2.5 groups, respectively. Independent of STZ injection, IL-1β levels in the adipose tissue were upregulated in mice pre-exposed to PM2.5 compared with FA. The addition of PM2.5 stimulated IL-1β and TNFα production in macrophages and pancreatic β cells, and inhibited the secretion of insulin from MIN6 cells in a dose-dependent manner. In conclusion, pre-exposure of PM2.5 impaired pancreatic β cells in mice upon STZ injection, partially via enhanced inflammation, and suppressed the secretion of insulin.",
"Environmental stressors that encounter in early-life and cause abnormal fetal and/or neonatal development may increase susceptibility to non-communicable diseases such as diabetes. Maternal exposure to ambient fine particulate matter (PM2.5) is associated with various fetal abnormalities, suggesting that it may program offspring's susceptibility to diabetes. In the present study, we therefore examined whether maternal exposure to diesel exhaust PM2.5 (DEP), one of the major sources of ambient PM2.5 in urban areas, programs adult offspring's glucose metabolism. Female C57Bl/6J mice were intratracheally instilled with DEP or vehicle throughout a 7-wk preconceptional period, gestation, and lactation, and the glucose homeostasis of their adult male offspring was assessed. Intraperitoneal glucose tolerance test (IPGTT) revealed that the maternal exposure to DEP significantly impaired adult male offspring's glucose tolerance. Unexpectedly, it did not influence their insulin sensitivity, whereas it significantly decreased their glucose-induced insulin secretion (GIIS). This deficit in insulin secretion was corroborated by their significant decrease in arginine-induced insulin secretion. Histological analysis demonstrated that the deficit in insulin secretion was accompanied by the decrease in pancreatic islet and β cell sizes. To differentiate the effects of maternal exposure to DEP before birth and during lactation, some offspring were cross-fostered once born. We did not observe any significant effect of cross-fostering on the glucose homeostasis of adult male offspring and the function and morphology of their β cells. Prenatal exposure to DEP programs the morphology and function of β cells and thus homeostatic regulation of glucose metabolism in adult male offspring.",
"Air pollution is associated with increased cardiovascular morbidity and mortality, as well as dyslipidemia and metabolic syndrome. Our goal was to dissect the mechanisms involved. Approach and Results: We assessed the effects of exposure to air pollution on lipid metabolism in mice through assessment of plasma lipids and lipoproteins, oxidized fatty acids 9-HODE (9-hydroxyoctadecadienoic) and 13-HODE (13-hydroxyoctadecadienoic), lipid, and carbohydrate metabolism. Findings were corroborated, and mechanisms were further assessed in HepG2 hepatocytes in culture. ApoE knockout mice exposed to inhaled diesel exhaust (DE, 6 h/d, 5 days/wk for 16 weeks) exhibited elevated plasma cholesterol and triglyceride levels, increased hepatic triglyceride content, and higher hepatic levels of 9-HODE and 13-HODE, as compared to control mice exposed to filtered air. A direct effect of DE exposure on hepatocytes was demonstrated by treatment of HepG2 cells with a methanol extract of DE particles followed by loading with oleic acid. As observed in vivo, this led to increased triglyceride content and significant downregulation of ACAD9 mRNA expression. Treatment of HepG2 cells with DE particles and oleic acid did not alter de novo lipogenesis but inhibited total, mitochondrial, and ATP-linked oxygen consumption rate, indicative of mitochondrial dysfunction. Treatment of isolated mitochondria, prepared from mouse liver, with DE particles and oleic acid also inhibited mitochondrial complex activity and β-oxidation. DE exposure leads to dyslipidemia and liver steatosis in ApoE knockout mice, likely due to mitochondrial dysfunction and decreased lipid catabolism.",
"Exposure to particulate matter (PM) air pollution may be an important environmental factor leading to exacerbations of inflammatory illnesses in the GI tract. PM can gain access to the gastrointestinal (GI) tract via swallowing of air or secretions from the upper airways or mucociliary clearance of inhaled particles. We measured PM-induced cell death and mitochondrial ROS generation in Caco-2 cells stably expressing oxidant sensitive GFP localized to mitochondria in the absence or presence of an antioxidant. C57BL/6 mice were exposed to a very high dose of urban PM from Washington, DC (200 μg/mouse) or saline via gastric gavage and small bowel and colonic tissue were harvested for histologic evaluation, and RNA isolation up to 48 hours. Permeability to 4 kD dextran was measured at 48 hours. PM induced mitochondrial ROS generation and cell death in Caco-2 cells. PM also caused oxidant-dependent NF-κB activation, disruption of tight junctions and increased permeability of Caco-2 monolayers. Mice exposed to PM had increased intestinal permeability compared with PBS treated mice. In the small bowel, colocalization of the tight junction protein, ZO-1 was lower in the PM treated animals. In the small bowel and colon, PM exposed mice had higher levels of IL-6 mRNA and reduced levels of ZO-1 mRNA. Increased apoptosis was observed in the colon of PM exposed mice. Exposure to high doses of urban PM causes oxidant dependent GI epithelial cell death, disruption of tight junction proteins, inflammation and increased permeability in the gut in vitro and in vivo. These PM-induced changes may contribute to exacerbations of inflammatory disorders of the gut.",
"In the last lustrum single-cell techniques such as single-cell quantitative PCR, RNA and DNA sequencing, and the state-of-the-art cytometry by time of flight (CyTOF) mass cytometer have allowed a detailed analysis of the sub-composition of different organs from the bone marrow hematopoietic compartment to the brain. These fine-grained analyses have highlighted the great heterogeneity within each cell compartment revealing previously unknown subpopulations of cells. In this review, we analyze how this fast technological evolution has improved our understanding of the biological processes with a particular focus on rare cells of the immune system.",
"Effective elimination of particles deposited in the respiratory tract is an important defense function to protect the organism from potentially adverse effects of inhaled particles. Delivery of radioactively labeled tracer particles and subsequent measurement in vivo of their retention in different regions of the respiratory tract provides an adequate method for characterizing this defensive function. However, the delivery of such tracer particles by inhalation may result in some external contamination of the animals and requires specific protective measures while working with radioactive aerosols. In this study, 85Sr-labeled tracer particles (3 microns) were administered to the lower respiratory tract of rats by intratracheal inhalation to avoid external contamination, and also by intratracheal instillation in order to compare the 2 technique with respect to their suitability for measuring normal and impaired particle clearance rates. It was postulated that particle clearance function in the alveolar region can be determined equally well with intratracheally instilled particles despite their uneven distribution in the lung. For both techniques, rats were anesthesized with halothane and the particles were administered via oral intubation. Retention in the lower respiratory tract of about 30 micrograms (inhalation) and 6 micrograms (instillation) of the administered particles was followed over a period of 180 days by external counting of lung 85Sr-activity in a collimated detection system. To impair alveolar particle clearance rates, groups of rats were subjected to 12 weeks of inhalation exposure prior to delivery of the tracer particles as follows: (1) sham-exposed control; (2) pigment-grade TiO2 particles to induce lung overload: (3) ultrafine TiO2 particles: (4) crystalline SiO2 particles (cristobalite). The following results were obtained: The long-term retention half-times (T1/2) of the tracer particles reflecting alveolar clearance consistently showed the same ranking of the treatment groups whether measured after intratracheal inhalation or instillation. Control values were 66 and 72 days, respectively, and significantly prolonged long-term clearance was measured by both methods for pigment-grade TiO2 (117 and 99 days), ultrafine TiO2 (541 and 600 days) and SiO2 (1901 and 1368 days). Comparison of these values between the two modes of administration of tracer particles showed no significant differences. In contrast, the short-term T1/2 (mucociliary clearance) of the intratracheally instilled tracer particles in the different treatment groups were variable and did not accurately reflect particle clearance from the conducting airways. However, short-term T1/2 after intratracheal inhalation of tracer particles were consistent with fast conducting airway clearance, and mucociliary clearance appears to be stimulated when alveolar clearance is significantly impaired due to particle overload or to effects of cytotoxic particles. The results suggest that intratracheal instillation of a low dose (< or = 10 micrograms) of tracer particles in the rat provides an adequate method for reliably determining effects of inhaled toxicants on alveolar particle clearance function. Further, intratracheal inhalation of tracer particles is useful for measuring both short-term (mucociliary) and long-term (alveolar) particle clearance rates in the lower respiratory tract of the rat."
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The Braverman Nature Assessment and Exercise Behavior
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The Braverman Nature Assessment (BNA) is intended to determine the dominant monoamine neurochemical that drives an individual's temperament and behavior. The measure has been colloquially praised for the ability to determine the most effective exercise protocols for an individual based on their "dominant nature." This study seeks to examine the proposed relationship between the Braverman Natures and exercise behavior. Seventy-three adults (57 females) between ages 18-65 (mean = 26 years) completed an online survey consisting of the BNA, Big Five Personality Inventory (BFI), and Aerobics Center Longitudinal Study Physical Activity Questionnaire (ACLSPAQ). All Natures showed significant correlations to unique sets of personality traits (BFI). Dopamine and Serotonin Nature scores (via BNA) showed positive correlations to total physical activity (PA)measures. Serotonin Nature had positive correlation with participation in resistance exercise (
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"Acetylcholine in the brain alters neuronal excitability, influences synaptic transmission, induces synaptic plasticity, and coordinates firing of groups of neurons. As a result, it changes the state of neuronal networks throughout the brain and modifies their response to internal and external inputs: the classical role of a neuromodulator. Here, we identify actions of cholinergic signaling on cellular and synaptic properties of neurons in several brain areas and discuss consequences of this signaling on behaviors related to drug abuse, attention, food intake, and affect. The diverse effects of acetylcholine depend on site of release, receptor subtypes, and target neuronal population; however, a common theme is that acetylcholine potentiates behaviors that are adaptive to environmental stimuli and decreases responses to ongoing stimuli that do not require immediate action. The ability of acetylcholine to coordinate the response of neuronal networks in many brain areas makes cholinergic modulation an essential mechanism underlying complex behaviors.",
"Ayahuasca is an Amazonian psychoactive plant beverage containing the serotonergic 5-HT(2A) agonist N,N-dimethyltryptamine (DMT) and monoamine oxidase-inhibiting alkaloids (harmine, harmaline and tetrahydroharmine) that render it orally active. Ayahuasca ingestion is a central feature in several Brazilian syncretic churches that have expanded their activities to urban Brazil, Europe and North America. Members of these groups typically ingest ayahuasca at least twice per month. Prior research has shown that acute ayahuasca increases blood flow in prefrontal and temporal brain regions and that it elicits intense modifications in thought processes, perception and emotion. However, regular ayahuasca use does not seem to induce the pattern of addiction-related problems that characterize drugs of abuse. To study the impact of repeated ayahuasca use on general psychological well-being, mental health and cognition, here we assessed personality, psychopathology, life attitudes and neuropsychological performance in regular ayahuasca users (n = 127) and controls (n = 115) at baseline and 1 year later. Controls were actively participating in non-ayahuasca religions. Users showed higher Reward Dependence and Self-Transcendence and lower Harm Avoidance and Self-Directedness. They scored significantly lower on all psychopathology measures, showed better performance on the Stroop test, the Wisconsin Card Sorting Test and the Letter-Number Sequencing task from the WAIS-III, and better scores on the Frontal Systems Behavior Scale. Analysis of life attitudes showed higher scores on the Spiritual Orientation Inventory, the Purpose in Life Test and the Psychosocial Well-Being test. Despite the lower number of participants available at follow-up, overall differences with controls were maintained one year later. In conclusion, we found no evidence of psychological maladjustment, mental health deterioration or cognitive impairment in the ayahuasca-using group.",
"Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.",
"A previous positron emission tomography (PET) study reported increased serotonin 5-HT(2A) receptor binding in unmedicated depressed patients with high scores on the Dysfunctional Attitudes Scale. The purpose of the present study was to use the highly selective 5-HT(2A) receptor ligand [(11)C]MDL 100,907 in a PET imaging paradigm to assess 1) 5-HT(2A) receptor binding potential in euthymic subjects with a history of recurrent depression and 2) the relationship between receptor binding and scores on the Dysfunctional Attitudes Scale. Cortical 5-HT(2A) receptor binding was measured in 20 unmedicated, fully recovered unipolar depressed patients and 20 age- and gender-matched comparison subjects. Regional estimates of binding potential were obtained using a reversible plasma input function compartmental model and the cerebellum as a reference region to estimate the free and non-specifically bound [(11)C]MDL 100,907 in brain tissue. Relative to the comparison subjects, the recovered depressed patients demonstrated significantly higher 5-HT(2A) receptor binding potential in the frontal cortex (mean increase: 19%), parietal cortex (mean increase: 25%), and occipital cortex (mean increase: 19%). 5-HT(2A) receptor binding potential correlated negatively with age in both patients and comparison subjects and positively with the Dysfunctional Attitudes Scale in the recovered patients. These findings should be considered preliminary but suggest that recovered subjects with a history of recurrent major depression have elevated binding potential of cortical 5-HT(2A) receptors. The correlation of increased 5-HT(2A) receptor binding potential with increased scores on Dysfunctional Attitudes Scale supports earlier work suggesting that increased 5-HT(2A) receptor availability characterizes a group of depressed patients with high levels of dysfunctional attitudes.",
"Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5-HT2A R) agonist psilocybin. However, no studies have investigated whether 5-HT2A R availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5-HT2A R binding in neocortex imaged with [18 F]altanserin or [11 C]Cimbi-36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory-Revised. No significant associations between neocortical 5-HT2A R binding and trait Openness were found for [18 F]altanserin (p = 0.5) or [11 C]Cimbi-36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5-HT2A R availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5-HT2A R with compounds such as psilocybin may contribute to long-term changes in trait Openness, there is no evidence in favor of an association between 5-HT2A R and trait Openness."
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Intramedullary spinal anaplastic ganglioglioma
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Gangliogliomas (GGs) are rare tumors of the central nervous system composed of neoplastic neural and glial cells and are typically low-grade. Intramedullary spinal anaplastic GGs (AGG) are rare, poorly understood, and often aggressive tumors that can result in widespread progression along the craniospinal axis. Due to the rarity of these tumors, data are lacking to guide clinical and pathologic diagnosis and standard of care treatment. Here, we present a case of pediatric spinal AGG to provide information on our institutional approach to work-up and to highlight unique molecular pathology.
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[
"Gangliogliomas are rare, low-grade intra-axial tumors that exhibit both neuronal and glial components. Although the vast majority present as an intracranial lesion, a rare subset exist as isolated lesions of the spinal cord. Gangliogliomas have also been shown to harbor mutations in the p53 tumor suppressor gene and BRAF oncogene. Previous studies in ganglioglioma have correlated p53 mutations with histologic transformation and BRAF mutations with worse prognosis. In this report, we describe a 35-year-old female who presented with multifocal ganglioglioma, involving both the conus medullaris and filum terminale. The dominant lesion in the filum terminale was resected, which revealed World Health Organization I grade, p53 mutant, and BRAF wildtype status. Our study documents the first report of a multifocal ganglioglioma, originating within the spinal cord. Importantly, this case contradicts previous reports of p53 and BRAF mutations portending worsened tumor behavior and prognosis and demonstrates that further studies are needed to delineate the role of genetic characterization in the biologic understanding and management of gangliogliomas.",
"Neurofibromatosis type 1 (NF1) patients have an 8-13% lifetime risk of developing malignant peripheral nerve sheath tumors (MPNST) which have a very poor prognosis. In this study, cells from eight MPNSTs (six primary and two recurrences) of six clinically and genetically well-characterized NF1 patients were taken into culture. Tracing of loss of heterozygosity (LOH) of the NF1, p53, and p16 gene regions or of abnormal karyotypes enabled identification of tumor cells from five MPNSTs. In two other MPNST-derived cell cultures, LOH of the relevant regions in the original tumors could not be detected, indicating that the obtained cells were nonneoplastic cells. Cells from most MPNSTs grew only under standard culture conditions but not under conditions optimized for Schwann cells. These cells were S100-negative and did not exhibit spindle shape which is a characteristic of Schwann cells. Drastically increased proliferation rates were found for most of the MPNST cells in comparison to Schwann cells derived from benign neurofibromas. Our study demonstrates that genetic analysis is effective and essential for verification of MPNST tumor cells in culture. These verified MPNST cells are valuable for further investigations of the biology and pathogenesis of this malignancy as well as for in vitro pharmacologic studies essential for the development of new therapies.",
"Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As co-occurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty-seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co-occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double-immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow-up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow-up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M-mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.",
"Intramedullary spinal cord tumors (IMSCTs) of the pediatric population are rare and comprise thirty-five percent of intraspinal neoplasms. Low-grade astrocytomas predominate; ependymomas increase in frequency with ascending age and become the most frequent IMSCT in adults. Gangliogliomas are very rare in adults but comprise nearly thirty percent of tumors in children under three years of age. The cervical spine is the region of the spine most affected. Pain is the most common presenting symptom with weakness, gait deterioration, torticollis also frequently reported. Hydrocephalus occurs with greater frequency than in adult patients and often requires a shunt. Motor and sensory evoked potential monitoring is routinely utilized. Osteoplastic laminotomy is performed to forestall the development of progressive spinal deformity. Gross total resection is feasible in most ependymomas and results in surgical cure. Astrocytomas are infiltrating neoplasms and gross total resection is occasionally possible only in the pediatric population. However, the role of radical resection of low-grade fibrillary astrocytomas of the spinal cord in children has not been definitively demonstrated in the literature. Outcome for low-grade astrocytomas is better in children than adults, but not as favorable as that for ependymomas. Malignant tumors have dismal outcomes and surgery in these patients serves only to provide a diagnosis.",
"Patients with neurofibromatosis 1 (NF1) are predisposed to develop multiple neurofibromas (NFs) and are at risk for transformation of NFs to malignant peripheral nerve sheath tumors (MPNSTs). Little is known, however, about the biological events involved in the malignant transformation of NFs. We examined the CDKN2A/p16 gene and p16 protein in NFs and MPNSTs from patients with NF1. On immunohistochemical analysis, all NFs expressed p16 protein. The MPNSTs, however, were essentially immunonegative for p16, with striking transitions in cases that contained both benign and malignant elements. None of the benign tumors had CDKN2A/p16 deletions, whereas three of six MPNSTs appeared to have homozygous CDKN2A/p16 deletions. Methylation analysis and mutation analysis of CDKN2A/p16 in MPNSTs did not reveal any abnormalities. These results show that malignant transformation of NF is associated with loss of p16 expression, which is often secondary to homozygous deletion of the CDKN2A/p16 gene. The findings suggest that CDKN2A/p16 inactivation occurs during the malignant transformation of NFs in NF1 patients and raises the possibility that p16 immunohistochemistry may provide ancillary information in the distinction of NF from MPNST.",
"Ganglioglioma (GG) represents an extremely rare tumor of the central nervous system, which is composed of two different cellular populations: a glial cell population and a neuronal cell population, the former being the one which will establish the histologic grade of the tumor. The current World Health Organization (WHO) Classification of Tumors of the Central Nervous System divides gangliogliomas into benign (WHO grade I) and malignant (WHO grade III). Several scientific studies acknowledge that some tumors are difficult to grade but, due to the scarcity of cases as well as the lack of multicentric epidemiological data, there are no extensive studies regarding this matter in the neuropathology literature. We report a short case series of three patients with ganglioglioma who were admitted and treated at the Neurosurgery Department of \"Bagdasar Arseni\" Emergency Hospital. The patients had different clinical presentations, varying from migraines and epileptic seizures to development of a large, slowly growing tumor. Tissue fragments were obtained through surgical resection and sent to the Pathology Department for microscopic investigation. Histopathologic examination revealed both components of the tumor, supporting the diagnosis of ganglioglioma, albeit the glial component featured different histologic grade in each tumor. The tumor diagnosed as grade II lacked mitoses, but showed conspicuous atypia and numerous multinucleated cells. Immunohistochemistry revealed immunoreactivity for synaptophysin, chromogranin A and neurofilament in the neuronal component and GFAP positivity in the glial component of the tumor. Neurofilament showed an unusual pattern of staining, in which areas with benign features showed patchy positivity, while areas with malignant features and striking nuclear pleomorphism were completely negative. Due to the completely different clinical outcome, we strongly believe that a grade II ganglioglioma should be differentiated from a grade III GG, based on the lack of mitoses, necrosis and microvascular proliferation. The differentiation between grade II GG and grade I GG should be made on the cellular pleomorphism of both components (glial and neuronal). Based on our experience, we conclude that immunohistochemistry could aid in this differentiation through markers like: Ki67, neurofilament, CD34 and chromogranin A. We strongly believe that further immunohistochemical research on larger study groups will eventually lead to a consensus regarding definitive criteria for grade II gangliogliomas.",
"To assess the value of chemotherapy and radiotherapy in children with malignant peripheral nerve sheath tumors (MPNSTs) and to identify risk factors associated with outcome. A total of 167 untreated eligible patients enrolled onto the Italian and German studies between 1975 and 1998 entered this analysis. Seventeen percent of patients had neurofibromatosis type 1 (NF1). Chemotherapy was administered to 74% of patients; radiotherapy was administered to 38% of patients. With a median follow-up of 7 years, 5-year overall survival (OS) and progression-free survival (PFS) were 51% and 37%, respectively. The 5-year OS and PFS by Intergroup Rhabdomyosarcoma Study (IRS) groupings were as follows: group I, 82% and 61%; group II, 62% and 37%; group III, 32% and 27%; group IV, 26% and 21%, respectively. Univariate analysis identified IRS groups, size, invasiveness, primary site, age, and presence of NF1 as prognostic factors; multivariate analysis identified absence of NF1, tumor invasiveness T1, IRS groups I to II and extremity of primary site as independent favorable factors for OS. A trend was observed toward a benefit from radiotherapy after initial gross resection. The overall response rate to primary chemotherapy, including minor responses, in group III patients was 45%. MPNST is an aggressive tumor for which complete surgical resection is the mainstay of successful treatment. Postoperative radiotherapy may have a role in improving local control in patients with minimal residual tumor. The reported responses to primary chemotherapy suggest that it may be effective in patients with tumor considered unresectable at diagnosis."
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Myelin integrity in brain donors exposed to repetitive head impacts from American football.
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American football players and other individuals exposed to repetitive head impacts can exhibit a constellation of later-life cognitive and neuropsychiatric symptoms. While tau-based diseases such as chronic traumatic encephalopathy can underpin certain symptoms, contributions from non-tau pathologies from repetitive head impacts are increasingly recognized. We examined cross-sectional associations between myelin integrity using immunoassays for myelin-associated glycoprotein and proteolipid protein 1 with risk factors and clinical outcomes in brain donors exposed to repetitive head impacts from American football. Immunoassays for myelin-associated glycoprotein and proteolipid protein 1 were conducted on dorsolateral frontal white matter tissue samples of 205 male brain donors. Proxies of exposure to repetitive head impacts included years of exposure and age of first exposure to American football play. Informants completed the Functional Activities Questionnaire, Behavior Rating Inventory of Executive Function-Adult Version (Behavioral Regulation Index), and Barratt Impulsiveness Scale-11. Associations between myelin-associated glycoprotein and proteolipid protein 1 with exposure proxies and clinical scales were tested. Of the 205 male brain donors who played amateur and professional football, the mean age was 67.17 (SD = 16.78), and 75.9% (
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"Cerebrospinal fluid (CSF) protein analysis may facilitate detection and elucidate mechanisms of neurological consequences from repetitive head impacts (RHI), such as chronic traumatic encephalopathy. We examined CSF concentrations of total tau (t-tau), phosphorylated tau, and amyloid β1-42 and their association with RHI in former National Football League (NFL) players. The role of microglial activation (using sTREM2) was examined as a pathogenic mechanism of chronic traumatic encephalopathy. Sixty-eight former NFL players and 21 controls underwent lumbar puncture to quantify t-tau, p-tau181, amyloid β1-42, and sTREM2 in the CSF using immunoassays. The cumulative head impact index estimated RHI. No between-group differences for CSF analytes emerged. In the former NFL players, the cumulative head impact index predicted higher t-tau concentrations (P = .041), and higher sTREM2 levels were associated with higher t-tau concentrations (P = .009). In this sample of former NFL players, greater RHI and increased microglial activation were associated with higher CSF t-tau concentrations.",
"One football season of sub-concussive head blows has been shown to be associated with subclinical white matter (WM) changes on diffusion tensor imaging (DTI). Prior research analyses of helmet-based impact metrics using mean and peak linear and rotational acceleration showed relatively weak correlations to these WM changes; however, these analyses failed to account for the emerging concept that neuronal vulnerability to successive hits is inversely related to the time between hits (TBH). To develop a novel method for quantifying the cumulative effects of sub-concussive head blows during a single season of collegiate football by weighting helmet-based impact measures for time between helmet impacts. We further aim to compare correlations to changes in DTI after one season of collegiate football using weighted cumulative helmet-based impact measures to correlations using non-weighted cumulative helmet-based impact measures and non-cumulative measures. We performed a secondary analysis of DTI and helmet impact data collected on ten Division III collegiate football players during the 2011 season. All subjects underwent diffusion MR imaging before the start of the football season and within 1 week of the end of the football season. Helmet impacts were recorded at each practice and game using helmet-mounted accelerometers, which computed five helmet-based impact measures for each hit: linear acceleration (LA), rotational acceleration (RA), Gadd Severity Index (GSI), Head Injury Criterion (HIC15), and Head Impact Technology severity profile (HITsp). All helmet-based impact measures were analyzed using five methods of summary: peak and mean (non-cumulative measures), season sum-totals (cumulative unweighted measures), and season sum-totals weighted for time between hits (TBH), the interval of time from hit to post-season DTI assessment (TUA), and both TBH and TUA combined. Summarized helmet-based impact measures were correlated to statistically significant changes in fractional anisotropy (FA) using bivariate and multivariable correlation analyses. The resulting R 2 values were averaged in each of the five summary method groups and compared using one-way ANOVA followed by Tukey post hoc tests for multiple comparisons. Total head hits for the season ranged from 431 to 1850. None of the athletes suffered a clinically evident concussion during the study period. The mean R 2 value for the correlations using cumulative helmet-based impact measures weighted for both TUA and TBH combined (0.51 ± 0.03) was significantly greater than the mean R 2 value for correlations using non-cumulative HIMs (vs. 0.19 ± 0.04, p < 0.0001), unweighted cumulative helmet-based impact measures (vs. 0.27 + 0.03, p < 0.0001), and cumulative helmet-based impact measures weighted for TBH alone (vs. 0.34 ± 0.02, p < 0.001). R 2 values for weighted cumulative helmet-based impact measures ranged from 0.32 to 0.77, with 60% of correlations being statistically significant. Cumulative GSI weighted for TBH and TUA explained 77% of the variance in the percent of white matter voxels with statistically significant (PWMVSS) increase in FA from pre-season to post-season, while both cumulative GSI and cumulative HIC15 weighted for TUA accounted for 75% of the variance in PWMVSS decrease in FA. A novel method for weighting cumulative helmet-based impact measures summed over the course of a football season resulted in a marked improvement in the correlation to brain WM changes observed after a single football season of sub-concussive head blows. Our results lend support to the emerging concept that sub-concussive head blows can result in sub-clinical brain injury, and this may be influenced by the time between hits. If confirmed in an independent data set, our novel method for quantifying the cumulative effects of sub-concussive head blows could be used to develop threshold-based countermeasures to prevent the accumulation of WM changes with multiple seasons of play.",
"This scientific statement provides an overview of the evidence on vascular contributions to cognitive impairment and dementia. Vascular contributions to cognitive impairment and dementia of later life are common. Definitions of vascular cognitive impairment (VCI), neuropathology, basic science and pathophysiological aspects, role of neuroimaging and vascular and other associated risk factors, and potential opportunities for prevention and treatment are reviewed. This statement serves as an overall guide for practitioners to gain a better understanding of VCI and dementia, prevention, and treatment. Writing group members were nominated by the writing group co-chairs on the basis of their previous work in relevant topic areas and were approved by the American Heart Association Stroke Council Scientific Statement Oversight Committee, the Council on Epidemiology and Prevention, and the Manuscript Oversight Committee. The writing group used systematic literature reviews (primarily covering publications from 1990 to May 1, 2010), previously published guidelines, personal files, and expert opinion to summarize existing evidence, indicate gaps in current knowledge, and, when appropriate, formulate recommendations using standard American Heart Association criteria. All members of the writing group had the opportunity to comment on the recommendations and approved the final version of this document. After peer review by the American Heart Association, as well as review by the Stroke Council leadership, Council on Epidemiology and Prevention Council, and Scientific Statements Oversight Committee, the statement was approved by the American Heart Association Science Advisory and Coordinating Committee. The construct of VCI has been introduced to capture the entire spectrum of cognitive disorders associated with all forms of cerebral vascular brain injury-not solely stroke-ranging from mild cognitive impairment through fully developed dementia. Dysfunction of the neurovascular unit and mechanisms regulating cerebral blood flow are likely to be important components of the pathophysiological processes underlying VCI. Cerebral amyloid angiopathy is emerging as an important marker of risk for Alzheimer disease, microinfarction, microhemorrhage and macrohemorrhage of the brain, and VCI. The neuropathology of cognitive impairment in later life is often a mixture of Alzheimer disease and microvascular brain damage, which may overlap and synergize to heighten the risk of cognitive impairment. In this regard, magnetic resonance imaging and other neuroimaging techniques play an important role in the definition and detection of VCI and provide evidence that subcortical forms of VCI with white matter hyperintensities and small deep infarcts are common. In many cases, risk markers for VCI are the same as traditional risk factors for stroke. These risks may include but are not limited to atrial fibrillation, hypertension, diabetes mellitus, and hypercholesterolemia. Furthermore, these same vascular risk factors may be risk markers for Alzheimer disease. Carotid intimal-medial thickness and arterial stiffness are emerging as markers of arterial aging and may serve as risk markers for VCI. Currently, no specific treatments for VCI have been approved by the US Food and Drug Administration. However, detection and control of the traditional risk factors for stroke and cardiovascular disease may be effective in the prevention of VCI, even in older people. Vascular contributions to cognitive impairment and dementia are important. Understanding of VCI has evolved substantially in recent years, based on preclinical, neuropathologic, neuroimaging, physiological, and epidemiological studies. Transdisciplinary, translational, and transactional approaches are recommended to further our understanding of this entity and to better characterize its neuropsychological profile. There is a need for prospective, quantitative, clinical-pathological-neuroimaging studies to improve knowledge of the pathological basis of neuroimaging change and the complex interplay between vascular and Alzheimer disease pathologies in the evolution of clinical VCI and Alzheimer disease. Long-term vascular risk marker interventional studies beginning as early as midlife may be required to prevent or postpone the onset of VCI and Alzheimer disease. Studies of intensive reduction of vascular risk factors in high-risk groups are another important avenue of research.",
"Late neuropathologies of repetitive head impacts from contact sports can include chronic traumatic encephalopathy (CTE) and white matter degeneration. White matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) MRI scans are often viewed as microvascular disease from vascular risk, but might have unique underlying pathologies and risk factors in the setting of repetitive head impacts. We investigated the neuropathologic correlates of antemortem WMH in brain donors exposed to repetitive head impacts. The association between WMH and repetitive head impact exposure and informant-reported cognitive and daily function were tested. This imaging-pathologic correlation study included symptomatic male decedents exposed to repetitive head impacts. Donors had antemortem FLAIR scans from medical records and were without evidence of CNS neoplasm, large vessel infarcts, hemorrhage, or encephalomalacia. WMH were quantified using log-transformed values for total lesion volume (TLV), calculated using the lesion prediction algorithm from the Lesion Segmentation Toolbox. Neuropathologic assessments included semiquantitative ratings of white matter rarefaction, cerebrovascular disease, hyperphosphorylated tau (p-tau) severity (CTE stage, dorsolateral frontal cortex), and β-amyloid (Aβ). Among football players, years of play was a proxy for repetitive head impact exposure. Retrospective informant-reported cognitive and daily function were assessed using the Cognitive Difficulties Scale (CDS) and Functional Activities Questionnaire (FAQ). Regression models controlled for demographics, diabetes, hypertension, and MRI resolution. Statistical significance was defined as p ≤ 0.05. The sample included 75 donors: 67 football players and 8 nonfootball contact sport athletes or military veterans. Dementia was the most common MRI indication (64%). Fifty-three (70.7%) had CTE at autopsy. Log TLV was associated with white matter rarefaction (odds ratio [OR] 2.32, 95% confidence interval [CI] 1.03, 5.24; p = 0.04), arteriolosclerosis (OR 2.38, 95% CI 1.02, 5.52; p = 0.04), CTE stage (OR 2.58, 95% CI 1.17, 5.71; p = 0.02), and dorsolateral frontal p-tau severity (OR 3.03, 95% CI 1.32, 6.97; p = 0.01). There was no association with Aβ. More years of football play was associated with log TLV (unstandardized β 0.04, 95% CI 0.01, 0.06; p = 0.01). Greater log TLV correlated with higher FAQ (unstandardized β 4.94, 95% CI 0.42, 8.57; p = 0.03) and CDS scores (unstandardized β 15.35, 95% CI -0.27, 30.97; p = 0.05). WMH might capture long-term white matter pathologies from repetitive head impacts, including those from white matter rarefaction and p-tau, in addition to microvascular disease. Prospective imaging-pathologic correlation studies are needed. This study provides Class IV evidence of associations between FLAIR white matter hyperintensities and neuropathologic changes (white matter rarefaction, arteriolosclerosis, p-tau accumulation), years of American football play, and reported cognitive symptoms in symptomatic brain donors exposed to repetitive head impacts.",
"Long-term consequences of playing professional football and hockey on brain function and structural neuronal integrity are unknown. To investigate multimodal metabolic and structural brain magnetic resonance imaging (MRI) differences in retired professional contact sport athletes compared with noncontact sport athletes. Twenty-one male contact sport athletes and 21 age-matched noncontact sport athletes were scanned on a 3 tesla (3T) MRI using a multimodal imaging approach. The MRI outcomes included presence, number, and volume of focal white matter signal abnormalities, volumes of global and regional tissue-specific brain structures, diffusion-tensor imaging tract-based spatial statistics measures of mean diffusivity and fractional anisotropy, quantitative susceptibility mapping of deep gray matter, presence, number, and volume of cerebral microbleeds, MR spectroscopy N-acetyl-aspartate, glutamate, and glutamine concentrations relative to creatine and phosphor creatine of the corpus callosum, and perfusion-weighted imaging mean transit time, cerebral blood flow, and cerebral blood volume outcomes. Subjects were also classified as having mild cognitive impairment. No significant differences were found for structural or functional MRI measures between contact sport athletes and noncontact sport athletes. This multimodal imaging study did not show any microstructural, metabolic brain tissue injury differences in retired contact versus non-contact sport athletes.",
"Youth football players may incur hundreds of repetitive head impacts (RHI) in one season. Our recent research suggests that exposure to RHI during a critical neurodevelopmental period prior to age 12 may lead to greater later-life mood, behavioral, and cognitive impairments. Here, we examine the relationship between age of first exposure (AFE) to RHI through tackle football and later-life corpus callosum (CC) microstructure using magnetic resonance diffusion tensor imaging (DTI). Forty retired National Football League (NFL) players, ages 40-65, were matched by age and divided into two groups based on their AFE to tackle football: before age 12 or at age 12 or older. Participants underwent DTI on a 3 Tesla Siemens (TIM-Verio) magnet. The whole CC and five subregions were defined and seeded using deterministic tractography. Dependent measures were fractional anisotropy (FA), trace, axial diffusivity, and radial diffusivity. Results showed that former NFL players in the AFE <12 group had significantly lower FA in anterior three CC regions and higher radial diffusivity in the most anterior CC region than those in the AFE ≥12 group. This is the first study to find a relationship between AFE to RHI and later-life CC microstructure. These results suggest that incurring RHI during critical periods of CC development may disrupt neurodevelopmental processes, including myelination, resulting in altered CC microstructure.",
"Exposure to repetitive head impacts (RHI) is associated with an increased risk of later-life neurobehavioral dysregulation and neurodegenerative disease. The underlying pathomechanisms are largely unknown. To investigate whether RHI exposure is associated with later-life corpus callosum (CC) microstructure and whether CC microstructure is associated with plasma total tau and neuropsychological/neuropsychiatric functioning. Retrospective cohort study. Seventy-five former professional American football players (age 55.2 ± 8.0 years) with cognitive, behavioral, and mood symptoms. Diffusion-weighted echo-planar MRI at 3 T. Subjects underwent diffusion MRI, venous puncture, neuropsychological testing, and completed self-report measures of neurobehavioral dysregulation. RHI exposure was assessed using the Cumulative Head Impact Index (CHII). Diffusion MRI measures of CC microstructure (i.e., free-water corrected fractional anisotropy (FA), trace, radial diffusivity (RD), and axial diffusivity (AD)) were extracted from seven segments of the CC (CC1-7), using a tractography clustering algorithm. Neuropsychological tests were selected: Trail Making Test Part A (TMT-A) and Part B (TMT-B), Controlled Oral Word Association Test (COWAT), Stroop Interference Test, and the Behavioral Regulation Index (BRI) from the Behavior Rating Inventory of Executive Function, Adult version (BRIEF-A). Diffusion MRI metrics were tested for associations with RHI exposure, plasma total tau, neuropsychological performance, and neurobehavioral dysregulation using generalized linear models for repeated measures. RHI exposure was associated with increased AD of CC1 (correlation coefficient (r) = 0.32, P < 0.05) and with increased plasma total tau (r = 0.34, P < 0.05). AD of the anterior CC1 was associated with increased plasma total tau (CC1: r = 0.30, P < 0.05; CC2: r = 0.29, P < 0.05). Higher trace, AD, and RD of CC1 were associated with better performance (P < 0.05) in TMT-A (trace, r = 0.33; AD, r = 0.31; and RD, r = 0.28) and TMT-B (trace, r = 0.31; RD, r = 0.34). Higher FA and AD of CC2 were associated with better performance (P < 0.05) in TMT-A (FA, r = 0.36; AD, r = 0.28), TMT-B (FA, r = 0.36; AD, r = 0.27), COWAT (FA, r = 0.36; AD, r = 0.32), and BRI (AD, r = 0.29). These results suggest an association among RHI exposure, CC microstructure, plasma total tau, and clinical functioning in former professional American football players. 3 Technical Efficacy Stage: 1.",
"Years of sport participation (YoP) is conventionally used to estimate cumulative repetitive head impacts (RHI) experienced by contact sport athletes. The relationship of this measure to other estimates of head impact exposure and the potential associations of these measures with neurobehavioral functioning are unknown. We investigated the association between YoP and the Head Impact Exposure Estimate (HIEE), and whether associations between the two estimates of exposure and neurobehavioral functioning varied. Former American football players (N = 58; age = 37.9 ± 1.5 years) completed in-person evaluations approximately 15 years following sport discontinuation. Assessments consisted of neuropsychological assessment and structured interviews of head impact history (i.e., HIEE). General linear models were fit to test the association between YoP and the HIEE, and their associations with neurobehavioral outcomes. YoP was weakly correlated with the HIEE, p = .005, R2 = .13. Higher YoP was associated with worse performance on the Symbol Digit Modalities Test, p = .004, R2 = .14, and Trail Making Test-B, p = .001, R2 = .18. The HIEE was associated with worse performance on the Delayed Recall trial of the Hopkins Verbal Learning Test-Revised, p = .020, R2 = .09, self-reported cognitive difficulties (Neuro-QoL Cognitive Function), p = .011, R2 = .10, psychological distress (Brief Symptom Inventory-18), p = .018, R2 = .10, and behavioral regulation (Behavior Rating Inventory of Executive Function for Adults), p = .017, R2 = .10. YoP was marginally associated with the HIEE, a comprehensive estimate of head impacts sustained over a career. Associations between each exposure estimate and neurobehavioral functioning outcomes differed. Findings have meaningful implications for efforts to accurately quantify the risk of adverse long-term neurobehavioral outcomes potentially associated with RHI.",
"In the United States alone, millions of athletes participate in sports with potential for head injury each year. Although poorly understood, possible long-term neurological consequences of repetitive sports-related concussions have received increased recognition and attention in recent years. A better understanding of the risk factors for concussion remains a public health priority. Despite the attention focused on mild traumatic brain injury (mTBI) in football, gaps remain in the understanding of the optimal methodology to determine concussion incidence and position-specific risk factors. To calculate the rates of concussion in professional football players using established and novel metrics on a group and position-specific basis. Case-control study; Level of evidence, 3. Athletes from the 2012-2013 and 2013-2014 National Football League (NFL) seasons were included in this analysis of publicly available data. Concussion incidence rates were analyzed using established (athlete exposure [AE], game position [GP]) and novel (position play [PP]) metrics cumulatively, by game unit and position type (offensive skill players and linemen, defensive skill players and linemen), and by position. In 480 games, there were 292 concussions, resulting in 0.61 concussions per game (95% CI, 0.54-0.68), 6.61 concussions per 1000 AEs (95% CI, 5.85-7.37), 1.38 concussions per 100 GPs (95% CI, 1.22-1.54), and 0.17 concussions per 1000 PPs (95% CI, 0.15-0.19). Depending on the method of calculation, the relative order of at-risk positions changed. In addition, using the PP metric, offensive skill players had a significantly greater rate of concussion than offensive linemen, defensive skill players, and defensive linemen (P < .05). For this study period, concussion incidence by position and unit varied depending on which metric was used. Compared with AE and GP, the PP metric found that the relative risk of concussion for offensive skill players was significantly greater than other position types. The strengths and limitations of various concussion incidence metrics need further evaluation. A better understanding of the relative risks of the different positions/units is needed to help athletes, team personnel, and medical staff make optimal player safety decisions and enhance rules and equipment.",
"Research now suggests that head impacts commonly occur during contact sports in which visible signs or symptoms of neurological dysfunction may not develop despite those impacts having the potential for neurological injury. Recent biophysics studies utilizing helmet accelerometers have indicated that athletes at the collegiate and high school levels sustain a surprisingly high number of head impacts ranging from several hundred to well over 1000 during the course of a season. The associated cumulative impact burdens over the course of a career are equally important. Clinical studies have also identified athletes with no readily observable symptoms but who exhibit functional impairment as measured by neuropsychological testing and functional MRI. Such findings have been corroborated by diffusion tensor imaging studies demonstrating axonal injury in asymptomatic athletes at the end of a season. Recent autopsy data have shown that there are subsets of athletes in contact sports who do not have a history of known or identified concussions but nonetheless have neurodegenerative pathology consistent with chronic traumatic encephalopathy. Finally, emerging laboratory data have demonstrated significant axonal injury, blood-brain barrier permeability, and evidence of neuroinflammation, all in the absence of behavioral changes. Such data suggest that subconcussive level impacts can lead to significant neurological alterations, especially if the blows are repetitive. The authors propose \"subconcussion\" as a significant emerging concept requiring thorough consideration of the potential role it plays in accruing sufficient anatomical and/or physiological damage in athletes and military personnel, such that the effects of these injuries are clinically expressed either contemporaneously or later in life."
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UV-induced skin photoaging: cellular and molecular mechanisms and mechanistic insights
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Skin areas exposed to ultraviolet radiation (UV) from sunlight are more prone to photoaging than unexposed areas evidenced by several signs which include skin dryness, irregular pigmentation, lentigines, hyperpigmentation, wrinkling, and decreased elasticity. Plant-based natural product ingredients with therapeutic potential against skin photoaging are gaining more attention. This article aims the reviewing the research work done in exploring the cellular and molecular mechanisms involved in UV-induced skin photoaging, followed by summarizing the mechanistic insights involved in its therapeutics by natural product-based ingredients. In the mechanistic section of the convoluted procedure of photoaging, we described the effect of UV radiation (UVR) on different cellular macromolecules (direct damage) and subsequently, the deleterious consequences of UVR-generated reactive oxygen species (indirect damage) and signaling pathways activated or inhibited by UV induced ROS generation in various cellular pathologies of skin photoaging like inflammation, extracellular matrix degradation, apoptosis, mitochondrial dysfunction, and immune suppression. We also discussed the effect of UV radiation on the adipose tissue, and transient receptor potential cation channel V of photoaging skin. In the past few decades, mechanistic studies performed in this area have deciphered various therapeutic targets, opening avenues for different available therapeutic options against this pathological condition. So the remaining portion of the review deals with various natural product-based therapeutic agents available against skin photodamage.
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"In our investigations towards the isolation of potentially biologically active constituents from Orchidaceae, we carried out phytochemical and biological analyses of Vanda species. A preliminary biological screening revealed that Vanda coerulea (Griff. ex. Lindl) crude hydro-alcoholic stem extract displayed the best DPPH /(•)OH radical scavenging activity and in vitro inhibition of type 2 prostaglandin (PGE-2) release from UV(B) (60 mJ/cm(2)) irradiated HaCaT keratinocytes. Bio-guided fractionation and phytochemical analysis led to the isolation of five stilbenoids: imbricatin (1) methoxycoelonin (2) gigantol (3) flavidin (4) and coelonin (5). Stilbenoids (1-3) were the most concentrated in crude hydro-alcoholic stem extract and were considered as Vanda coerulea stem biomarkers. Dihydro-phenanthropyran (1) and dihydro-phenanthrene (2) displayed the best DPPH/(•)OH radical scavenging activities as well as HaCaT intracellular antioxidant properties (using DCFH-DA probe: IC(50) 8.8 µM and 9.4 µM, respectively) compared to bibenzyle (3) (IC(50) 20.6 µM). In turn, the latter showed a constant inhibition of PGE-2 production, stronger than stilbenoids (1) and (2) (IC(50) 12.2 µM and 19.3 µM, respectively). Western blot analysis revealed that stilbenoids (1-3) inhibited COX-2 expression at 23 µM. Interestingly, stilbenoids (1) and (2) but not (3) were able to inhibit human recombinant COX-2 activity. Major antioxidant stilbenoids (1-3) from Vanda coerulea stems displayed an inhibition of UV(B)-induced COX-2 expression. Imbricatin (1) and methoxycoelonin (2) were also able to inhibit COX-2 activity in a concentration-dependent manner thereby reducing PGE-2 production from irradiated HaCaT cells. Our studies suggest that stilbenoids (1-3) could be potentially used for skin protection against the damage caused by UV(B) exposure.",
"Human cutaneous photodamage is a major medical problem that includes premature aging and fragility of the skin. Nonxenografted animal models have not been comparatively evaluated for how well they resemble the changes seen in human skin. Here, we sought to identify a suitable mouse model that recapitulates key anatomic, cellular and molecular responses observed in human skin during acute UV exposure. Adult females from three strains of mice, C57BL/6J, SKH1 and Balb/c were exposed to UVB and then evaluated 3 or 20 h after the last irradiation. Skin from UVB-exposed C57BL/6J mice showed features resembling human photodamage, including epidermal thickening, infiltration of the dermis with inflammatory cells, induction of tumor necrosis factor-α (TNF-α) mRNA, accumulation of glycosaminoglycans, particularly hyaluronan in the epidermis and loss of collagen. Hairless SKH1 mouse skin responded similarly, but without any induction of TNF-α mRNA or chondroitin sulfate. Irradiated Balb/c mice were the least similar to humans. Our results in C57BL/6J mice and to a lesser extent in SKH1 mice, show cutaneous responses to a course of UVB-irradiation that mirror those seen in human skin. Proper choice of model is critical for investigating cellular and molecular mechanisms of photodamage and photoaging.",
"Ultraviolet (UV) light-induced wrinkle formation is a major dermatological problem and is associated with alteration in collagen. Here, we investigated the potential of α-ionone, a naturally occurring aromatic compound, in regulation of UVB-induced photoaging in human Hs68 dermal fibroblasts and identified the mechanisms involved. We found that in human dermal fibroblasts, α-ionone inhibited UVB-induced loss of collagen. α-Ionone upregulated the molecules participating in the TGF-β-SMAD pathway (TGF-β1, phospho-SMAD2/3, Col1A1, and Col1A2), but downregulated the molecules involved in the MAPK-AP-1 signaling pathway (phospho-p38, phospho-JNK, phospho-ERK, phospho-c-Fos, phospho-c-Jun, MMP1, MMP3, and MMP9), in human dermal fibroblasts. α-Ionone treatment also increased hyaluronic acid contents, and this effect was accompanied by an upregulation of mRNA expression of genes (HAS1 and HAS2) involved in hyaluronic acid synthesis. Thus, α-ionone is effective in the prevention of UVB-induced decrease of collagen and hyaluronic acid in human dermal fibroblasts. We propose that α-ionone may prove beneficial for the prevention of UV-induced wrinkle formation and skin damage.",
"Ultraviolet (UV) exposure of human skin induces local and systemic immune suppression. This phenomenon has been well documented when UVB radiation (290-320 nm) is used. The mechanism is thought to involve Langerhans cells (LCs), the epidermal dendritic cells that play a crucial role in antigen presentation. A variety of studies have clearly demonstrated that UVB radiation decreases LC density and alters their morphology and immunological function, but little is known about the effects of the entire UV spectrum (ultraviolet solar simulated radiation, UV-SSR or UVB + UVA) or UVA (320-400 nm) radiation alone. The purpose of this study was to analyse and compare the effects of a single exposure of human volunteers to UV-SSR, total UVA or UVA1 (340-400 nm) in the human epidermal LC density and morphology. Immunohistochemistry on epidermal sheets with various antibodies and transmission electron microscopy (TEM) were used. Immunostaining for class II antigen revealed that a single UV-SSR exposure, corresponding to twice the minimal erythemal dose (MED), induced a significant reduction in LC density with only slight morphological alterations of remaining cells. After a single UVA exposure, LC density showed a dose-dependent reduction with a significant effect at 60 J cm(-2) (well above the MED). Moreover, the reduction of LC dendricity was also dose-dependent and significant for doses exceeding 30 J cm(-2). UVA1 radiation was as effective as total UVA for the later endpoint. As demonstrated by TEM, the location of Birbeck granules containing epidermal cells was modified in UVA-exposed areas. They were located in the spinous rather than in the suprabasal layer. In addition, the morphology of these cells was altered. We observed a rounding up of the cell body with a reduction of dendricity. Alterations of mitochondrial membrane and ridges were also seen. A single exposure of human skin in vivo to UV-SSR, UVA or UVA1 radiation results in different alterations of density and/or morphology of LCs. All these alterations may impair the antigen-presenting function of LCs leading to an alteration of immune response.",
"The cyclooxygenase isoforms, COX-1 and COX-2, are involved in the biosynthesis of prostaglandin E2, a major prostaglandin involved in epidermal homeostasis and repair. Cancer originating in the epidermis can develop when keratinocyte proliferation and apoptosis become dysregulated, resulting in sustained epidermal hyperplasia. COX-2 inhibitors, which demonstrate significant in vivo selectivity relative to COX-1, suppress both ultraviolet-induced epidermal tumor development and progression, suggesting that prostaglandin regulation of keratinocyte biology is involved in the pathogenesis of epidermal neoplasia. In this study, we characterized the expression of COX-1 and COX-2, as well as keratinocyte proliferation, differentiation, and apoptosis, following acute ultraviolet irradiation in the hairless SKH-1 mouse. Following acute ultraviolet exposure, COX-2 expression was predominantly induced in the basal keratinocyte layer coincident with an increase in keratinocyte proliferation and apoptosis. The role of COX-2 was further evaluated using a selective COX-2 inhibitor, SC-791, as well as the traditional nonsteroidal COX inhibitor, indomethacin. Following acute ultraviolet irradiation, inhibition of COX-2 with either inhibitor decreased epidermal keratinocyte proliferation. Likewise, keratinocyte apoptosis was increased with COX-2 inhibition, particularly in the proliferating basal keratinocyte layer. There was also a modest inhibition of keratinocyte differentiation. These data suggest that COX-2 expression is probably necessary for keratinocyte survival and proliferation occurring after acute ultraviolet irradiation. We hypothesize that selective COX-2 inhibition, as described herein, may lead to enhanced removal of ultraviolet-damaged keratinocytes, thereby decreasing malignant transformation in the epidermis.",
"Xanthohumol (XH), the principal prenylflavonoid of the hop plant (Humulus lupulus L.), dose-dependently inhibited isobutylmethylxanthine (IBMX)-induced melanogenesis in B16 melanoma cells, with little cytotoxicity at the effective concentrations. Decreased melanin content was accompanied by reduced tyrosinase enzyme activity, protein and mRNA expression. The levels of tyrosinase-related protein 1 and 2 mRNAs were decreased by XH. XH also inhibited alpha-melanocyte stimulating hormone- or forskolin-induced increases in melanogenesis, suggesting an action on the cAMP-dependent melanogenic pathway. XH downregulated the protein and mRNA expression of microphthalmia-associated transcription factor (MITF), a master transcriptional regulator of key melanogenic enzymes. These results suggest that XH might act as a hypo-pigmenting agent through the downregulation of MITF in the cAMP-dependent melanogenic pathway.",
"The p38 mitogen-activated protein kinase (MAPK) signaling pathway is activated by numerous inflammatory mediators and environmental stresses. We assessed the effects of ultraviolet B (UVB) on the p38 MAPK pathway and determined whether cyclooxygenase (COX)-2 expression is downstream of this kinase in the skin of UVB-irradiated SKH-1 mice. SKH-1 mice were irradiated with a single dose of UVB (360 mJ per cm2), and activation of the epidermal p38 MAPK pathway was assessed. UVB-induced phosphorylation of p38 MAPK occurred in a time-dependent manner. Phosphorylation of MAPK-activated protein kinase-2 (MAPKAPK-2) also was detected and correlated with an increase in its kinase activity. Phosphorylation of heat shock protein 27 (HSP27), a substrate for MAPKAPK-2, also was detected post-irradiation. Oral administration of the p38 inhibitor, SB242235, prior to UVB irradiation, blocked activation of the p38 MAPK cascade, and abolished MAPKAPK-2 kinase activity and phosphorylation of HSP27. Moreover, SB242235 inhibited expression of the pro-inflammatory cytokines interleukin (IL)-6 and KC (murine IL-8) and COX-2. Our data demonstrate that UVB irradiation of murine skin activates epidermal p38 MAPK signaling and induces a local pro-inflammatory response. Blockade of the p38 MAPK pathway may offer an effective approach to reducing or preventing skin damage resulting from acute solar radiation.",
"The aging process of the skin can be divided into intrinsic and photoaging. Clinically, naturally aged skin is smooth, pale and finely wrinkled. In contrast, photoaged skin is coarsely wrinkled and associated with dyspigmentation and telangiectasia. Although the population of Asia is more than half the population of the Earth, no well-designed study has been undertaken to investigate the characteristics of cutaneous photodamage in Asian skin. As Asian skin is more pigmented, the acute and chronic cutaneous responses to UV irradiation seen in brown skin differ from those in white skin. The clinical characteristics of photoaging in Asian skin, such as pigmentary changes and wrinkle patterns, differ from those of Caucasian skin. This review provides an outline of the characteristic features of photoaging on the brown skin of Asians.",
"Xanthohumol, prenylchacone flavonoid, is a natural product with multi-biofunctions purified from Hops Humulus lupulus. Its anti-HIV-1 activity was tested in the present study. Results showed that xanthohumol inhibited HIV-1 induced cytopathic effects, the production of viral p24 antigen and reverse transcriptase in C8166 lymphocytes at non-cytotoxic concentration. The EC50 values were 0.82, 1.28 and 0.50 microg/ml, respectively. The therapeutic index (TI) was about 10.8. Xanthohumol also inhibited HIV-1 replication in PBMC with EC50 value of 20.74 microg/ml. The activity of recombinant HIV-1 reverse transcriptase and the HIV-1 entry were not inhibited by xanthohumol. The results from this study suggested that xanthohumol is effective against HIV-1 and might serve as an interesting lead compound. It may represent a novel chemotherapeutic agent for HIV-1 infection. However, the mechanism of its anti-HIV-1 effect needs to be further clarified.",
"Sphingosylphosphorylcholine (SPC) is emerging as a potent signaling-lipid mediator. In this study, we investigated the effects of SPC on melanogenesis using cultured human melanocytes. Our results show that SPC significantly inhibits melanin synthesis in a concentration-dependent manner, and further that it reduces the activity of tyrosinase, the rate-limiting melanogenic enzyme. SPC treatment was also found to induce short-thick dendrites in human melanocytes, but not to reduce tyrosinase activity in a cell-free system, whereas kojic acid directly inhibited tyrosinase. These results suggest that SPC reduces pigmentation by indirectly regulating tyrosinase. In further experiments, SPC was found to downregulate microphthalmia-associated transcription factor (MITF) and tyrosinase, and Western blotting showed that SPC induces the activations of extracellular signal-regulated kinase (ERK) and 90 kDa ribosomal S6 kinase (RSK-1). Moreover, the specific ERK pathway inhibitor, PD98059, blocked the hypopigmentation effect of SPC, and abrogated the SPC-mediated downregulation of MITF. These results suggest that the ERK pathway is involved in the melanogenic signaling cascade, and that ERK activation by SPC reduces melanin synthesis via MITF downregulation."
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Epidermal Threads in Hagfish Epidermis
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When attacked, hagfishes produce a soft, fibrous defensive slime within a fraction of a second by ejecting mucus and threads into seawater. The rapid setup and remarkable expansion of the slime make it a highly effective and unique form of defense. How this biomaterial evolved is unknown, although circumstantial evidence points to the epidermis as the origin of the thread- and mucus-producing cells in the slime glands. Here, we describe large intracellular threads within a putatively homologous cell type from hagfish epidermis. These epidermal threads averaged ~2 mm in length and ~0.5 μm in diameter. The entire hagfish body is covered by a dense layer of epidermal thread cells, with each square millimeter of skin storing a total of ~96 cm threads. Experimentally induced damage to a hagfish's skin caused the release of threads, which together with mucus, formed an adhesive epidermal slime that is more fibrous and less dilute than the defensive slime. Transcriptome analysis further suggests that epidermal threads are ancestral to the slime threads, with duplication and diversification of thread genes occurring in parallel with the evolution of slime glands. Our results support an epidermal origin of hagfish slime, which may have been driven by selection for stronger and more voluminous slime.
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"The \"thread keratins (TK)\" alpha and gamma so far have been considered highly specialized intermediate filament (IF) proteins restricted to hagfish. From lamprey, we now have sequenced five novel IF proteins closely related to TKalpha and TKgamma, respectively. Moreover, we have detected corresponding sequences in EST and genomic databases of teleosts and amphibians. The structure of the TKalpha genes and the positions of their deduced amino acid sequences in a phylogenetic tree clearly support their classification as type II keratins. The genes encoding TKgamma show a structure typical for type III IF proteins, whereas their positions in phylogenetic trees favor a close relationship to the type I keratins. Considering that most keratin-like sequences detected in the lancelet also exhibit a gene structure typical for type III IF proteins, it seems likely that the keratin gene(s) originated from an ancient type III IF protein gene. According to EST analyses, the expression of the thread keratins in teleost fish and amphibians may be particularly restricted to larval stages, which, in conjunction with the observed absence of TKalpha and TKgamma genes in any of the available Amniota databases, indicates a thread keratin function closely related to larval development in an aquatic environment.",
"Hagfishes defend themselves from fish predators by releasing large volumes of gill-clogging slime when they are attacked. Slime release is not anticipatory, but is only released after an attack has been initiated, raising the question of how hagfishes survive the initial attack, especially from biting predators such as sharks. We tested two hypotheses that could explain how hagfishes avoid damage from shark bites: puncture-resistant skin, and a loose and flaccid body design that makes it difficult for teeth to penetrate body musculature and viscera. Based on data from skin puncture tests from 22 fish species, we found that hagfish skin is not remarkably puncture resistant. Simulated shark bites on hagfish and their closest living relatives, lamprey, as well as whole animal inflation tests, revealed that the loose attachment of hagfish skin to the rest of the body and the substantial 'slack volume' in the subcutaneous sinus protect hagfish musculature and viscera from penetrating teeth. While recent work has found evidence that the capacious subcutaneous sinus in hagfishes is important for behaviours such as knot-tying and burrowing, our work demonstrates that it also plays a role in predator defence.",
"Epidermal club cells (ECCs), along with mucus cells, are present in the skin of many fishes, particularly in the well-studied Ostariophysan family Cyprinidae. Most ECC-associated literature has focused on the potential role of ECCs as a component of chemical alarm cues released passively when a predator damages the skin of its prey, alerting nearby prey to the presence of an active predator. Because this warning system is maintained by receiver-side selection (senders are eaten), there is want of a mechanism to confer fitness benefits to the individual that invests in ECCs to explain their evolutionary origin and maintenance in this speciose group of fishes. In an attempt to understand the fitness benefits that accrue from investment in ECCs, we reviewed the phylogenetic distribution of ECCs and their histochemical properties. ECCs are found in various forms in all teleost superorders and in the chondrostei inferring either early or multiple independent origins over evolutionary time. We noted that ECCs respond to several environmental stressors/immunomodulators including parasites and pathogens, are suppressed by immunomodulators such as testosterone and cortisol, and their density covaries with food ration, demonstrating a dynamic metabolic cost to maintaining these cells. ECC density varies widely among and within fish populations, suggesting that ECCs may be a convenient tool with which to assay ecoimmunological tradeoffs between immune stress and foraging activity, reproductive state, and predator-prey interactions. Here, we review the case for ECC immune function, immune functions in fishes generally, and encourage future work describing the precise role of ECCs in the immune system and life history evolution in fishes.",
"In many models of sexual selection, conspicuous ornaments are preferred by mates because they indicate heritable signaler viability. To function as indicators, ornaments must exhibit a proportional relationship between expression and viability. In cases where the evolutionary interests of signaler and receiver diverge, selection favors exploitative exaggeration by low-viability individuals producing unreliable signals. Theory suggests that the evolutionary stability of such communication systems requires costs that prevent low-viability males from expressing disproportionately intense signals. Therefore, given ecological variation in signaling cost, the reliability of signaling systems will vary concomitantly. In this study, we assess the effect of a variable signal cost, predation, on signal intensity and reliability among 16 populations of Bahamas mosquitofish (Gambusia hubbsi) that use colorful dorsal fins in courtship displays. We found that fin coloration was more intense in low-predation sites and could be used to predict body condition. However, this predictive relationship was apparent only in populations subject to predation risk. We demonstrate an important role for ecological signaling cost in communication and show that ecological heterogeneity drives interpopulation variation in both the intensity and the reliability of a sexual signal."
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Time Deficit and Divorce Rates in Low Income Couples
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Shared time is a centrally important component of relationship maintenance, and over the past few decades, couples have reported spending increasingly more time together. However, over this same time period divorce rates have risen much higher for lower income couples compared to higher income couples. One theorized explanation for the disparity in divorce rates between lower and higher income couples is a difference across the socioeconomic strata in the quantity and quality of time couples spend together. This theory argues that lower income couples may experience a time deficit because they face a greater number of stressors that take up time, diminishing the
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"Although marital satisfaction starts high and declines for the average newlywed, some spouses may follow qualitatively distinct trajectories. Using eight self-reports of satisfaction collected over 4 years from 464 newlywed spouses, we identified five trajectory groups, including patterns defined by high intercepts and no declines in satisfaction, moderate intercepts and minimal declines, and low intercepts and substantial declines. The groups varied systematically in their 4- and 10-year divorce rates, and wives tended to follow more satisfying trajectories than their husbands. Personality traits, stress, aggression, and communication behaviors assessed shortly after marriage discriminated among groups in expected directions. We conclude by outlining theoretical and practical implications of identifying distinct and predictable patterns of change in relationship satisfaction.",
"Assumptions that single mothers are \"time poor\" compared with married mothers are ubiquitous. We tested theorized associations derived from the time poverty thesis and the gender perspective using the 2003-2012 American Time Use Surveys (ATUS). We found marital status differentiated housework, leisure, and sleep time, but did not influence the amount of time that mothers provided childcare. Net of the number of employment hours, married mothers did more housework and slept less than never-married and divorced mothers, counter to expectations of the time poverty thesis. Never-married and cohabiting mothers reported more total and more sedentary leisure time than married mothers. We assessed the influence of demographic differences among mothers to account for variation in their time use by marital status. Compositional differences explained more than two-thirds of the variance in sedentary leisure time between married and never-married mothers, but only one-third of the variance between married and cohabiting mothers. The larger unexplained gap in leisure quality between cohabiting and married mothers is consistent with the gender perspective.",
"Social-learning perspectives explicitly recognize the role of partners' personal histories and contexts as possible causes of couple communication behavior, but these assumptions are rarely tested directly, and operationalizations of context in behavioral research on couples rarely extend beyond the interacting dyad. To broaden our understanding of why couples differ in communication, the current study examined whether observed behaviors in marital interactions covary with individual experiences and contextual factors. Behaviors coded from in-home conversations of 414 ethnically diverse newlywed couples were examined simultaneously in relation to childhood and family-of-origin experiences, financial strain and stressful life events, depressive symptoms, and relationship satisfaction. A latent factor representing financial strain and stressful life events was the strongest correlate of negative communication, with higher levels of stress predicting more negativity. Relationship satisfaction was the strongest correlate of observed positivity, with higher levels of satisfaction predicting more positivity. Childhood and family experiences were unrelated to behaviors, whereas results for depressive symptoms were complex and counterintuitive. Because the negative behaviors highlighted in social-learning models of relationship functioning, and often targeted in educational interventions, covary reliably with the stresses and financial strains that couples experience, contextual factors merit greater emphasis in models designed to explain and prevent marital deterioration."
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Parent and Adolescent Emotional Variability and Adolescent Psychopathology
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Emotional variability has been posited as a risk factor for adolescent psychopathology. However, it is unclear whether parent emotional variability may also function as a risk factor that heightens adolescent mental health problems. To fill this gap, the present study examined whether parent and adolescent emotional variability in both positive emotion (PE) and negative emotion (NE) is associated with adolescent psychopathology and potential sex differences in these associations. Participants were 147 adolescents and their parents in Taiwan who completed a baseline assessment, a 10-day daily diary study, and a 3-month follow-up assessment. The results indicated that parent NE variability was associated with risk for adolescent internalizing problems and depressive symptoms, after accounting for baseline levels, adolescent NE variability, parent internalizing problems, and mean levels of parent and adolescent NE. Adolescent PE variability was also associated with the risk for adolescent externalizing problems. Furthermore, higher parent PE variability was associated with more internalizing problems only for female but not male adolescents. The findings highlight the importance of assessing emotion dynamics in both parents and adolescents to better understand the development of adolescent psychopathology. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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"Family-based assessments of risk factors for adolescent emotional, behavioral, and substance use problems can be used to identify adolescents who are at risk and intervene before problems cause clinically significant impairment. Expanding traditional methods for assessing risk, this study evaluates whether lability, referring to the degree to which parent-adolescent relationships and parenting fluctuate from day to day, might offer additional value to assessment protocols aimed at identifying precursor risk factors. This study sampled 151 adolescents and caregivers, collecting data at a baseline assessment, a 21-day daily diary protocol, and a 12-month follow-up assessment. Daily diary data were used to calculate within-family lability scores in parenting practices, parent-adolescent connectedness, and parent-adolescent conflict. Regression analyses evaluated whether lability predicted adolescent's depression, anxiety, antisocial behavior (ASB), drunkenness, and marijuana use at 12-month follow-up. Lability in parent-adolescent connectedness, accounting for baseline levels, gender, age, and initial levels of outcomes, was associated with risk for depression, anxiety, ASB, drunkenness, and marijuana use. Lability in parenting practices also was associated with risk for depression, anxiety, and drunkenness. Baseline levels moderated some of these effects. Parent-adolescent conflict lability was only associated with depression. These findings provide evidence for substantial value added when including dynamic assessments of family lability in predicting long-term adolescent risk outcomes and call for integration of dynamic methods into assessment practices.",
"Temporal instability of affect is a defining characteristic of psychological disorders such as borderline personality disorder (BPD) and mood cycling disorders. Ecological momentary assessment (EMA) enables researchers to directly assess such frequent and extreme fluctuations over time. The authors examined 4 operationalizations of such temporal instability: the within-person variance (WPV), the first-order autocorrelation, the mean square successive difference (MSSD), and the probability of acute change (PAC). It is argued that the MSSD and PAC measures are preferred indices of affective instability because they capture both variability and temporal dependency in a time series. Additionally, the performance of these 2 measures in capturing within- and between-day instability is discussed. To illustrate, the authors present EMA data from a study of negative mood in BPD and major depressive disorder patients. In this study, MSSD and PAC captured affective instability better than did WPV. Given that MSSD and PAC are individual difference measures, the authors propose that group differences on these indices be explored using generalized multilevel models. Versions of MSSD and PAC that adjust for randomly elapsed time interval between assessments are also presented.",
"This longitudinal study examined how a multimethod (youth report, parent report, direct observation) assessment of family relationship quality (cohesion and conflict) in adolescence (age 16-17) predicted growth and maintenance of effortful control across ages 17, 22, and 23 years old, and, ultimately, subjective well-being, emotional distress, and aggressive behavior in emerging adulthood (23). A diverse sample of 792 youth at age 17 and their families, and youth at ages 22 and 23, were studied to examine family cohesion and conflict and the growth and maintenance of effortful control as predictors of emerging adult social and emotional health. Results indicated that family cohesion and conflict during late adolescence and mean-level effortful control at age 22 each served as unique pathways to emerging adult adjustment. These findings underscore the importance of family functioning during adolescence and the maintenance of effortful control into emerging adulthood for understanding adjustment during the emerging adulthood period.",
"The developmental model of adolescent antisocial behavior advanced by Patterson and colleagues (e.g., Patterson, Reid, & Dishion, 1992) appears to generalize the development of a diverse set of problem behaviors. Structural equation modeling methods were applied to 18-month longitudinal data from 523 adolescents. The problem behavior construct included substance use, antisocial behavior, academic failure, and risky sexual behavior. Families with high levels of conflict were less likely to have high levels of parent-child involvement. Such family conditions resulted in less adequate parental monitoring of adolescent behavior, making associations with deviant peers more likely. Poor parental monitoring and associations with deviant peers were strong predictors of engagement in problem behavior. These constructs accounted for 46% of the variance in problem behavior. Although association with deviant peers was the most proximal social influence on problem behavior, parental monitoring and family factors (conflict and involvement) were key parenting practices that influenced this developmental process."
] |
Discrete Fourier transform-based gene clustering
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Within the realms of human thoughts on nature, Fourier analysis is considered as one of the greatest ideas currently put forwarded. The Fourier transform shows that any periodic function can be rewritten as the sum of sinusoidal functions. Having a Fourier transform view on real-world problems like the DNA sequence of genes, would make things intuitively simple to understand in comparison with their initial formal domain view. In this study we used discrete Fourier transform (DFT) on DNA sequences of a set of genes in the bovine genome known to govern milk production, in order to develop a new gene clustering algorithm. The implementation of this algorithm is very user-friendly and requires only simple routine mathematical operations. By transforming the configuration of gene sequences into frequency domain, we sought to elucidate important features and reveal hidden gene properties. This is biologically appealing since no information is lost via this transformation and we are therefore not reducing the number of degrees of freedom. The results from different clustering methods were integrated using evidence accumulation algorithms to provide in insilico validation of our results. We propose using candidate gene sequences accompanied by other genes of biologically unknown function. These will then be assigned some degree of relevant annotation by using our proposed algorithm. Current knowledge in biological gene clustering investigation is also lacking, and so DFT-based methods will help shine a light on use of these algorithms for biological insight.
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[
"The major signal in coding regions of genomic sequences is a three-base periodicity. Our aim is to use Fourier techniques to analyse this periodicity, and thereby to develop a tool to recognize coding regions in genomic DNA. The three-base periodicity in the nucleotide arrangement is evidenced as a sharp peak at frequency f = 1/3 in the Fourier (or power) spectrum. From extensive spectral analysis of DNA sequences of total length over 5.5 million base pairs from a wide variety or organisms (including the human genome), and by separately examining coding and non-coding sequences, we find that the relative-height of the peak at f = 1/3 in the Fourier spectrum is a good discriminator of coding potential. This feature is utilized by us to detect probable coding regions in DNA sequences, by examining the local signal-to-noise ratio of the peak within a sliding window. While the overall accuracy is comparable to that of other techniques currently in use, the measure that is presently proposed is independent of training sets or existing database information, and can thus find general application. A computer program GeneScan which locates coding open reading frames and exonic regions in genomic sequences has been developed, and is available on request.",
"Hierarchical clustering is a widely used method for detecting clusters in genomic data. Clusters are defined by cutting branches off the dendrogram. A common but inflexible method uses a constant height cutoff value; this method exhibits suboptimal performance on complicated dendrograms. We present the Dynamic Tree Cut R package that implements novel dynamic branch cutting methods for detecting clusters in a dendrogram depending on their shape. Compared to the constant height cutoff method, our techniques offer the following advantages: (1) they are capable of identifying nested clusters; (2) they are flexible-cluster shape parameters can be tuned to suit the application at hand; (3) they are suitable for automation; and (4) they can optionally combine the advantages of hierarchical clustering and partitioning around medoids, giving better detection of outliers. We illustrate the use of these methods by applying them to protein-protein interaction network data and to a simulated gene expression data set. The Dynamic Tree Cut method is implemented in an R package available at http://www.genetics.ucla.edu/labs/horvath/CoexpressionNetwork/BranchCutting.",
"In this paper, a revision for the existing method of locating exons by genomic signal processing technique employing four binary indicator sequences is presented. The existing method relies on the pronounced period three peaks observed in the Fourier power spectrum of the exon regions which are absent in non-coding regions. The authors have abandoned the four sequences all together and adopted a single 'EIIP indicator sequence' which is formed by substituting the electron-ion interaction pseudopotentials (EIIP) of the nucleotides A, G, C and T in the DNA sequence, reducing the computational overhead by 75%. The power spectrum of this sequence reveals period three peaks for exon regions. Also a number of exons have been identified which exhibit period three peaks when mapped to 'EIIP indicator sequence' and which do not show the same when the binary indicator sequences are employed. We could get better discrimination between exon areas and non-coding areas of a number of genomes when the sequences are mapped to EIIP indicator sequences and the power spectra of the same are taken in a sliding Kaiser window, compared to the existing method using a rectangular window which utilizes binary indicator sequences."
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Neoadjuvant Chemotherapy: Imaging and Surgical Approaches
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Neoadjuvant chemotherapy (NACT) today represents a cornerstone in the treatment of locally advanced breast cancer and highly chemo-sensitive tumors at early stages, increasing the possibilities of performing more conservative treatments and improving long term outcomes. Imaging has a fundamental role in the staging and prediction of the response to NACT, thus aiding surgical planning and avoiding overtreatment. In this review, we first examine and compare the role of conventional and advanced imaging techniques in preoperative T Staging after NACT and in the evaluation of lymph node involvement. In the second part, we analyze the different surgical approaches, discussing the role of axillary surgery, as well as the possibility of non-operative management after-NACT, which has been the subject of recent trials. Finally, we focus on emerging techniques that will change the diagnostic assessment of breast cancer in the near future.
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[
"There is ongoing debate regarding the optimal sequence of sentinel lymph node (SLN) biopsy and neoadjuvant chemotherapy (CTX) for breast cancer. We report the accuracy of comprehensive pre-neoadjuvant CTX and post-neoadjuvant CTX axillary staging via ultrasound imaging, fine-needle aspiration (FNA) biopsy, and SLN biopsy. From 2001 to 2004, 91 neoadjuvant CTX patients at the University of Michigan Comprehensive Cancer Center underwent axillary staging by ultrasonography, ultrasound-guided FNA biopsy, SLN biopsy, or a combination of these. Axillary staging was pathologically negative by pre-neoadjuvant CTX SLN biopsy in 53 cases (58%); these patients had no further axillary surgery. In 38 cases (42%), axillary metastases were confirmed at presentation by either ultrasound-guided FNA or SLN biopsy. These 38 patients underwent completion axillary lymph node dissection (ALND) after delivery of neoadjuvant CTX. Follow-up lymphatic mapping was attempted in 33 of these cases, and the SLN was identified in 32 (identification rate, 97%). One third of these cases were completely node negative on ALND. Residual metastatic disease was identified in 22 cases, and the SLN was falsely negative in 1 (4.5%). Patients receiving neoadjuvant CTX can have accurate axillary nodal staging by ultrasound-guided FNA or SLN biopsy. In cases of documented axillary metastasis at presentation, repeat axillary staging with SLN biopsy can document the post-neoadjuvant CTX nodal status. This strategy optimizes pre-neoadjuvant CTX and post-neoadjuvant CTX staging information by distinguishing the patients who are node negative at presentation from those who have been downstaged to node negativity and offers the potential for avoiding unnecessary ALNDs in both of these patient subsets.",
"We prospectively compared the ability of magnetic resonance imaging (MRI) to measure residual breast cancer in patients treated with different neoadjuvant chemotherapy regimen. Forty patients with locally advanced breast carcinoma underwent neoadjuvant chemotherapy. Twelve patients received 5-fluoro-uracyl-epirubicin-cyclophosphamide (FEC-group, six cycles), 28 (DXL-group) received docetaxel-based chemotherapy (six cycles DXL-epirubicin: 13 patients, eight cycles DXL alone: 15 patients). All patients had baseline and preoperative MRI. The spread of pathologic residual disease (PRd) was compared to preoperative MRI measures according to chemotherapy regimen. MRI over/underestimation of the spread of residual tumour was never superior to 15mm in FEC group, whereas it appeared in 11/28 (39%, 30-48%-95% CI) patients in DXL group (p=0.017). Tumour shrinkage led to single nodular residual lesions in FEC group, whereas vast numerous microscopic nests were observed in docetaxel group in pathology. Among tumours treated with a taxane-containing regimen, residual disease was frequently underestimated by MRI because of PRd features.",
"It had been previously shown that patients who receive neoadjuvant systemic therapy (NST) are more likely to undergo breast-conserving therapy (BCT) than those who have primary surgery. However, the frequency with which patients who are not BCT-eligible prior to NST convert to BCT-eligible with treatment is unknown. To document this conversion rate in a subset of patients expected to have a high clinical response rate to NST, we studied surgical assessment and management of patients enrolled on a randomized neoadjuvant trial for stage II-III HER2-positive breast cancer (HER2 + BC)(CALGB 40601). The treating surgeon assessed BCT candidacy based on clinico-radiographic criteria both before and after NST. Definitive breast surgical management was at surgeon and patient discretion. We sought to determine (1) the conversion rate from BCT-ineligible to BCT-eligible (2) the percentage of BCT-eligible patients who chose breast conservation, and (3) the rate of successful BCT. We also evaluated surgeon-determined factors for BCT-ineligibility and the correlation between BCT eligibility and pathologic complete response (pCR). Of 292 patients with pre- and post-NST surgical assessments, 59 % were non-BCT candidates at baseline. Of the 43 % of these patients who converted with NST, 67 % opted for BCT, with an 80 % success rate. NST increased the BCT-eligible rate from 41 to 64 %. Common factors cited for BCT-ineligibility prior to NST including tumor size (56 %) and probable poor cosmetic outcome (26 %) were reduced by 67 and 75 %, respectively, with treatment, while multicentricity, the second most common factor (33 %), fell by only 16 %. Since 23 % of the BCT-eligible patients chose mastectomy, BCT was the final surgical procedure in just 40 % of the patients. Patients considered BCT-eligible both at baseline and after NST had a pCR rate of 55 %, while patients who were BCT-ineligible prior to NST had the same pCR rate (44 %) whether they converted to BCT-eligible or not. Many patients with HER2 + BC deemed ineligible for BCT at baseline can be converted to BCT-eligible with NST; excluding patients with multicentric disease substantially increases that percentage. In converted patients who opt for BCT, the success rate is similar to that of patients considered BCT-eligible at baseline. Whether a BCT-ineligible patient converts to BCT eligibility or not does not appear to affect the likelihood of achieving a pCR. Despite the efficacy of NST in this patient cohort, only 40 % of patients had successful BCT; further research into why BCT-eligible patients often opt for mastectomy is needed.",
"The American College of Surgeons Oncology Group trial Z0011 was a prospective, randomized, multicenter trial comparing overall survival between patients with positive sentinel lymph nodes (SLNs) who did and did not undergo axillary lymph node dissection (ALND). The current study compares complications associated with SLN dissection (SLND) plus ALND, versus SLND alone. From May 1999 to December 2004, 891 patients were randomly assigned to SLND + ALND (n = 445) or SLND alone (n = 446). Information on wound infection, axillary seroma, paresthesia, brachial plexus injury (BPI), and lymphedema was available for 821 patients. Adverse surgical effects were reported in 70% (278 of 399) of patients after SLND + ALND and 25% (103 of 411) after SLND alone (P <or= .001). Patients in the SLND + ALND group had more wound infections (P <or= .0016), seromas (P <or= .0001), and paresthesias (P <or= .0001) than those in the SLND-alone group. At 1 year, lymphedema was reported subjectively by 13% (37 of 288) of patients after SLND + ALND and 2% (six of 268) after SLND alone (P <or= .0001). The difference between the two groups' lymphedema, assessed by arm measurements at 30 days (P = .36), 6 months (P = .22), and 1 year (P = .078), although close to the cutoff for significance at 1 year, was not significant. BPIs occurred in less than 1% of patients. In trial Z0011, the use of SLND + ALND resulted in more wound infections, axillary seromas, and paresthesias than SLND alone. Lymphedema was more common after SLND + ALND but was significantly different only by subjective report. The use of SLND alone resulted in fewer complications."
] |
Upscaling cervical cancer screening and treatment services at a rural referral hospital in Tanzania
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Cervical cancer (CC) is nearly always caused by persistent human papillomavirus (HPV) infection. It is the most common cancer among women living with HIV (WLWH) and is the leading cause of cancer-related death in women in East Africa, with 10,241 new cases reported in Tanzania in 2020. In 2019, the World Health Organization (WHO) presented a global strategy for the elimination of CC as a public health problem, proposing targets to meet by 2030 for HPV vaccine coverage (90% of all 15-year-old girls), CC screening (70% of all women once at 35 and again at 45 years of age) and treatment delivery, to be scaled at national and subnational levels with a context-sensitive approach. This study aims to evaluate the upscaling of screening and treatment services at a rural referral hospital in Tanzania in order to address the second and third WHO targets.
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[
"Implementation of a novel, rapid, high-volume, see-and-treat cervical cancer screening programme using self-swab human papillomavirus (HPV) testing and digital colposcopy in underserved regions of Yunnan China. 480-980 women per day self-swabbed for high-risk HPV (hrHPV+). Four careHPV machines (Qiagen) were run simultaneously to test the specimens. All hrHPV+ patients were contacted the same day and digital colposcopy was performed with the enhanced visual assessment system (MobileODT). Digital images were obtained, and all suspected lesions were biopsied and then treated. Rural and underserved areas of the Yunnan province, Kunming municipality. 3600 women, mean age 50.2 years, who had never been screened for cervical cancer. The women were of the Yi, Hui, Dai and Han ethnicities. Cryotherapy was performed on all lesions suspicious for cervical intraepithelial neoplasia (CIN) 1 and loop electrosurgical excision procedure was performed on all lesions suspicious for ≥CIN2. Endocervical curettage was performed if the transformation zone was not fully visualised. 216 women (6%) were hrHPV+. 168 underwent same-day colposcopy (23 CIN1, 17≥CIN2). Digital colposcopy was able to identify 15 of 16 (93.8%)≥CIN2 lesions. This study illustrates a high-volume, rapid and practical strategy that can be used to screen and treat an ethnically diverse group of Chinese women. First, HPV self-sampling allows large numbers of women to be screened rapidly and relatively inexpensively. Only hrHPV+ women will then require further evaluation. Digital colposcopy is then performed on hrHPV+ women with a portable digital colposcope. The high-resolution images obtained can facilitate appropriate same-day treatment as they are able to accurately distinguish between CIN1 and ≥CIN2 lesions.",
"To examine the test performance of careHPV, Hybrid Capture2 (HC2) and visual inspection with acetic acid (VIA) for detection of cytologically diagnosed high-grade cervical lesions or cancer (HSIL+). Cross-sectional study. Ocean Road Cancer Institute (ORCI) and Kilimanjaro Christian Medical Center (KCMC), Tanzania. Women attending routine cervical cancer screening. We enrolled 4080 women (25-60 years) in the study. The women were interviewed on lifestyle habits, and tested for HIV. A cervical specimen for careHPV testing (performed at ORCI and KCMC), and a liquid-based cytology sample for HPV DNA detection using HC2 (performed at Tuebingen University Hospital, Germany) and for cytology assessment (performed at Vejle Hospital, Denmark) were obtained at a gynecological examination. Subsequently, VIA was performed. With cytology as gold standard, the sensitivity and specificity of careHPV, HC2, and VIA for detection of HSIL+ were calculated. Altogether, 23.6% had a positive careHPV test, 19.1% had positive HC2 test, and 6.3% had a positive VIA test. The sensitivity/specificity was 88.9%/78.9% for careHPV and 91.1%/83.7%, for HC2. VIA showed a low sensitivity of 31.1% but a high specificity (94.6%) for detection of HSIL+. The sensitivity of careHPV, HC2 and VIA was higher among younger women, and among HIV positive women. VIA triage of careHPV positive women improved specificity, but sensitivity dropped to 27%. Our results confirm the low sensitivity of VIA for detection of HSIL+ and further document that careHPV test is promising as a primary screening method for cervical-cancer prevention in low-resource regions. A suitable triage test has to be identified.",
"careHPV, a lower-cost DNA test for human papillomavirus (HPV), is being considered for cervical cancer screening in low- and middle-income countries. However, not a single large-scaled study exists to investigate the optimal positive cutoff point of careHPV test. We pooled data for 9,785 women participating in two individual studies conducted from 2007 to 2011 in rural China. Woman underwent multiple screening tests, including careHPV on clinician-collected specimens (careHPV-C) and self-collected specimens (careHPV-S), and Hybrid Capture 2 on clinician-collected specimens (HC2-C) as a reference standard. The primary endpoint was cervical intraepithelial neoplasia grade 3 or more severe (CIN3+) (n = 127), and secondary endpoint was CIN2+ (n = 213). The area under the curves (AUCs) for HC2-C and careHPV-C were similar (0.954 versus 0.948, P = 0.166), and better than careHPV-S (0.878; P < 0.001 versus both). The optimal positive cutoff points for HC2-C, careHPV-C, and careHPV-S were 1.40, 1.74, and 0.85, respectively. At the same cutoff point, careHPV-C was not significantly less sensitive and more specific for CIN3+ than HC2-C, and careHPV-S was significantly less sensitive for CIN3+ than careHPV-C and HC2-C. Raising the cutoff point of careHPV-C from 1.0 to 2.0 could result in nonsignificantly lower sensitivity but significantly higher specificity. Similar results were observed using CIN2+ endpoint. careHPV using either clinician- or self-collected specimens performed well in detecting cervical precancer and cancer. We found that the optimal cutoff points of careHPV were 2.0 on clinician-collected specimens and 1.0 on self-collected specimens.",
"Cervical cancer is the most common type of cancer in sub-Saharan Africa, and it is also the cancer disease that most women die from. The high mortality rate is partly due to low attendance rates to screening services and low sensitivity of visual inspection with acetic acid, which is the standard screening method used in screening programs in sub-Saharan Africa. In order to overcome of the burden of disease new screening strategies and methods are warranted. This study aims to explore the acceptability and feasibility of HPV self-sampling compared to provider-based sampling among cervical cancer screening clients living in Dar es Salaam. Women attending cervical cancer screening at Ocean Road Cancer Institute in Dar es Salaam, Tanzania between February - April 2017 were invited into the study. The participants had (1) a provider-collected sample, and (2) a self-sample for HPV on top of the regular cervical cancer screening. 50% of the participants conducted the self-sample after receiving a written instruction guide of how to collect the sample (written). The other 50% received both the written and an oral introduction to self-sampling (written+). All participants could ask for nurse assistance during self-sample collection if needed. Individual semi-structured interviews were conducted with the participants post sample collection. Data collection stopped when saturation was reached. Data were analysed using a thematic content analysis. Twenty-one women participated in the study. Regardless of how women were introduced to the self-sample (written or written+), there was a high demand for nurse presence as they felt uncertain of their personal capabilities to collect the self-sample correctly. However, as long as nurse assistance was an option most women perceived self-sampling as easy and comfortable though few experienced bleeding and pain. The majority of women preferred self-sampling over provider-sampling primarily due to the method being more private than the provider-sampling. HPV self-sampling was well-perceived and accepted, however, for the method to be feasible a nurse needed to be present. HPV Self-sampling may be an alternative method to increase uptake of cervical cancer screening. Larger quantitative studies are recommended to support the study findings.",
"To assess and compare the accuracy of visual inspection with acetic acid (VIA), visual inspection with Lugol's iodine (VILI), and human papillomavirus (HPV) testing as alternative standalone methods for primary cervical cancer screening in sub-Saharan Africa. Systematic review and meta-analysis of diagnostic test accuracy studies. Systematic searches of multiple databases including Medline, Embase, and Scopus for studies published between January 1994 and June 2014. Inclusion criteria for studies were: alternative methods to cytology used as a standalone test for primary screening; study population not at particular risk of cervical cancer (excluding studies focusing on HIV positive women or women with gynaecological symptoms); women screened by nurses; reference test (colposcopy and directed biopsies) performed at least in women with positive screening results. Two reviewers independently screened studies for eligibility and extracted data for inclusion, and evaluated study quality using the quality assessment of diagnostic accuracy studies 2 (QUADAS-2) checklist. Primary outcomes were absolute accuracy measures (sensitivity and specificity) of screening tests to detect cervical intraepithelial neoplasia grade 2 or worse (CIN2+). 15 studies of moderate quality were included (n=61,381 for VIA, n=46,435 for VILI, n=11,322 for HPV testing). Prevalence of CIN2+ did not vary by screening test and ranged from 2.3% (95% confidence interval 1.5% to 3.3%) in VILI studies to 4.9% (2.7% to 7.8%) in HPV testing studies. Positivity rates of VILI, VIA, and HPV testing were 16.5% (9.8% to 24.7%), 16.8% (11.0% to 23.6%), and 25.8% (17.4% to 35.3%), respectively. Pooled sensitivity was higher for VILI (95.1%; 90.1% to 97.7%) than VIA (82.4%; 76.3% to 87.3%) in studies where the reference test was performed in all women (P<0.001). Pooled specificity of VILI and VIA were similar (87.2% (78.1% to 92.8%) v 87.4% (77.1% to 93.4%); P=0.85). Pooled sensitivity and specificity were similar for HPV testing versus VIA (both P ≥ 0.23) and versus VILI (both P ≥ 0.16). Accuracy of VIA and VILI increased with sample size and time period. For primary screening of cervical cancer in sub-Saharan Africa, VILI is a simple and affordable alternative to cytology that demonstrates higher sensitivity than VIA. Implementation studies are needed to assess the effect of these screening strategies on the incidence and outcomes of cervical cancer in the region.",
"Cervical cancer is a major cause of death among women in Eastern Africa, and the distribution of human papillomavirus (HPV) according to HIV status is inadequately characterised in this region. In order to guide future cervical cancer preventive strategies that involve HPV testing, the Comprehensive Cervical Cancer Prevention in Tanzania (CONCEPT) study was established in 2015. The CONCEPT cohort aims to investigate the natural history of HPV and determine acquisition and persistence patterns of high-risk (HR) HPV among HIV-positive and HIV-negative women. Further, the influence of lifestyle and sexual/reproductive factors will be investigated. The main objective of this article is to describe how the CONCEPT cohort was established. Women aged 25-60 years were enrolled from cervical cancer screening clinics in Dar-es-Salaam and Moshi, Tanzania. Data were collected at baseline, at 14 months (first follow-up) and at 28 months (second follow-up). Biological samples included two cervical swabs for careHPV DNA testing, cytology, Hybrid Capture 2, genotyping and blood samples for HIV. Visual inspection with acetic acid was performed, and sociodemographic, lifestyle and sexual/reproductive characteristics were collected through a standardised questionnaire. 4043 women were included in the cohort from August 2015 to May 2017. At baseline, 696 (17.1%) women were HR HPV positive, and among these, 31.6% were HIV positive; 139 women (3.4%) had high-grade squamous intraepithelial lesions. 3074 women (81%) attended the first follow-up. The majority attended after receiving a phone call reminder (35%) or from home via self-samples (41%). At first follow-up, 438 (14.4%) were HR HPV positive and 30.4% of these were HIV positive. A second follow-up is underway (17 December 2018-October 2020). We plan to integrate our data with a previous cross-sectional HPV study from Tanzania to increase the power of our findings. Researchers interested in collaborating are welcomed, either by extracting data or jointly requesting further investigation from the cohort.",
"Rapid human papillomavirus (HPV) DNA testing is an emerging cervical cancer screening strategy in resource-limited countries, yet it requires follow-up of women who test HPV positive. This study aimed to determine if one-way text messages improved attendance to a 14-month follow-up cervical cancer screening among HPV-positive women. This multicenter, parallel-group randomized controlled trial was conducted at 3 hospitals in Tanzania. Eligible participants were aged between 25 and 60 years, had tested positive to a rapid HPV test during a patient-initiated screening, had been informed of their HPV result, and had a private mobile phone with a valid number. Participants were randomly assigned in a 1:1 ratio to the intervention or control group through an incorporated algorithm in the text message system. The intervention group received one-way text messages, and the control group received no text messages. The primary outcome was attendance at a 14-month health provider-initiated follow-up screening. Participants were not blinded, but outcome assessors were. The analysis was based on intention to treat. Between August 2015 and July 2017, 4080 women were screened for cervical cancer, of which 705 were included in this trial-358 women were allocated to the intervention group, and 347 women were allocated to the control group. Moreover, 16 women were excluded before the analysis because they developed cervical cancer or died (8 from each group). In the intervention group, 24.0% (84/350) women attended their follow-up screening, and in the control group, 23.8% (80/335) women attended their follow-up screening (risk ratio 1.02, 95% CI 0.79-1.33). Attendance to a health provider-initiated follow-up cervical cancer screening among HPV-positive women was strikingly low, and one-way text messages did not improve the attendance rate. Implementation of rapid HPV testing as a primary screening method at the clinic level entails the challenge of ensuring a proper follow-up of women. ClinicalTrials.gov NCT02509702; https://clinicaltrials.gov/ct2/show/NCT02509702. RR2-10.2196/10.2196/15863."
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Effects of Fenretinide on LDLR in Mice
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Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR
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[
"Differences in the composition of control diets may confound outcomes in studies investigating dietary effects. We compared the effects of two control diets commonly used in mice studies, chow (SD) and a purified low-fat diet (LFD), in relation to a chronic high-fat diet (HFD). We hypothesized that SD and LFD will have similar effects on phenotypic, metabolic, and behavioral outcomes. Fifty-four 5-week-old male C57BL/6J mice were randomly assigned to one of the three dietary interventions (SD, LFD, or HFD) for 18 weeks. At week 16, mice were tested for behavioral changes. Glucose tolerance testing was conducted at week 17 and terminal blood collection at week 18. SD and LFD mice exhibited no differences in cognitive performance on the Y-maze test and comparable anxiety-like behavior in the open-field and elevated zero maze tests. Significant declines in cognitive function and greater anxiety-like behavior were observed in the HFD group compared to both SD and LFD. Areas under the glucose tolerance curve were similar for SD and LFD, as were levels of high-density lipoprotein, triglycerides, cytokines, and adipocytokines. Only total cholesterol was significantly higher in LFD mice compared to SD mice. All measures were significantly higher in the HFD group. Our data demonstrate that young mice develop similar phenotypic, metabolic, and behavioral profiles when fed SD vs. LFD. The two diets may thus be equally appropriate as controls for an HFD, although some studies may want to consider differences in effects on cholesterol levels.",
"Physiological adaptations resulting in the development of the metabolic syndrome in man occur over a time span of several decades. This combined with the prohibitive financial cost and ethical concerns to measure key metabolic parameters repeatedly in subjects for the major part of their life span makes that comprehensive longitudinal human data sets are virtually nonexistent. While experimental mice are often used, little is known whether this species is in fact an adequate model to better understand the mechanisms that drive the metabolic syndrome in man. We took up the challenge to study the response of male apoE*3-Leiden.CETP mice (with a humanized lipid profile) to a high-fat high-cholesterol diet for 6 months. Study parameters include body weight, food intake, plasma and liver lipids, hepatic transcriptome, VLDL - triglyceride production and importantly the use of stable isotopes to measure hepatic de novo lipogenesis, gluconeogenesis, and biliary/fecal sterol secretion to assess metabolic fluxes. The key observations include (1) high inter-individual variation; (2) a largely unaffected hepatic transcriptome at 2, 3, and 6 months; (3) a biphasic response curve of the main metabolic features over time; and (4) maximum insulin resistance preceding dyslipidemia. The biphasic response in plasma triglyceride and total cholesterol appears to mimic that of men in cross-sectional studies. Combined, these observations suggest that studies such as these can help to delineate the causes of metabolic derangements in patients suffering from metabolic syndrome.",
"Atherosclerosis is one of the primary causes of cardiovascular disease and mortality. This chronic immunometabolic disease evolves during decades in humans and encompasses different organs and immune cell types, as well as local and systemic processes that promote the progression of the disease. The most frequently used animal model to study these atherogenic processes and inter-organ crosstalk in a short time frame are genetically modified mouse models. Some models have been used throughout the last decades, and some others been developed recently. These models have important differences in cholesterol and lipoprotein metabolism, reverse cholesterol transport pathway, obesity and diabetes as well as inflammatory processes. Therefore, the disease develops and progresses differently in the various mouse models. Since atherosclerosis is a multifaceted disease and many processes contribute to its progression, the choice of the right mouse model is important to study specific aspects of the disease. We will describe the different mouse models and provide a roadmap to facilitate current and future atherosclerosis researchers to choose the right model depending on their scientific question.",
"Uptake of cholesterol, mediated by the low-density lipoprotein (LDL)-receptor, plays a crucial role in lipoprotein metabolism. The LDL-receptor is responsible for the binding and subsequent cellular uptake of apolipoprotein B- and E-containing lipoproteins. To accomplish this, the receptor has to be transported from the site of synthesis, the membranes of the rough endoplasmatic reticulum (ER), through the Golgi apparatus, to its position on the surface of the cellular membrane. The translation of LDL-receptor messenger RNA into the polypeptide chain for the receptor protein takes place on the surface-bound ribosomes of the rough ER. Immature O-linked carbohydrate chains are attached to this integral precursor membrane protein. The molecular weight of the receptor at this stage is 120.000 d. The precursor-protein is transported from the rough ER to the Golgi apparatus, where the O-linked sugar chains are elongated until their final size is reached. The molecular weight has then increased to 160.000 d. The mature LDL-receptor is subsequently guided to the \"coated pits\" on the cell surface. These specialized areas of the cell membrane are rich in clathrin and interact with the LDL-receptor protein. Only here can the LDL-receptor bind LDL-particles. Within 3 to 5 minutes of its formation, the LDL-particle-receptor complex is internalized through endocytosis and is further metabolized through the receptor-mediated endocytosis pathway. Mutations in the gene coding for the LDL-receptor can interfere to a varying extent with all the different stages of the posttranslational processing, binding, uptake, and subsequent dissociation of the LDL-particle-LDL-receptor complex, but invariably the mutations lead to familial hypercholesterolemia. Thus, mutations in the LDL-receptor gene give rise to a substantially varying clinical expression of familial hypercholesterolemia."
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Neutrophil extracellular trap formation in myeloproliferative neoplasms
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Myeloproliferative neoplasms (MPNs) are hematologic malignancies characterized by gene mutations that promote myeloproliferation and resistance to apoptosis via constitutively active signaling pathways, with Janus kinase 2-signal transducers and the activators of transcription (JAK-STAT) axis as a core part. Chronic inflammation has been described as a pivot for the development and advancement of MPNs from early stage cancer to pronounced bone marrow fibrosis, but there are still unresolved questions regarding this issue. The MPN neutrophils are characterized by upregulation of JAK target genes, they are in a state of activation and with deregulated apoptotic machinery. Deregulated neutrophil apoptotic cell death supports inflammation and steers them towards secondary necrosis or neutrophil extracellular trap (NET) formation, a trigger of inflammation both ways. NETs in proinflammatory bone marrow microenvironment induce hematopoietic precursor proliferation, which has an impact on hematopoietic disorders. In MPNs, neutrophils are primed for NET formation, and even though it seems obvious for NETs to intervene in the disease progression by supporting inflammation, no reliable data are available. We discuss in this review the potential pathophysiological relevance of NET formation in MPNs, with the intention of contributing to a better understanding of how neutrophils and neutrophil clonality can orchestrate the evolution of a pathological microenvironment in MPNs.
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[
"Neutrophils cast neutrophil extracellular traps (NETs) to ensnare microbial pathogens. Nevertheless, the molecular rheostats that regulate NETosis in response to bacteria are not clearly established. We hypothesized that stress-activated protein kinase or c-Jun N-terminal Kinase (SAPK/JNK) is a molecular switch that turns on NETosis in response to increasing concentrations of lipopolysaccharide (LPS)- and Gram-negative bacteria. Here we show that Escherichia coli LPS (0111:B4; 10-25 μg/ml), but not phorbol myristate acetate (PMA), activates JNK in human neutrophils in a dose-dependent manner. JNK inhibitors SP600125 and TCSJNK6o, and a TLR4 inhibitor TAK242 suppress reactive oxygen species production and NETosis in LPS-, but not PMA-treated neutrophils. Diphenyleneiodonium suppresses LPS-induced NETosis, confirming that endotoxin induces NADPH oxidase-dependent NETosis. Immunoblots, Sytox Green assays, and confocal microscopy of cleaved caspase-3 and nuclear morphology show that JNK inhibition does not induce apoptosis in LPS-stimulated neutrophils. JNK inhibition also suppresses NETosis induced by two typical Gram-negative bacteria, E. coli and Pseudomonas aeruginosa. Therefore, we propose that neutrophils use a TLR4-dependent, JNK-mediated molecular sensing mechanism to initiate NADPH oxidase-dependent suicidal NETosis in response to increasing concentrations of LPS, and Gram-negative bacteria. The LPS-TLR4-JNK activation axis determines the fate of these cells: to be or not to be NETotic neutrophils.",
"Myelofibrosis (MF) is characterized by cytopenias, constitutional symptoms, splenomegaly, and marrow histopathological abnormalities (fibrosis, increased microvessel density, and osteosclerosis). The microenvironmental abnormalities are likely a consequence of the elaboration of a variety of inflammatory cytokines generated by malignant megakaryocytes and monocytes. We observed that levels of a specific inflammatory cytokine, lipocalin-2 (LCN2), were elevated in the plasmas of patients with myeloproliferative neoplasms (MF > polycythemia vera or essential thrombocythemia) and that LCN2 was elaborated by MF myeloid cells. LCN2 generates increased reactive oxygen species, leading to increased DNA strand breaks and apoptosis of normal, but not MF, CD34(+) cells. Furthermore, incubation of marrow adherent cells or mesenchymal stem cells with LCN2 increased the generation of osteoblasts and fibroblasts, but not adipocytes. LCN2 priming of mesenchymal stem cells resulted in the upregulation of RUNX2 gene as well as other genes that are capable of further affecting osteoblastogenesis, angiogenesis, and the deposition of matrix proteins. These data indicate that LCN2 is an additional MF inflammatory cytokine that likely contributes to the creation of a cascade of events that results in not only a predominance of the MF clone but also a dysfunctional microenvironment.",
"Coronavirus disease 2019 (COVID-19) is a virus-induced respiratory disease that may progress to acute respiratory distress syndrome (ARDS) and is triggered by immunopathological mechanisms that cause excessive inflammation and leukocyte dysfunction. Neutrophils play a critical function in the clearance of bacteria with specific mechanisms to combat viruses. The aim of this review is to highlight the current advances in the pathways of neutrophilic inflammation against viral infection over the past ten years, focusing on the production of neutrophil extracellular traps (NETs) and its impact on severe lung diseases, such as COVID-19. We focused on studies regarding hyperinflammation, cytokine storms, neutrophil function, and viral infections. We discuss how the neutrophil's role could influence COVID-19 symptoms in the interaction between hyperinflammation (overproduction of NETs and cytokines) and the clearance function of neutrophils to eliminate the viral infection. We also propose a more in-depth investigation into the neutrophil response mechanism targeting NETosis in the different phases of COVID-19.",
"Neutrophils represent the major fraction of circulating immune cells and are rapidly recruited to sites of infection and inflammation. The inflammasome is a multiprotein complex that regulates the generation of IL-1 family proteins. The precise subcellular localization and functionality of the inflammasome in human neutrophils are poorly defined. Here we demonstrate that highly purified human neutrophils express key components of the NOD-like receptor family, pyrin domain containing 3 (NLRP3), and absent in melanoma 2 (AIM2) inflammasomes, particularly apoptosis-associated speck-like protein containing a CARD (ASC), AIM2, and caspase-1. Subcellular fractionation and microscopic analyses further showed that inflammasome components were localized in the cytoplasm and also noncanonically in secretory vesicle and tertiary granule compartments. Whereas IL-1β and IL-18 were expressed at the mRNA level and released as protein, highly purified neutrophils neither expressed nor released IL-1α at baseline or upon stimulation. Upon inflammasome activation, highly purified neutrophils released substantially lower levels of IL-1β protein compared with partially purified neutrophils. Serine proteases and caspases were differentially involved in IL-1β release, depending on the stimulus. Spontaneous activation of the NLRP3 inflammasome in neutrophils in vivo affected IL-1β, but not IL-18 release. In summary, these studies show that human neutrophils express key components of the inflammasome machinery in distinct intracellular compartments and release IL-1β and IL-18, but not IL-1α or IL-33 protein. Targeting the neutrophil inflammasome may represent a future therapeutic strategy to modulate neutrophilic inflammatory diseases, such as cystic fibrosis, rheumatoid arthritis, or sepsis.",
"A common feature of malignancies is increased reactive oxygen species (ROS) and reactive nitrogen species (RNS). We analyzed the influence of oxidative and nitrosative stress on the activation of AKT/mTOR signaling pathway in myeloproliferative neoplasms (MPN). Oxidative stress-induced gene expression in circulatory CD34+ cells of MPN patients was studied by microarray analysis. Biomarkers of oxidative and nitrosative stress were determined using spectrophotometry in plasma and erythrocyte lysate. The levels of nitrotyrosine, inducible NO synthase (iNOS) and AKT/mTOR/p70S6K phosphorylation were determined by immunocytochemistry and immunoblotting in granulocytes of MPN patients. Antioxidants superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPx1) gene expression were increased in circulatory CD34+ cells, while SOD1 and GPx enzymes were reduced in the erythrocytes of MPN. Plasma malonyl-dialdehyde and protein carbonyl levels were elevated in MPN. The total antioxidant capacity in plasma and erythrocyte catalase (CT) activities was the most prominent in primary myelofibrosis (PMF) with JAK2V617F heterozygosity. The total nitrite/nitrate (NOx) level was augmented in the plasma of PMF patients (p<0.001), while nitrotyrosine and iNOS were generally increased in the granulocytes of MPN patients. Activation of AKT/mTOR signaling was the most significant in PMF (p<0.01), but demonstrated JAK2V617F dependence and consequent p70S6K phosphorylation in the granulocytes of essential thrombocytemia (ET) and polycythemia vera (PV) patients. Hydrogen peroxide stimulated mTOR pathway, iNOS and nitrotyrosine quantities, the last one prevented by the antioxidant n-acetyl-cysteine (NAC) in the granulocytes of MPN. Our study showed increased levels of oxidative and nitrosative stress parameters in MPN with JAK2V617F dependence. The ROS enhanced the constitutive activation of AKT/mTOR signaling and nitrosative parameters in MPN.",
"Neutrophil extracellular traps (NETs) have been shown to promote thrombus formation. Little is known about the exact composition of thrombi that cause ischemic stroke. In particular, no information is yet available on the presence of NETs in cerebral occlusions. Such information is, however, essential to improve current thrombolytic therapy with tissue plasminogen activator (t-PA). This study aimed at investigating the presence of neutrophils and more specifically NETs in ischemic stroke thrombi. Sixty-eight thrombi retrieved from ischemic stroke patients undergoing endovascular treatment were characterized by immunostaining using neutrophil markers (CD66b and neutrophil elastase) and NET markers (citrullinated histone H3 [H3Cit] and extracellular DNA). Neutrophils and NETs were quantified. In addition, extracellular DNA was targeted by performing ex vivo lysis of retrieved thrombi with DNase 1 and t-PA. Neutrophils were detected extensively throughout all thrombi. H3Cit, a hallmark of NETs, was observed in almost all thrombi. H3Cit-positive area varied up to 13.45% of total thrombus area. Colocalization of H3Cit with extracellular DNA released from neutrophils confirmed the specific presence of NETs. H3Cit was more abundant in thrombi of cardioembolic origin compared to other etiologies. Older thrombi contained significantly more neutrophils and H3Cit compared to fresh thrombi. Interestingly, ex vivo lysis of patient thrombi was more successful when adding DNase 1 to standard t-PA. Neutrophils and NETs form important constituents of cerebral thrombi. Targeting of NETs with DNase 1 might have prothrombolytic potential in treatment of acute ischemic stroke. Ann Neurol 2017;82:223-232.",
"Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.",
"In response to inflammation, neutrophils deiminate histones and externalize chromatin. Neutrophil extracellular traps (NETs) are an innate immune defense mechanism, yet NETs also may aggravate chronic inflammatory and autoimmune disorders. Activation of peptidylarginine deiminase 4 (PAD4) is associated with NET release (NETosis) but the precise mechanisms of PAD4 regulation are unknown. We observed that, in human neutrophils, calcium ionophore induced histone deimination, whereas phorbol myristate acetate (PMA), an activator of protein kinase C (PKC), suppressed ionophore-induced deimination. Conversely, low doses of chelerythrine and sanguinarine, two inhibitors of PKC, reversed PMA inhibition and enhanced ionophore-stimulated deimination. In addition, a peptide inhibitor of PKCα superinduced ionophore activation of PAD4, thus identifying PKCα as the PMA-induced inhibitor of PAD4. At higher doses, chelerythrine, sanguinarine, and structurally unrelated PKC inhibitors blocked histone deimination, suggesting that a different PKC isoform activates histone deimination. We identify PKCζ as activator of PAD4 because a specific peptide inhibitor of this PKC isoform suppressed histone deimination. Confocal microscopy confirmed that, in the presence of PMA, NETosis proceeds without detectable histone deimination, and that ionophore cooperates with PMA to induce more extensive NET release. Broad inhibition of PKC by chelerythrine or specific inhibition of PKCζ suppressed NETosis. Our observations thus reveal an intricate antagonism between PKC isoforms in the regulation of histone deimination, identify a dominant role for PKCα in the repression of histone deimination, and assign essential functions to PKCζ in the activation of PAD4 and the execution of NETosis. The precise balance between opposing PKC isoforms in the regulation of NETosis affirms the idea that NET release underlies specific and vitally important evolutionary selection pressures.",
"Myeloproliferative neoplasms (MPNs) are diseases caused by mutations in the haematopoietic stem cell (HSC) compartment. Most MPN patients have a common acquired mutation of Janus kinase 2 (JAK2) gene in HSCs that renders this kinase constitutively active, leading to uncontrolled cell expansion. The bone marrow microenvironment might contribute to the clinical outcomes of this common event. We previously showed that bone marrow nestin(+) mesenchymal stem cells (MSCs) innervated by sympathetic nerve fibres regulate normal HSCs. Here we demonstrate that abrogation of this regulatory circuit is essential for MPN pathogenesis. Sympathetic nerve fibres, supporting Schwann cells and nestin(+) MSCs are consistently reduced in the bone marrow of MPN patients and mice expressing the human JAK2(V617F) mutation in HSCs. Unexpectedly, MSC reduction is not due to differentiation but is caused by bone marrow neural damage and Schwann cell death triggered by interleukin-1β produced by mutant HSCs. In turn, in vivo depletion of nestin(+) cells or their production of CXCL12 expanded mutant HSC number and accelerated MPN progression. In contrast, administration of neuroprotective or sympathomimetic drugs prevented mutant HSC expansion. Treatment with β3-adrenergic agonists that restored the sympathetic regulation of nestin(+) MSCs prevented the loss of these cells and blocked MPN progression by indirectly reducing the number of leukaemic stem cells. Our results demonstrate that mutant-HSC-driven niche damage critically contributes to disease manifestation in MPN and identify niche-forming MSCs and their neural regulation as promising therapeutic targets.",
"Neutrophils play a critical role as a first line of defense against invading pathogens. Recently, a new defense strategy of neutrophils was described, in which pathogens are trapped and killed by NETs. However, the exact underlying mechanisms leading to the formation of NETs remain elusive. Here, we explored the role of the Rac small GTPases in the formation of NETs using neutrophils that lack Rac1, Rac2, or both isoforms. Efficient NET formation was observed in WT and Rac1null neutrophils. In contrast, NET formation was markedly impaired in cells lacking Rac2 or both Rac2 and Rac1. The defect in NET formation in Rac2null cells was rescued by exogenous ROS sources, suggesting that Rac2-mediated ROS generation is required for NET formation. In addition, we assessed the role of NO in NET formation in mouse neutrophils. Blocking NO production with the NOS inhibitor L-NAME significantly reduced NET formation. Moreover, we show that Rac2null cells produce significantly less NO than Rac1null cells or their WT counterparts. Our data suggest that Rac2 is essential for NET formation via pathways involving ROS and NO."
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Systemic exposure to cisplatin and paclitaxel after adjuvant intraperitoneal administration in patients with advanced ovarian cancer who underwent primary debulking surgery
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To determine the systemic exposure to cisplatin and paclitaxel after adjuvant intraperitoneal administration in patients with advanced ovarian cancer who underwent primary debulking surgery. This could provide an explanation for the high incidence of systemic adverse events associated with this treatment regimen.
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"Plasma concentrations of cisplatin, total platinum, and total filterable platinum were monitored in 24 patients after either 50 or 100 mg/m2 of cisplatin by rapid intravenous injection. Half the patients at each dose were pretreated with mannitol. Total platinum levels declined in a triphasic fashion with a terminal half-life (t1/2)greater than or equal to 24 hr. Both total filterable platinum and cisplatin levels declined in a monophasic manner and exhibited t1/2 of 0.3 to 0.5 hr. The ratio of cisplatin to total filterable platinum in plasma remained constant (0.6 to 0.8) over the time period (2 hr) during which they could be detected, while the ratio of the plasma levels of cisplatin to total platinum decreased continuously from approximately 0.5 at 5 min to approximately 0.10 at 2 hr. Larger doses of cisplatin resulted in higher plasma levels of all three species monitored, and although the increases appeared somewhat less than proportional to dose, terminal plasma slopes were not dose dependent. Neither mannitol nor dose had an effect on the various species ratios, nor did mannitol appear to affect either plasma levels or terminal plasma decline.",
"The clinical pharmacology of cisplatin was determined in six patients with malignant ascites secondary to ovarian cancer, and in one patient with peritoneal mesothelioma, following intraperitoneal administration of cisplatin (25-60 mg/m2). The drug was administered in 1 liter of normal saline as a 15- to 30-min infusion. Total, and in some patients free (ultrafilterable), platinum concentrations were determined in plasma, urine, and ascitic fluid by flameless atomic absorption spectrometry. The peak total platinum concentrations in ascitic fluid at the end of infusion were related to dose, a 50 mg/m2 dose producing a 20 to 80 micrograms cisplatin/ml concentration. Filterable platinum represented between 3 and 59% of total platinum in the peritoneum at 4 to 6.5 hr following its administration. Plasma platinum concentrations ranged between 0.2 to 1.6 micrograms/ml 4 hr following administration, and reached a plateau for the next 24 to 48 hr largely in the form of protein-bound platinum. The urinary excretion of cisplatin was consistent with variation in absorption from the peritoneum. Minimal gastrointestinal, bone marrow, and renal toxicities during therapy suggest that sustained free platinum concentrations in ascites may be obtained without significant toxicity and support the intraperitoneal route of administration as an effective strategy for cisplatin therapy of intra-abdominal malignancies.",
"This study was designed to define the maximum-tolerated dose (MTD) and pharmacology of paclitaxel administered by the intraperitoneal (IP) route on a weekly schedule. Thirty-three patients with residual ovarian cancer following standard chemotherapy were entered onto this phase I trial. Patients were treated weekly with IP paclitaxel administered in 2 L of normal saline following premedication. Patients with nonassessable disease received 16 weekly courses. The initial dose level was 20 mg/m2/wk. There was no intrapatient dose escalation. Multiple grade 2 toxicities were observed at the 75-mg/m2/wk dose level. These toxicities included abdominal pain, nausea, vomiting, leukopenia, and fatigue. One episode of grade 4 vomiting thought to be secondary to a transient partial small-bowel obstruction occurred at this dose level. At dose levels > or = 60 to 65 mg/m2, pharmacology studies documented the persistence of significant IP paclitaxel levels 1 week after drug administration, suggesting very slow peritoneal clearance and continuous exposure of the peritoneal cavity to active concentrations of paclitaxel. Low plasma paclitaxel concentrations were detected in the majority of patients treated at dose levels > or = 55 mg/m2. Paclitaxel can be delivered by the IP route on a weekly schedule with both an acceptable toxicity profile and a major pharmacokinetic advantage for cavity exposure. The recommended dose and schedule for phase II study of IP paclitaxel is 60 to 65 mg/m2 weekly.",
"The plasma kinetics of platinum after i.v. bolus administration of cisplatin was determined for 17 patients with advanced cancer. Statistical analysis of individual values revealed a high correlation between the area under the plasma concentration-time curve (AUC) of free platinum (unbound to proteins) and the concentration of platinum bound to plasma proteins 24 h after drug administration (Cp24). A similar correlation was found between the peak plasma values of ultrafiltrable platinum (Cp0) and Cp24. When studied in the same patient, increases in free platinum AUC and Cp0 were also found to result in increased Cp24. It is suggested that a single measurement of plasma platinum concentration 24 h after i.v. infusion of cisplatin could be a simple method either of detecting patients with extreme values of AUC and Cp0 or of studying the evolution of these parameters during multiple courses of treatment, although it cannot be used to give precise values for AUC and Cp0.",
"It has been hypothesized that the paclitaxel vehicle Cremophor EL (CrEL) is responsible for nonlinear drug disposition by micellar entrapment. To gain further insight into the role of CrEL in taxane pharmacology, we studied the pharmacokinetics of paclitaxel in the presence and absence of CrEL after i.p. and i.v. dosing. Patients received an i.p. tracer dose of [G-(3)H]paclitaxel in ethanol without CrEL (100 microCi diluted further in isotonic saline) on day 1, i.p. paclitaxel formulated in CrEL (Taxol; 125 mg/m(2)) on day 4, an i.v. tracer of [G-(3)H]paclitaxel on day 22, and i.v. Taxol (175 mg/m(2)) on day 24. Four patients (age range, 54-74 years) were studied, and serial plasma samples up to 72 h were obtained and analyzed for total radioactivity, paclitaxel, and CrEL. In the presence of CrEL, i.v. paclitaxel clearance was 10.2 +/- 3.76 liters/h/m(2) (mean +/- SD), consistent with previous findings. The terminal disposition half-life was substantially prolonged after i.p. dosing (17.0 +/- 11.3 versus 28.7 +/- 8.72 h), as was the mean residence time (7.28 +/- 2.76 versus 40.7 +/- 13.8 h). The bioavailability of paclitaxel was 31.4 +/- 5.18%, indicating insignificant systemic concentrations after i.p. treatment. CrEL levels were undetectable after i.p. dosing (<0.05 microl/ml), whereas after i.v. dosing, the mean clearance was 159 +/- 58.4 ml/h/m(2), in line with earlier observations. In the absence of CrEL, the bioavailability and systemic concentrations of i.p. paclitaxel were significantly increased. This finding is consistent with the postulated concept that CrEL is largely responsible for the pharmacokinetic advantage for peritoneal cavity exposure to total paclitaxel compared with systemic delivery.",
"To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma. Eligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m2 over 3 hours day 1, IP cisplatin 75 mg/m2 day 2, and IP paclitaxel 60 mg/m2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22. A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm. Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.",
"Pharmacokinetic studies were performed in 51 patients who received cisplatin infusions. Two treatment regimens (single-day or daily for 5 days) and three infusion schedules (for 4 to 15 minutes, 2 to 3 hours, or 24 hours) were used. The daily dose of cisplatin varied from 20 to 120 mg/m2. The kinetics of total platinum studied up to day 5 revealed differences only during the initial period after the infusion. Peak levels were both dose and schedule dependent and initial t1/2 values in the decay curves were only schedule dependent (mean values: 13 minutes for rapid infusions, 40.3 minutes for 2 to 3-hour infusions, and 220.5 minutes for 24-hour infusion). The t1/2 values between days 1 and 5 were neither dose nor schedule dependent (mean 5.0 to 7.3 days). Concentrations of free platinum declined biexponentially after the rapid and 2 to 3-hour infusions, but they declined monoexponentially after 24-hour infusions. Final t1/2 values ranged from 26.0 to 78.8 minutes. In patients with normal renal and hepatic function, the free platinum AUC was identical for cisplatin infusions of different duration when equal doses were given. Free platinum clearance correlated with creatinine clearance (P = 0.017). The uptake of platinum in red blood cells was rapid, and peak concentrations correlated with the free platinum AUC (P = 0.0006), independent of the infusion schedule. The decay of platinum levels in red blood cells was biphasic. The mean terminal t1/2 for the interval between days 5 and 15 was 29.8 days. This suggests a breakdown of red blood cells that results from cisplatin dosing."
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The role of genetic counsellors in a highly specialised service for people with or suspected to have Ehlers Danlos syndrome
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With genomic testing being increasingly integrated into every day clinical practice and a wide range of practitioners ordering genetic tests, it is important that the scope of the genetic counselling role continues to evolve alongside these changes. We present an exemplary role for genetic counsellors in a highly specialised service within England's National Health Service for people who have or are suspected to have rare genetic types of Ehlers Danlos syndrome. The service employs genetic counsellors and consultants from the fields of genetics and dermatology. The service also works closely with other specialists and related charities and patient organisations. The genetic counsellors in the service provide routine genetic counselling such as diagnostic and predictive testing, but their role also includes the writing of patient literature and emergency and well-being resources, delivering workshops and talks, and the development of qualitative and quantitative research on the patient experience. Data from such research has informed the development of patient self-advocacy and supportive resources, raised awareness amongst healthcare professionals and enhanced the standard of care and outcomes for patients. The service aims to be an example of innovation and accessibility and provides a model that can be potentially adopted by other highly specialised services of rare genetic diseases.
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[
"Researchers define self-advocacy as the ability of an individual with cancer to overcome challenges in getting their preferences, needs, and values met. While imperative in all health care settings, self-advocacy is especially important in cancer care. The goal of this article is to present a conceptual framework for self-advocacy in cancer. We review foundational studies in self-advocacy, define the elements of the conceptual framework, discuss underlying assumptions of the framework, and suggest future directions in this research area. This framework provides an empirical and conceptual basis for studies designed to understand and improve self-advocacy among women with cancer.",
"Although patient self-advocacy is a critical component of patient-centered care, the association between symptom burden and self-
advocacy has received little attention.
. This analysis evaluates the degree to which self-advocacy is associated with symptom burden among women with a history of cancer.
. Participants completed online or paper questionnaires. Descriptive statistics and ordinary least squares regression models were used to analyze the association between the three dimensions of self-advocacy and two dimensions of symptom burden. Participants reported moderate levels of symptom burden. Fatigue, disturbed sleep, and memory problems were most common. Informed decision making was positively associated with symptom burden and participants' burden across the three most severe symptoms. Effective communication was negatively associated with total symptom burden and the degree to which symptoms interfered with daily life.",
"An observational study of 648 routine medical visits with 69 physicians examined patient gender in relation to patient and physician communication, patient preference for the physician's communication style, patient satisfaction, and the physician's awareness of the patient's satisfaction. Data consisted of audiotapes as well as patient and physician questionnaires. Women appeared to be more actively engaged in the talk of medical visits--they sent and received more emotionally charged talk and were judged by independent raters as more anxious and interested both globally and in terms of voice quality than men. Consistent with the more emotional talk, women reported preferring a more \"feeling-oriented\" physician than male patients did. Mean levels of satisfaction with communication did not differ by gender, and communication predictors of satisfaction were similar for male and female patients, although they were stronger for male patients. Physicians were significantly less aware of some aspects of female patients' satisfaction compared to male patients' satisfaction. In light of the weaker correlations between patients' communication and their satisfaction for women, we suggest that women provided fewer obvious cues to their satisfaction. Training in communication skills may increase open discussion about feelings and emotions and may also produce greater physician sensitivity to patients' satisfaction, particularly with female patients."
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Metabolites in pheochromocytoma/paraganglioma
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Metabolites represent the highest layer of biological information. Their diverse chemical nature enables networks of chemical reactions that are critical for maintaining life by providing energy and building blocks. Quantification by targeted and untargeted analytical methods using either mass spectrometry or nuclear magnetic resonance spectroscopy has been applied to pheochromocytoma/paraganglioma (PPGL) with the long-term goal to improve diagnosis and therapy. PPGLs have unique features that provide useful biomarkers and clues for targeted treatments. First, high production rates of catecholamines and metanephrines allow for specific and sensitive detection of the disease in plasma or urine. Secondly, PPGLs are associated with heritable pathogenic variants (PVs) in around 40% of cases, many of which occur in genes encoding enzymes, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH). These genetic aberrations lead to the overproduction of oncometabolites succinate or fumarate, respectively, and are detectable in tumors and blood. Such metabolic dysregulation can be exploited diagnostically, with the aim to ensure appropriate interpretation of gene variants, especially those with unknown significance, and facilitate early tumor detection through regular patient follow-up. Furthermore, SDHx and FH PV alter cellular pathways, including DNA hypermethylation, hypoxia signaling, redox homeostasis, DNA repair, calcium signaling, kinase cascades, and central carbon metabolism. Pharmacological interventions targeted toward such features have the potential to uncover treatments against metastatic PPGL, around 50% of which are associated with germline PV in SDHx. With the availability of omics technologies for all layers of biological information, personalized diagnostics and treatment is in close reach.
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"Pheochromocytomas and paragangliomas (PPGLs) have a heterogeneous prognosis, the basis of which remains unclear. We, therefore, assessed disease-specific survival (DSS) and potential predictors of progressive disease in patients with PPGLs and head/neck paragangliomas (HNPGLs) according to the presence or absence of metastases. This retrospective study included 582 patients with PPGLs and 57 with HNPGLs. DSS was assessed according to age, location and size of tumours, recurrent/metastatic disease, genetics, plasma metanephrines and methoxytyramine. Among all patients with PPGLs, multivariable analysis indicated that apart from older age (HR = 5.4, CI = 2.93-10.29, P < 0.0001) and presence of metastases (HR = 4.8, CI = 2.41-9.94, P < 0.0001), shorter DSS was also associated with extra-adrenal tumour location (HR = 2.6, CI = 1.32-5.23, P = 0.0007) and higher plasma methoxytyramine (HR = 1.8, CI = 1.11-2.85, P = 0.0170) and normetanephrine (HR = 1.8, CI = 1.12-2.91, P = 0.0160). Among patients with HNPGLs, those with metastases presented with longer DSS compared to patients with metastatic PPGLs (33.4 versus 20.2 years, P < 0.0001) and only plasma methoxytyramine (HR = 13, CI = 1.35-148, P = 0.0380) was an independent predictor of DSS. For patients with metastatic PPGLs, multivariable analysis revealed that apart from older age (HR = 6.2, CI = 3.20-12.20, P < 0.0001), shorter DSS was associated with the presence of synchronous metastases (HR = 4.9, CI = 2.78-8.80, P < 0.0001), higher plasma methoxytyramine (HR = 2.4, CI = 1.44-4.14, P = 0.0010) and extensive metastatic burden (HR = 2.1, CI = 1.07-3.79, P = 0.0290). DSS among patients with PPGLs/HNPGLs relates to several presentations of the disease that may provide prognostic markers. In particular, the independent associations of higher methoxytyramine with shorter DSS in patients with HNPGLs and metastatic PPGLs suggest the utility of this biomarker to guide individualized management and follow-up strategies in affected patients.",
"Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma. An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed. There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.",
"Pheochromocytoma and paraganglioma (PCPGs) are rare neuroendocrine tumors that arise from the chromaffin tissue of adrenal medulla and sympathetic ganglia. Although metastatic PCPGs account for only 10% of clinical cases, morbidity and mortality are high because of the uncontrollable mass effect and catecholamine level generated by these tumors. Despite our expanding knowledge of PCPG genetics, the clinical options to effectively suppress PCPG progression remain limited. Several recent translational studies revealed that PCPGs with different molecular subtypes exhibit distinctive oncogenic pathways and spectrum of therapy resistance. This suggests that therapeutics can be adjusted based on the signature molecular and metabolic pathways of PCPGs. In this review, we summarized the latest findings on PCPG genetics, novel therapeutic targets, and perspectives for future personalized medicine.",
"In this report, we describe a new patient with unexplained familial bilateral pheochromocytoma. Following the recent description of TMEM127 as a new pheochromocytoma susceptibility gene, the aim of this study was to test the hypothesis of a causative TMEM127 gene mutation in this patient. Pheochromocytoma susceptibility genes were analyzed in germline DNA and losses of heterozygosity (LOH) assessed by BAC array comparative genomic hybridization in tumor DNA. SDHB expression and S6 kinase (S6K) phosphorylation were analyzed by immunohistochemistry. Genome-wide expression microarray studies were performed, and vascular density was quantified after CD34 immunohistochemistry. A first germline variant was identified in the SDHB gene (c.158G>A; p.Gly53Glu). However, a positive SDHB immunostaining in the tumor indicated that this SDHB variant was a non-functional polymorphism. A novel TMEM127 germline mutation (c.140C>A, p.Ala47Asp) associated with a 2q11 LOH was found. Transcriptome and immunohistochemical analyses showed that TMEM127-related pheochromocytoma clusterized with NF1-related and RET-related tumors in a large series of pheochromocytomas and paragangliomas, exhibited a reduced TMEM127 mRNA expression and displayed a low vascularization. The phosphorylation of S6K observed in this tumor was suggestive of an activation of the MTOR pathway. Pathological and genomic data demonstrated that a TMEM127 gene mutation not previously described was causative of a new case of familial bilateral pheochromocytoma. This report highlights the importance of supplementary analyses on tumor tissue to provide an accurate pheochromocytoma/paraganglioma genetic testing result to affected patients.",
"Germ-line mutations in the genes encoding succinate dehydrogenase complex subunits B (SDHB) and D (SDHD) have been reported in familial paragangliomas and apparently sporadic phaeochromocytomas (ASP), but the genotype-phenotype relationships of these mutations are unknown. Eighty-four patients (all but 2 followed up for 8.8 +/- 5.7 years) with ASP (57 with adrenal tumors, 27 with extra-adrenal, multiple, malignant, or recurrent tumors) were screened for the major susceptibility genes for phaeochromocytoma (RET, VHL, SDHD, and SDHB). Thirty-three tumors were available for molecular analysis, enzyme assays, and immunohistochemistry. No (0%) RET and 2 (2.4%) VHL mutations were detected. Only two coding single nucleotide polymorphisms in the SDHD gene (G12S and H50R) were found in 6 patients (7%). Conversely, six deleterious mutations in the SDHB gene were identified in 8 patients (9.5%). Ectopic site and recurrence or malignancy were strongly associated with SDHB mutations (7 of 8, 87%, versus 20 of 76, 26%; P = 0.001). Somatic DNA analysis indicated a loss of heterozygosity at chromosome 1p36 (SDHB locus) in 16 of 33 cases (48%). A loss of heterozygosity at the SDHB locus was found in all tumors with SDHB mutation, and assays of respiratory chain enzymes showed a complete loss of complex II catalytic activity. The vascular architecture of tumors with SDHB mutations displayed features typical of malignancy. These data strongly suggest that SDHB gene is a tumor suppressor gene and that the identification of germ-line mutations in SDHB gene in patients with ASPs should be considered as a high-risk factor for malignancy or recurrence.",
"Pheochromocytomas and paragangliomas (PPGLs) are potentially lethal yet usually surgically curable causes of endocrine hypertension; therefore, once clinical suspicion is aroused it is imperative that clinicians choose the most appropriate laboratory tests to identify the tumors. Compelling evidence now indicates that initial screening for PPGLs should include measurements of plasma free metanephrines or urine fractionated metanephrines. LC-MS/MS offers numerous advantages over other analytical methods and is the method of choice when measurements include methoxytyramine, the O-methylated metabolite of dopamine. The plasma test offers advantages over the urine test, although it is rarely implemented correctly, rendering the urine test preferable for mainstream use. To ensure optimum diagnostic sensitivity for the plasma test, reference intervals must be established for blood samples collected after 30 min of supine rest and after an overnight fast when measurements include methoxytyramine. Similarly collected blood samples during screening, together with use of age-adjusted reference intervals, further minimize false-positive results. Extents and patterns of increases in plasma normetanephrine, metanephrine, and methoxytyramine can additionally help predict size and adrenal vs extraadrenal locations of tumors, as well as presence of metastases and underlying germline mutations of tumor susceptibility genes. Carried out correctly at specialist endocrine centers, collection of blood for measurements of plasma normetanephrine, metanephrine, and methoxytyramine not only provides high accuracy for diagnosis of PPGLs, but can also guide clinical decision-making about follow-up imaging strategies, genetic testing, and therapeutic options. At other centers, measurements of urine fractionated metanephrines will identify most PPGLs.",
"Neovascularization and increased glycolysis, two universal characteristics of solid tumors, represent adaptations to a hypoxic microenvironment that are correlated with tumor invasion, metastasis, and lethality. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-1alpha subunit. In this study, HIF-1alpha expression was analyzed by immunohistochemistry in 179 tumor specimens. HIF-1alpha was overexpressed in 13 of 19 tumor types compared with the respective normal tissues, including colon, breast, gastric, lung, skin, ovarian, pancreatic, prostate, and renal carcinomas. HIF-1alpha expression was correlated with aberrant p53 accumulation and cell proliferation. Preneoplastic lesions in breast, colon, and prostate overexpressed HIF-1alpha, whereas benign tumors in breast and uterus did not. HIF-1alpha overexpression was detected in only 29% of primary breast cancers but in 69% of breast cancer metastases. In brain tumors, HIF-1alpha immunohistochemistry demarcated areas of angiogenesis. These results provide the first clinical data indicating that HIF-1alpha may play an important role in human cancer progression."
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Autophagy, phagocytosis and NETosis in diabetes
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Type 2-diabetes, particularly poorly controlled diabetes, is a risk factor for several infections such as lower respiratory tract and skin infections. Hyperglycemia, a characteristic downstream effect of poorly controlled diabetes, has been shown to impair the function of immune cells, in particular neutrophils. Several studies have demonstrated that hyperglycemia-mediated priming of NADPH oxidase results in subsequent elevated levels of reactive oxygen species (ROS). In healthy neutrophils, ROS plays an important role in pathogen killing by phagocytosis and by induction of Neutrophil Extracellular Traps (NETs). Given the key role of ROS in autophagy, phagocytosis and NETosis, the relationship between these pathways and the role of diabetes in the modulation of these pathways has not been explored previously. Therefore, our study aimed to understand the relationship between autophagy, phagocytosis and NETosis in diabetes. We hypothesized that hyperglycemia-associated oxidative stress alters the balance between phagocytosis and NETosis by modulating autophagy. Using whole blood samples from individuals with and without type 2-diabetes (in the presence and absence of hyperglycemia), we demonstrated that (i) hyperglycemia results in elevated levels of ROS in neutrophils from those with diabetes, (ii) elevated levels of ROS increase LCIII (a marker for autophagy) and downstream NETosis. (iii) Diabetes was also found to be associated with low levels of phagocytosis and phagocytic killing of
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"Rationale: Patients with newly diagnosed tuberculosis often have inconsistent glycemic measurements during and after treatment. Distinct glycemic trajectories after the diagnosis of tuberculosis are not well characterized, and whether patients with stress hyperglycemia have poor treatment outcomes is not known.Objectives: To identify distinct glycemic trajectories from the point of tuberculosis diagnosis to the posttreatment period and to assess the relationship between glycemic trajectories and tuberculosis treatment outcomes.Methods: Patients with newly diagnosed, drug-susceptible tuberculosis and with at least three fasting plasma glucose tests at tuberculosis diagnosis and during the third and sixth month of treatment were identified and included from Jiangsu Province, China. Patients were also given an additional fasting plasma glucose test at 2 and 4 months after treatment.Measurements and Main Results: Several distinct glycemic trajectories from the point of tuberculosis diagnosis to the posttreatment period were found, including consistently normal glycemic testing results (43%), transient hyperglycemia (24%), erratic glycemic instability (12%), diabetes (16%), and consistent hyperglycemia without diabetes (6%). Compared with participants with a consistently normal glycemic trajectory, patients with transient hyperglycemia were more likely to experience treatment failure (adjusted odds ratio [AOR], 4.20; 95% confidence interval [CI], 1.57-11.25; P = 0.004) or erratic glycemic instability (AOR, 5.98; 95% CI, 2.00-17.87; P = 0.001). Patients living with diabetes also had a higher risk of experiencing treatment failure (AOR, 6.56; 95% CI, 2.22-19.35; P = 0.001), and this was modified by glycemic control and metformin use.Conclusions: Among patients with tuberculosis without diabetes, glycemic changes were common and may represent an important marker for patient response to tuberculosis treatment.",
"Previous studies have suggested that diabetes increases the risk of Parkinson disease (PD); however, this has not been conclusively established. We analyzed the risk of PD based on baseline glucose tolerance status in a large-scale cohort representative of the general Korean population. This analysis was performed in a cohort of 15,168,021 adults aged ≥40 years who underwent health checkups under the National Health Insurance Service between January 2009 and December 2010. The clinical course of subjects was monitored until December 2016. Subjects were classified into the following groups: no diabetes, impaired fasting glucose (IFG), diabetes duration <5 years, and diabetes duration ≥5 years. We analyzed the adjusted hazard ratio of PD for each group. During the observation period of 49,076,148.74 person-years, PD occurred in 31,577 patients. Compared with the nondiabetes group, the adjusted hazard ratio was 1.038 (95% CI, 1.009-1.067) in the IFG group, 1.185 (95% CI, 1.143-1.229) in the diabetes duration <5 years group, and 1.618 (95% CI, 1.566-1.672) in the diabetes duration ≥5 years group. These results were consistent with those of the subgroup analysis, and the presence of diabetes further increased the risk of PD regardless of comorbidities such as cardiovascular, cerebrovascular, and chronic kidney diseases. This population-based cohort study suggests that diabetes is an independent risk factor for PD.",
"Heparin-induced thrombocytopenia (HIT) is associated with severe and potentially lethal thrombotic complications. NETosis was recently shown to be an important driver of thrombosis in HIT. We investigated the role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and their contributions to thrombus development in HIT. We showed that neutrophil activation by HIT immune complexes induced ROS-dependent NETosis. Analysis of thrombi formed in a microfluidics system showed ROS production in both platelets and neutrophils, and abundant neutrophil extracellular traps (NETs) and ROS distributed throughout the clot. Neutrophil-targeted ROS inhibition was sufficient to block HIT-induced NETosis and thrombosis using human blood. Inhibition of NOX2 with diphenyleneiodonium chloride or GSK2795039 abrogated HIT-induced thrombi in vivo using FcγRIIa+/hPF4+-transgenic mice. Thrombocytopenia in mice remained unaffected by ROS inhibition. Increased ROS production in activated neutrophils was also confirmed using fresh blood from patients with active HIT. Our findings show that ROS and NOX2 play a crucial role in NETosis and thrombosis in HIT. This enhances our understanding of the processes driving thrombosis in HIT and identifies NOX2 as a potential new therapeutic target for antithrombotic treatment of HIT.",
"Phagocytic function was assessed by serial whole blood chemiluminescence in poorly controlled type 2 (non-insulin dependent) diabetic patients during efforts to improve glycaemic control and compared with a group of well controlled type 1 (insulin dependent) diabetic patients. Chemiluminescence (corrected to a standard polymorphonuclear count) remained below normal (0.15-0.30 photons/second/cell) for most of the type 2 patients until 12 weeks when the value was significantly increased in patients showing improved glycaemic control (mean (range) 0.25 (0.01-0.43) photons/second/cell) compared with those showing no improvement (0.12(0.01-0.31) photons/second/cell). There was a significant inverse correlation of delta HbA1 with delta chemiluminescence. Although mean chemiluminescence for the type 1 diabetic patients was within the normal range, there was a wide scatter of values (0.19 (0.04-0.43) photons/second/cell) and there was no significant difference compared with the final value of type 2 patients with improved control. Glycaemic control is therefore a major determinant of phagocytic function in diabetic patients, but other factors must contribute, particularly in type 1 (insulin dependent) patients.",
"Gliomas, the most common form of brain cancer, can range from relatively slow-growing low-grade to highly aggressive glioblastoma that has a median overall survival of only 15 months despite multimodal standard therapy. Although immunotherapy with checkpoint inhibitors has significantly improved patient survival for some cancers, to date, these agents have not shown consistent efficacy against malignant gliomas. Therefore, there is a pressing need to better understand the impact of host inflammatory responses on the efficacy of emerging immunotherapy approaches for these resistant tumors. RAGE is a multi-ligand pattern recognition receptor that is activated in various inflammatory states such as diabetes, Alzheimer's disease, cystic fibrosis, and cancer. Low levels of RAGE can be found under normal physiological conditions in neurons, immune cells, activated endothelial, and vascular smooth muscle cells, but it is over-expressed under chronic inflammation due to the accumulation of its ligands. RAGE binds to a range of damage-associated molecular pattern molecules (DAMPs) including AGEs, HMGB1, S100s, and DNA which mediate downstream cellular responses that promote tumor growth, angiogenesis, and invasion. Both in vitro and in vivo studies have shown that inhibition of RAGE signaling can disrupt inflammation and cancer progression and metastasis. Here, we will review our current understanding of the role of RAGE pathway on glioma progression and how it could be exploited to improve the efficacy of immunotherapy approaches.",
"The risk of tuberculosis (TB) associated with diabetes status, considering impaired fasting glucose or duration of diabetes, has not been well established. To evaluate the association of diabetes status with the development of TB in the general population. This population-based cohort study used data from the Korean National Health Insurance System database. Adult participants without a history of TB who underwent a health screening in 2009 were included. Eligible participants were followed up for incident TB cases from 1 year after the day of health screening until December 31, 2018. Data analysis was performed from September 2019 to September 2020. Five levels of diabetes status were evaluated: normal glucose, impaired fasting glucose (considered as without diabetes), new-onset diabetes, diabetes duration less than 5 years, and diabetes duration 5 years or longer (considered as having diabetes). Newly diagnosed TB. Among 4 423 177 participants, the mean (SD) age was 46.5 (13.9) years, and there were 2 597 142 men (58.7%). A total of 26 458 participants (0.6%) received a diagnosis of TB within a median (interquartile range) of 8.3 (8.1-8.6) years of follow-up. An increased risk of TB was observed in participants with diabetes compared with those without diabetes (adjusted hazard ratio [aHR], 1.48; 95% CI, 1.42-1.53). Although participants with impaired fasting glucose did not show an increased risk of TB incidence (aHR, 0.97; 95% CI, 0.93-1.01), the risk of TB incidence increased with diabetes duration (new-onset diabetes, aHR, 1.32; 95% CI, 1.23-1.42; diabetes duration <5 years, aHR, 1.45; 95% CI, 1.36-1.54; diabetes duration ≥5 years, aHR, 1.57; 95% CI, 1.48-1.66). Among participants with new-onset diabetes, compared with those in the lowest decile (fasting plasma glucose [FPG] level ≥126 but <128 mg/dL), the risk of TB was significantly increased for those in the highest decile (FPG level ≥202 mg/dL, aHR, 1.79; 95% CI, 1.42-2.26). These findings suggest that longer diabetes duration is associated with development of TB, showing a dose-response association. Among participants with new-onset diabetes, incident TB was more common among those with FPG levels greater than or equal to 202 mg/dL.",
"The aim of this study, carried out in a specialized centre for chest diseases in Turkey, was to determine the prevalence of glucose intolerance in tuberculosis (TB) and pneumonia so as to assess the specificity of the association of TB with diabetes mellitus. The study group comprised 58 active pulmonary TB patients without any history of diabetes mellitus and the matched control group consisted of 23 community-acquired pneumonia patients. An oral glucose tolerance test (OGTT) was performed at the time of diagnosis and 3 months after the treatment was started in both groups. Glucose intolerance was found in six (10.4%) patients and diabetes mellitus in five (8.6%) patients in the TB group. In the control group, four (17.4%) patients were found to be diabetic and none of them were glucose intolerant. There was no significant difference between the two groups (p > 0.05). There was a higher prevalence of abnormal OGTT results among elderly patients in both groups. OGTT results returned to normal in both the TB and pneumonia groups after treatment. The results suggest that glucose intolerance occurs in the setting of infection and is reversible following adequate antimicrobial treatment."
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Effect of acute atrial fibrillation on renal water and sodium metabolism in mice
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To construct an animal model of atrial fibrillation and observe the effect of acute atrial fibrillation on renal water and sodium metabolism in mice. A total of 20 C57 mice were randomly assigned to 2 groups (n = 10/group): control group (CON) and atrial fibrillation group (AF). The mice model of atrial fibrillation was induced by chlorhexidine gluconate (CG) in combination with transesophageal atrial spacing. The urine of the two groups of mice was collected, and then we calculate the urine volume and urine sodium content. The expression of TGF-β and type III collagen in the atrial myocardium of the two groups was detected by immunohistochemistry and Western Blot. The levels of CRP and IL-6 in blood were observed by ELISA, and the NF-κB, TGF-β, collagen type III, AQP2, AQP3, AQP4, ENaC-β, ENaC-γ, SGK1 and NKCC proteins in the kidneys of the two groups of mice was observed by Western Blot. Compared with CON, the expression of TGF-β and type III collagen in the atrial myocardium of the mice in AF were increased, the levels of CRP and IL-6 in the blood in AF were increased, and the renal NF-κB, TGF-β, type III collagen AQP2, AQP3, ENaC-β, ENaC-γ, SGK1 and NKCC protein expression in AF were up-regulated. The level of urine volume and urine sodium content in AF were significantly reduced. In the acute attack of atrial fibrillation, the formation of renal inflammatory response and fibrosis is activated, and the renal water and sodium metabolism is hindered, which is related to the up-regulated of the expressions of renal NKCC, ENaC and AQPs.
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"In heart failure, the renal responsiveness to exogenous and endogenous atrial natriuretic peptide (ANP) is blunted. The mechanisms of renal hyporesponsiveness to ANP are complex, but one potential mechanism is decreased expression of natriuretic peptide receptor-A (NPR-A) in inner medullary collecting duct (IMCD) cells. Newly emerging evidence shows that glucocorticoids could produce potent diuresis and natriuresis in patients with heart failure, but the precise mechanism is unclear. In the present study, we found dexamethasone (Dex) dramatically increased the expression of NPR-A in IMCD cells in vitro. The NPR-A overexpression induced by Dex presented in a time- and dose-dependent manner, which emerged after 12 h and peaked after 48 h. The cultured IMCD cells were then stimulated with exogenous rat ANP. Consistent with the findings with NPR-A expression, Dex greatly increased cGMP (the second messenger for the ANP) generation in IMCD cells, which presented in a time- and dose-dependent manner as well. In rats with decompensated heart failure, Dex dramatically increased NPR-A expression in inner renal medulla, which was accompanied by a remarkable increase in renal cGMP generation, urine flow rate, and renal sodium excretion. It is noteworthy that Dex dramatically lowered plasma ANP, cGMP levels, and left ventricular end diastolic pressure. These favorable effects induced by Dex were glucocorticoid receptor (GR)-mediated and abolished by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486). Collectively, glucocorticoids could improve renal responsiveness to ANP by up-regulating NPR-A expression in the IMCD and induce a potent diuretic action in rats with decompensated heart failure.",
"Local atrial tissue angiotensin II (AngII) level is elevated in atrial fibrillation (AF), but the mechanism is unknown. We hypothesized that atrial myocytes express all components of the renin-angiotensin system (RAS) and investigated whether rapid depolarization alone is sufficient to increase paracrine AngII production by up-regulating RAS component expression. In the HL-1 atrial cell line, rapid depolarization was induced by rapid field electrical stimulation (RES) at 1.0 V/cm and 600/min (10 Hz) in atrial HL-1 cells. In a pig model of AF, AF was induced by atrial pacing at 600/min in 10 adult pigs and 10 sham-operated pigs for comparison. In atrial myocytes, RES induced a sustained elevation of intracellular calcium, and up-regulation of angiotensin-converting enzyme (ACE), chymase and angiotensinogen, resulting in increased AngII production. RES-induced AngII production was attenuated by enalapril [ACE inhibitor (ACEI)] and chymostatin (chymase inhibitor). Conditioned medium from RES-stimulated atrial myocytes increased [3H]leucine uptake and atrial natriuretic peptide expression in atrial myocytes, and [3H]proline uptake and collagen type 1 alpha 1 expression in atrial fibroblasts. Both were attenuated by co-incubation with the AngII type 1 receptor blocker (ARB) losartan. In the porcine model, significant structural changes and a similar pattern of changes of RAS components were noted in AF pigs. Atrial cells expressed all components of RAS and rapid depolarization alone was sufficient to up-regulate RAS components, increase paracrine AngII production and induce atrial structural changes, which are attenuated by ACEI, ARB and chymase inhibitor.",
"To investigate whether atrial expression of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) of right atrial appendages are altered in patients with rheumatic valvular disease during chronic atrial fibrillation. A total of 48 patients with rheumatic heart disease were included. 27 patients had no history of atrial fibrillation, 21 patients had atrial fibrillation. Atrial tissue was obtained from the right atrial appendage during open heart surgery. The protein expression of IL-1beta and TNF-alpha was detected by immunohistochemistry method. The fibrosis of right atrial appendage was detected by Masson staining. The fibrosis of right atrial appendage was significantly increased in patients with chronic atrial fibrillation. The protein expression of IL-1beta and TNF-alpha were significantly increased in patients with chronic atrial fibrillation. The protein expression of IL-1beta and TNF-alpha were significantly increased in patients with rheumatic valvular disease during chronic atrial fibrillation. Inflammation may be one of the mechanisms for the development and persistence of atrial fibrillation.",
"Although downregulation of L-type Ca2+ current (I(Ca,L)) in chronic atrial fibrillation (AF) is an important determinant of electrical remodeling, the molecular mechanisms are not fully understood. Here, we tested whether reduced I(Ca,L) in AF is associated with alterations in phosphorylation-dependent channel regulation. We used whole-cell voltage-clamp technique and biochemical assays to study regulation and expression of I(Ca,L) in myocytes and atrial tissue from 148 patients with sinus rhythm (SR) and chronic AF. Basal I(Ca,L) at +10 mV was smaller in AF than in SR (-3.8+/-0.3 pA/pF, n=138/37 [myocytes/patients] and -7.6+/-0.4 pA/pF, n=276/86, respectively; P<0.001), though protein levels of the pore-forming alpha1c and regulatory beta2a channel subunits were not different. In both groups, norepinephrine (0.01 to 10 micromol/L) increased I(Ca,L) with a similar maximum effect and comparable potency. Selective blockers of kinases revealed that basal I(Ca,L) was enhanced by Ca2+/calmodulin-dependent protein kinase II in SR but not in AF. Norepinephrine-activated I(Ca,L) was larger with protein kinase C block in SR only, suggesting decreased channel phosphorylation in AF. The type 1 and type 2A phosphatase inhibitor okadaic acid increased basal I(Ca,L) more effectively in AF than in SR, which was compatible with increased type 2A phosphatase but not type 1 phosphatase protein expression and higher phosphatase activity in AF. In AF, increased protein phosphatase activity contributes to impaired basal I(Ca,L). We propose that protein phosphatases may be potential therapeutic targets for AF treatment.",
"Human atrial fibrillation (AF) has been associated with increased atrial oxidative stress. In animal models, inhibition of reactive oxygen species prevents atrial remodeling induced by rapid pacing, suggesting that oxidative stress may play an important role in the pathophysiology of AF. NAD(P)H oxidase is a major source of superoxide in the cardiovascular system; however, whether this enzyme contributes to atrial oxidative stress in AF remains to be elucidated. We investigated the sources of superoxide production (using inhibitors and substrates of a range of oxidases, RT-PCR, immunofluorescence, and immunoblotting) in tissue homogenates and isolated atrial myocytes from the right atrial appendage (RAA) of patients undergoing cardiac surgery (n=54 in sinus rhythm [SR] and 15 in AF). A membrane-bound gp91phox containing NAD(P)H oxidase in atrial myocytes was the main source of atrial superoxide production in SR and in AF. NADPH-stimulated superoxide release from RAA homogenates was significantly increased in patients with AF in the absence of changes in mRNA expression of the p22phox and gp91phox subunits of the NAD(P)H oxidase. In contrast with findings in SR patients, NO synthases (NOSs) contributed significantly to atrial superoxide production in fibrillating atria, suggesting that increased oxidative stress in AF may lead to NOS \"uncoupling.\" These findings indicate that a myocardial NAD(P)H oxidase and, to a lesser extent, dysfunctional NOS contribute significantly to superoxide production in the fibrillating human atrial myocardium and may play an important role in the atrial oxidative injury and electrophysiological remodeling observed in patients with AF.",
"Natriuretic peptides (NPs) are excellent diagnostic and prognostic markers of heart failure, but their roles in atrial fibrillation (AF), particularly of isolated cardiac valvular origin, are unclear. We assessed the mRNA and protein content of pro-atrial natriuretic peptide (pro-ANP) and pro-brain natriuretic peptide (pro-BNP) in right atrial appendages (RAAs) and their N-terminal fragments (nt-proANP and nt-proBNP) in the plasma of 30 patients with paroxysmal AF (PaAF) and 40 patients with persistent AF (PeAF) matched with 34 patients in sinus rhythm (SR) undergoing isolated valvular replacement. To explore the underlying mechanism, fibrosis related examinations were simultaneously carried out in RAAs. Unexpectedly, atrial expression of pro-NPs mRNA was notably augmented in the PaAF subgroup, but not so pronounced in the PeAF subgroup. Atrial content of pro-NPs proteins and plasma nt-proNPs, between which surprisingly strong positive correlations were found (pro-ANP and nt-proANP: r=0.918, p<0.001; pro-BNP and nt-proBNP: r=0.913, p<0.001), were increased analogously in PaAF and PeAF subgroups. We identified significantly increasing gradients of atrial collagen volume fraction (CVF), levels of collagen I and III in the SR, PaAF and PeAF groups, and convincing negative linear correlations between CVF, levels of collagen I and III, and atrial transcripts of pro-NPs. These findings suggest that the discordance between transcripts and protein contents of pro-NPs was possibly due to the more outstanding atrial fibrosis in PeAF, and that circulating nt-proNPs levels could reflect the corresponding atrial pro-NPs contents in this report.",
"We measured mRNA levels of delayed rectifier potassium channels in human atrial tissue to investigate the mechanism of the shortening of the atrial effective refractory period and the loss of rate-adaptive shortening of the atrial effective refractory period in human atrial fibrillation. A total of 34 patients undergoing open heart surgery were included. Atrial tissue was obtained from the right atrial free wall, right atrial appendage, left atrial free wall and left atrial appendage, respectively. The mRNA amounts of KVLQT1 (IKs), minK (beta-subunit of IKs), HERG (IKr), and KV1.5 (IKur) were measured by reverse transcription-polymerase chain reaction and normalized to the mRNA amount of GAPDH. We found that the mRNA levels of KV1.5, HERG and KVLQT1 were all significantly decreased in patients with persistent atrial fibrillation for more than 3 months. In contrast, the mRNA level of minK was significantly increased in patients with persistent atrial fibrillation for more than 3 months. We further showed that these changes were independent of the underlying cardiac disease, atrial filling pressure, gender and age. We also found that there was no spatial dispersion of mRNA levels among the four atrial sampling sites. Because the decrease in potassium currents results in a prolonged action potential, the shortening of the atrial effective refractory period in atrial fibrillation should be attributed to other factors. However, the decrease in IKs might contribute, at least in part, to the loss of rate-adaptive shortening of the atrial refractory period.",
"Atrial fibrillation (AF) is the most common clinically encountered abnormal heart beat. It is associated with an increased risk of stroke and symptoms of heart failure. Current therapies are directed toward controlling the rate of ventricular activation and preventing strokes through anticoagulation. Attempts at suppressing the arrhythmia are often ineffective, in part because the underlying pathogenesis is poorly understood. Recently, structural and electrical remodeling has been shown to occur during AF. These changes involve alterations in gene regulation and help perpetuate the arrhythmia. Some signals for remodeling are have been identified. Moreover, AF is associated with oxidative stress, and this redox imbalance may contribute to the altered gene regulation. One likely mediator of this change in transcriptional regulation is the redox sensitive transcription factor, nuclear factor-kappaB (NF-kappaB). Recently, NF-kappaB has been shown to downregulate transcription of the cardiac sodium channel in response to oxidative stress. NF-kappaB may contribute to the regulation of other ion channels, transcription factors, or splicing factors altered in AF and may represent a therapeutic target in AF management.",
"The epicardial adipose tissue (EAT) or epicardial fat is a visceral fat depot in the heart that contains intrinsic adrenergic and cholinergic nerves, through which it interacts with the cardiac sympathetic (adrenergic) and parasympathetic (cholinergic) nervous systems. These EAT nerves represent a significant source of several adipokines and other bioactive molecules, including norepinephrine, epinephrine, and free fatty acids. The production of these molecules is biologically relevant for the heart, since abnormalities in EAT secretion are implicated in the development of pathological conditions, including coronary atherosclerosis, atrial fibrillation, and heart failure. Sympathetic hyperactivity and parasympathetic (cholinergic) derangement are associated with EAT dysfunction, leading to a variety of adverse cardiac conditions, such as heart failure, diastolic dysfunction, atrial fibrillation, etc.; therefore, several studies have focused on exploring the autonomic regulation of EAT as it pertains to heart disease pathogenesis and progression. In addition, Regulator of G protein Signaling (RGS)-4 is a protein with significant regulatory roles in both adrenergic and muscarinic receptor signaling in the heart. In this review, we provide an overview of the autonomic regulation of EAT, with a specific focus on cardiac RGS4 and the potential roles this protein plays in this regulation.",
"The three peroxisome proliferator-activated receptors (PPARs) isotypes (PPAR alpha, beta/delta and gamma) belong to the nuclear hormone receptor family. During the last decade, they have been identified as anti-inflammatory transcription factors. Part of this regulation antiinflammatory is mediated through negative interference between PPARs and other nuclear factors such as NFkB, AP-1 and C/EBP, which regulate innate as well as adaptative immunity. In addition, the PPARs control the functions of macrophages, B cells and T cells. In this review, we summarise the pathways through which the PPARs control inflammatory responses. We also discuss the potential utilisation of PPAR specific ligands in the treatment of inflammatory diseases, such as inflammatory bowel diseases, atherosclerosis, Parkinson's and Alzheimer's diseases."
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The Effects of Sun-Dried Azolla (Azolla sativa L.)
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This study investigated the effects of using sun-dried Azolla (
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"In the recent past,few studies have been carried out in chicken to assess the effect of Azolla meal and raw Azolla feeding on the performance of chicken. If turkeys effectively use unconventional feedstuffs like Azolla without reducing the performance, it will increase the profitability of turkey business. Hence, a study was carried out to evaluate the effect of dried Azolla pinnata vis-a-vis raw Azolla as choice feeding on the growth, feed conversion ratio (FCR), blood biochemical attributes, and immune competence traits of growing turkeys under intensive system. A total of 72, 8-week-old grower turkey poults of black variety were randomly distributed into three dietary treatments having three replicates each with eight birds. The birds of the control group (T1) were fed a basal diet (CP - 19.71% and ME - 2789.79 Kcal/kg), while the other group (T2) and choice-feeding group (T3) were fed 5% of basal diet replaced by dry Azolla powder on DM basis and ad libitumAzolla along with basal diet, respectively. There was no significant difference among the different groups in the average weekly weight gain during the entire experiment. FCR was significantly better (p<0.05) in the choice-feeding group compared to the other two experimental groups during 8-16 weeks of age. There was no significant difference among the treatment groups in any of the blood biochemical indices except plasma uric acid, which was significantly decreased (p<0.01) in T2 compared to T1 at 16 weeks of age. HA and IgM response to 1% sheep red blood cells (log2 titer) were numerically better in T2 and T3 compared to the T1. Thus, it may be inferred that choice feeding with Azolla, and basal diet may improve FCR without any adverse effect on blood biochemical attributes and immune competence traits.",
"Dairy donkey milking procedures require separating foals from their dams for a few hours a day. Artificial suckling in this species is a good technique for improving milk production and foal welfare. The aim of the work is to compare the effect of two different diets on donkey foals when separated from jennies for milking procedures with and without a milk replacer. Forty newborn Martina Franca donkey foals were subdivided into two experimental groups. Both groups were separated from their respective dams from 8.00to 20.00to allow the jennies to be milked. During the separation, all the foals had access ad libitum to water, hay and feed. During the separation period, one group had the availability of a mechanical milk replacer dispenser, so foals were partially artificially suckled (AS), while the other group had no milk replacer available, and so were totally naturally suckled (NS). The AS group had milk replacer availability until 120±7d of life. Both groups were naturally weaned at 168±7d. Blood samples were collected weekly starting from birth until two wks after weaning (i.e. at 182d), from all the foals included in the trial. Almost all the analytes were influenced by suckling technique and age of foals. Alanine-aminotransferase, aspartate-aminotransferase, alkaline phosphatase, NEFA, lipid hydroperoxides, serum proteins showed the greatest differences between the two experimental groups. Separating foals from their dams for 12hdaily for 24 weeks does not lead to pathological subclinical and metabolic conditions, thus confirming the high rusticity and resistance of the donkey.",
"A line of chickens selected for ability to product high antibody titers to sheep red blood cells exhibited stronger antibody to Newcastle disease, was more resistant to Mycoplasma gallisepticum, Eimeria necatrix, a splenomeglia virus, and feather mites and less resistant to Escherichia coli and Staphylococcus aureus infection than a line selected for a lack of ability to produce antibody titers. A line of chickens selected for a nonpersistance of antibody titers to sheep red blood cells was relatively more susceptible to all infectious agents tested than a line selected for a persistence of atibody titers."
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Chloramphenicol Resistance Mechanisms and Drug Resistance
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Chloramphenicol is a broad-spectrum antibiotic widely used for treating ophthalmic infections, but concerns about rising bacterial resistance to chloramphenicol have been observed due to its frequent use as an over-the-counter medication. This review assessed the common ophthalmic bacterial pathogens, their chloramphenicol resistance mechanisms, and rates of drug resistance.
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"Eye infections can cause loss or impairment of visual function and can lead to severe impairment. Bacteria are the most common pathogens that affect the structure of the eye. As a result, quick identification of the causative agents and testing of their medication susceptibility are essential for effective treatment of eye infections. This study was intended for determining the extent of bacterial isolates from external eye infections (EEIs) and their susceptibility to antibiotics. A facility-based cross-sectional study was conducted among patients attending Menelik II Referral Hospital. The study comprised patients who had EEIs verified. EEI samples were collected using sterile methods. Bacterial isolates were identified using gram stain, colony morphology, and biochemical tests. The Kirby-Bauer disk diffusion technique was used to conduct a drug susceptibility test. Totally, 323 participants were recruited for this study and 184 bacterial isolates were obtained from 175 (54.5%) participants. The main clinical diagnosis was blepharitis 122 (37.8%), followed by conjunctivitis 73 (22.6%) and keratitis 57 (17.6%). The gram-positive isolates were 171 (92.9%). CoNS with a frequency of 76 (41.3%) was the most common bacterial isolates, followed by S. aureus 67 (36.4%), Viridans streptococcus 16 (8.7%), and Klebsiella species 6(3.3%). Gram-positive isolates were sensitive to tobramycin, gentamicin, chloramphenicol, vancomycin, and ceftriaxone. In contrast, 94.0% of these gram-positive isolates showed resistance to penicillin. Multidrug resistance (MDR) was observed in both gram-positive and negative bacteria at rates of 123 (72%) and 12 (92.1%), respectively. The overall MDR rate among the isolates was 135 (73.4%). In this study, blepharitis was the major EEI, followed by conjunctivitis. The predominant bacterial species isolated from EEIs were CoNS, followed by S. aureus. More than half of the isolates were drug-resistant, with a large number being multidrug-resistant, highlighting the necessity for continued and coordinated surveillance to hunt for infections that are known to be resistant.",
"To document changes in the profile of bacterial isolates from cases of keratitis and changes in their susceptibility to first line antibiotic therapies. A retrospective review was performed of all bacterial isolates from cases of keratitis seen between 1984 and 1999. In vitro laboratory susceptibilities to antibiotics were determined by the Kirby-Bauer disc diffusion method. The number of isolates, changes in the proportion of bacterial types, and the number that were fully resistant to monotherapy (ofloxacin), dual therapy (gentamicin and cefuroxime), and prophylactic treatment (chloramphenicol) were calculated. There were 1312 bacterial isolates over 16 years. Gram positive bacteria accounted for 54.7% of isolates and Staphylococcus species (33.4%) were the most frequently isolated organisms. During the study period there has been an increase in the proportion of Pseudomonas species isolates but no overall increase in the proportion of Gram negative isolates. There has not been an increase in the proportion of isolates resistant to ofloxacin since 1995 or an increase in resistance to the combination of gentamicin and cefuroxime. However, since 1984 there has been a significant increase in proportion of Gram negative organisms resistant to chloramphenicol (p=0.0019). An increase in the in vitro resistance of organisms to first line therapies for bacterial keratitis has not been observed. An increased resistance to chloramphenicol indicates that this drug is unlikely to provide prophylactic cover when Gram negative infection is a risk. Continued monitoring for the emergence of antibiotic resistance is recommended.",
"The global emergence of antibacterial resistance among common and atypical respiratory pathogens in the last decade necessitates the strategic application of antibacterial agents. The use of bactericidal rather than bacteriostatic agents as first-line therapy is recommended because the eradication of microorganisms serves to curtail, although not avoid, the development of bacterial resistance. Bactericidal activity is achieved with specific classes of antimicrobial agents as well as by combination therapy. Newer classes of antibacterial agents, such as the fluoroquinolones and certain members of the macrolide/lincosamine/streptogramin class have increased bactericidal activity compared with traditional agents. More recently, the ketolides (novel, semisynthetic, erythromycin-A derivatives) have demonstrated potent bactericidal activity against key respiratory pathogens, including Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Moraxella catarrhalis. Moreover, the ketolides are associated with a low potential for inducing resistance, making them promising first-line agents for respiratory tract infections.",
"To compare the prevalence of antibiotic resistance found in nasopharyngeal Streptococcus pneumoniae between villages treated with topical tetracycline or systemic azithromycin as part of a trachoma control programme. All children aged 1-10 years were offered either single dose oral azithromycin treatment (20 mg/kg) or a course of topical 1% tetracycline ointment, depending on the area. Treatment was given annually for 3 years. Six months after the third annual treatment in each village, children were surveyed for nasopharyngeal carriage of S pneumoniae and resistance was determined using broth dilution MIC technique. Children in two additional villages, which had not yet been treated, were also surveyed. Nasopharyngeal carriage of S pneumoniae was similar in the tetracycline treated, azithromycin treated, and untreated areas (p=0.57). However, resistance to tetracycline and azithromycin was distributed differently between the three areas (p=0.004). The village treated with topical tetracycline had a higher prevalence of tetracycline resistance than the other villages (p=0.010), while the oral azithromycin treated village had a higher prevalence of macrolide resistance than the other villages (p=0.014). Annual mass treatment with oral azithromycin may alter the prevalence of drug resistant S pneumoniae in a community. Surprisingly, topical tetracycline may also increase nasopharyngeal pneumococcal resistance. Topical antibiotics may have an effect on extraocular bacterial resistance."
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Quality Indicators for Gastroenterological Endoscopy
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The quality and safety of gastrointestinal endoscopy varies considerably across regions and facilities worldwide. In this field, quality management has traditionally focused on individual performance of endoscopists, with most indicators addressing process measures and limited evidence of improvement in health outcomes. Indicators of quality can be classified according to their nature and sequence. The various professional societies and organizations have proposed many systems of indicators, but a universal system is necessary so that healthcare professionals are not overburdened and confused with a variety of quality improvement approaches. In this paper, we propose guidelines by the Saudi Gastroenterology Association pertaining to quality in endoscopic procedures aiming to improve the awareness of endoscopy unit staff toward important quality indications to enhance and standardize quality of care provided to our patients.
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"The European Society of Gastrointestinal Endoscopy (ESGE) and United European Gastroenterology present a list of key performance measures for endoscopy services. We recommend that these performance measures be adopted by all endoscopy services across Europe. The measures include those related to the leadership, organization, and delivery of the service, as well as those associated with the patient journey. Each measure includes a recommendation for a minimum and target standard for endoscopy services to achieve. We recommend that all stakeholders in endoscopy take note of these ESGE endoscopy services performance measures to accelerate their adoption and implementation. Stakeholders include patients and their advocacy groups; service leaders; staff, including endoscopists; professional societies; payers; and regulators.",
"To evaluate the prognosis after esophagectomy for squamous cell carcinoma of the thoracic esophagus and its prognostic factors. Six hundred five patients with primary squamous cell carcinoma of the thoracic esophagus who underwent curative esophagectomy between June 1997 and June 1998 were collected from 3 medical centers. Among them, 26 patients died from the operation and 26 patients did not complete adjuvant treatment owing to toxicity. Univariate and multivariate analysis was performed to identify prognostic factors for survival. The effect of adjuvant treatment on survival was also evaluated. The 1-, 3-, 5-, and 10-year overall survivals of 605 patients were 90%, 65%, 36%, and 8%, respectively. Multivariate analysis identified the following as independent prognostic factors: number of lymph node metastases (P < .001), histologic differentiation (P < .001), tumor location (P = .002), depth of invasion (P = .020), and vascular invasion (P = .023). Several pathologic characteristics of the primary tumor are correlated with the outcome of esophagectomy for squamous carcinoma of the thoracic esophagus. Patients with fewer than 2 metastatic nodes after curative esophagectomy have a better prognosis than those with multiple involved nodes (>2). To stratify patients appropriately for prognosis, it is necessary to refine the current 6th edition TNM staging system.",
"A hospital-based case-control study of oesophageal cancer was carried out in the Heilongjiang Province, a low-risk area for oesophageal cancer in China. From May 1985 to May 1989, 196 histologically confirmed cases and 392 controls with other (non-neoplastic) diseases were personally interviewed in the wards of 5 major hospitals. Information was obtained about usual consumption in the early 1980s of 32 major contributors to the diet in the province, socio-demographic status, smoking and alcohol consumption. Odds ratios (OR) were obtained from logistic regression models, and confounding was controlled by means of multivariate models. Smoking and alcohol consumption were major risk factors for oesophageal cancer in this population. Smokers of handmade cigarettes exhibited a particularly high risk. A near multiplicative synergism was found between smoking and alcohol consumption. There was a significant inverse dose-risk trend for combined consumption of vegetables and fruits; a 300-g increase per day lowered risk by 35%. Vitamin C intake was negatively associated with risk; a 100-mg increase per day lowered risk by 39%. Our data suggest a modifying effect of vitamin C and beta-carotene on risk associated with smoking, but the power of analyses was low. Salt, salt-preserved foods and pickled vegetables were not associated with increased risk. High temperature of meals and drinks was a strong risk indicator in this population. The strength of tea and overall tea consumption were independent determinants of the risk.",
"Maintaining the quality of medical images and videos is an essential part of the e-services provided by the healthcare sector. The convergence of modern communication systems and the healthcare industry necessitates the provision of better quality of service and experience by the service provider. Recent inclusion and standardization of the high efficiency video coder (HEVC) has made it possible for medical data to be compressed and transmitted over wireless networks with minimal compromise of the quality. Quality evaluation and assessment of these medical videos transmitted over wireless networks is another important research area that requires further exploration and attention. In this paper, we have conducted an in-depth study of video quality assessment for compressed wireless capsule endoscopy (WCE) videos. Our study includes the performance evaluation of several state-of-the-art objective video quality metrics in terms of determining the quality of compressed WCE videos. Subjective video quality experiments were conducted with the assistance of experts and non-experts in order to predict the diagnostic and visual quality of these medical videos, respectively. The evaluation of the metrics is based on three major performance metrics that include, correlation between the subjective and objective scores, relative statistical performance and computation time. Results show that the metrics information fidelity criterion (IFC), visual information fidelity-(VIF) and especially pixel based VIF stand out as best performing metrics. Furthermore, our paper reports the performance of HEVC compression on medical videos and according to the results, it performs optimally in preserving the diagnostic and visual quality of WCE videos at Quantization Parameter (QP) values of up to 35 and 37 respectively.",
"The current practice of open-access endoscopy allows primary care and other non-gastroenterology physicians to directly refer patients for routine gastrointestinal endoscopic procedures. Open-access endoscopy is considered to be more cost-effective and time efficient than the traditional practice of referring patients for preprocedural consultation with a gastrointestinal endoscopist. Several studies have evaluated the performance of endoscopic procedures in an open-access environment and the utility of structured referral mechanisms to ensure safe and appropriately indicated procedures. This review focuses on 4 common preprocedural issues in gastrointestinal endoscopy encountered by primary care physicians: management of anticoagulation and antiplatelet therapy, indication for prophylactic antibiotic drug therapy, need for anesthesia-assisted sedation, and management of poor bowel preparation. We summarize the current guidelines that address these 4 common preprocedural issues to facilitate safe and clinically appropriate procedures in open-access endoscopy.",
"The site of surgical failure in cases of thoracic esophageal cancer (TEC) may be affected by the vertical location of the cancer in this longitudinal organ, suggesting the need to select the mode of adjuvant therapy based on location. We classified 501 TECs (92% squamous cell carcinomas) that underwent curative surgery without preoperative treatment as 13% upper thoracic (Ut), 51% middle thoracic (Mt), and 36% lower thoracic (Lt) lesions. Recurrent disease was discovered in 180 (36%) of the patients during a postoperative survey, most frequently in the cervical nodes (19%), liver (18%), abdominal paraaortic nodes (17%), and upper mediastinal nodes (17%). Although postoperative survival rates were similar (5-year survival: Ut 51%, Mt 55%, Lt 54%), the tumor recurrence site was significantly affected by the TEC vertical location, with recurrence in the cervical and upper mediastinal nodes being most frequent for Ut and Mt cases and in the liver and abdominal paraaortic nodes for Lt cases. Insufficient surgical lymph node clearance could be assessed by the recurrence index (RI), defined as the frequency of metastasis at recurrence divided by that at surgery. The RI was significantly lower for the upper abdominal nodes (4%, 8/184) than the lower mediastinal nodes (15%, 19/123) or the upper mediastinal nodes (19%, 30/154). These findings indicated that regional tumor recurrence, corresponding to the surgical field, was more frequent in the Ut and Mt cases (53% and 51%) than the Lt cases (18%); and distant recurrence was more frequent in the Lt cases (62%) than in Ut or Mt cases (25% and 36%). Thus the vertical location of the thoracic esophageal cancer can be said to affected strongly the site of tumor recurrence after curative surgery. Regional radiotherapy might be expected to have an adjuvant effect on Ut/Mt tumors and systemic chemotherapy on Lt tumors.",
"Unsedated esophagogastroduodenoscopy (EGD) is simpler and safer than sedated EGD; however, approximately 40% of patients cannot tolerate it. Early identification of patients likely to poorly tolerate unsedated EGD is valuable for improving compliance. The modified Mallampati classification (MMC) has been used to evaluate difficult tracheal intubation and laryngoscope insertion. We tried to assess the efficacy of MMC to predict the tolerance of EGD in unsedated patients. Two hundred patients who underwent an unsedated diagnostic EGD were recruited. They were stratified according to the view of the oropharynx as either MMC class I + II (good view) or class III + IV (poor view). EGD tolerance was assessed in three ways: gag reflex by endoscopist assessment, patient satisfaction by interview, and the degree of change in vital signs. MMC was significantly correlated to gag reflex (P < 0.001), patient satisfaction (P = 0.028), and a change of vital signs (P = 0.024). Patients in the poor view group had a 3.87-fold increased risk of gag reflex (P < 0.001), a 1.78-fold increased risk of unsatisfaction (P = 0.067), and a 1.96-fold increased risk of a change in vital signs (P = 0.025) compared to those in the good view group. MMC appears to be a clinically useful predictor of EGD tolerance. Patients with poor view of oropharynx by MMC criteria may be candidates for sedated or transnasal EGD."
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Mesenchymal stem cell-derived exosomes-based regimen for treating intrauterine adhesions
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Intrauterine adhesions (IUA), which is characterized by endometrial fibrosis, continue to be the most common cause of uterine infertility globally. Our work revealed that 3 fibrotic progression markers (Vimentin, COL5A2, and COL1A1) were significantly increased in the endometrium of IUA patients. Mesenchymal stem cell-derived exosomes (EXOs) have been recently revealed as a cell-free therapy for fibrosis diseases. Nevertheless, the application of EXOs is restricted by the short residency duration in the target tissue. To overcome this limitation, herein, we reported an exosome-based regimen (EXOs-HP) that thermosensitive poloxamer hydrogel possessed the ability to efficiently promote the residency duration of EXOs in the uterine cavity. By downregulating fibrotic progression markers (Vimentin, COL5A2, and COL1A1), EXOs-HP could significantly restore the function and structure of the injured endometrium in the IUA model. Our work provides the theoretical and experimental foundation of EXOs-HP in treating IUA, highlighting the clinical potential of topical EXOs-HP delivery system in IUA patients.
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"Transforming growth factor (TGF)‑β1 has a key role in the regulation of fibrosis and organ dysfunction. During the pathogenesis and progression of vital organ fibrosis, the microRNA (miR)‑29 family is irregularly downregulated and exogenous supplementation of miR‑29b has a strong anti‑fibrotic capacity. However, whether TGF‑β1 is able to provoke endometrial fibrosis, and the role of miR‑29 in endometrial fibrosis remain unclear. In the present study, RT‑qPCR, immunocytochemistry, western blot analysis, scanning electron microscopy, immunofluorescence staining, cell proliferation assay and flow cytometric analysis were employed. The results demonstrated that the expression levels of collagen, type 1, alpha 1 (COL1A1), α‑smooth muscle actin (α‑SMA) and phosphorylated (p)‑Smad2/3 were increased, whereas miR‑29b and maternally expressed gene 3 (MEG3) were decreased in primary endometrial stromal cells (ESCs) in response to TGF‑β1 stimulation, in a time and dose‑dependent manner. Furthermore, overexpression of miR‑29b markedly reduced the expression levels of COL1A1 and α‑SMA, and decreased the expression and nuclear accumulation of p‑Smad2/3. In addition, ectopic overexpression of miR‑29b increased the expression levels of MEG3, inhibited myofibroblast‑like cell proliferation and induced apoptosis. These findings indicated that miR‑29b may have a significant anti‑fibrotic role, and may attenuate TGF‑β1‑induced fibrosis in ESCs. Therefore, exogenous miR‑29b may serve as a potential therapeutic agent for the treatment of endometrial fibrosis.",
"Pulmonary fibrosis has an aggressive course and is usually fatal an average of 3 to 6 years after the onset of symptoms. Pulmonary fibrosis is associated with deposition of extracellular matrix (ECM) components in the lung interstitium. Matrix metalloproteinases (MMPs) are a major group of proteinases known to regulate the ECM remodeling and so they are hypothesized to be important in the process of lung fibrosis. These led to the concept that modulation of airway remodeling including excessive proteolytic damage of the tissue may be of interest for future treatment. The excessive airway remodeling as a result of an imbalance in the equilibrium of the normal processes of synthesis and degradation of extracellular matrix components could argue in favor of antiprotease treatments. Moreover, these observations emphasize that effective therapies for these disorders must be given early in the natural history of the disease, prior to the development of expensive lung destruction and fibrosis.",
"Following acute kidney injury (AKI), renal tubular cells may stimulate fibroblasts in a paracrine fashion leading to interstitial fibrosis, but the paracrine factors and their regulation under this condition remain elusive. Here we identify a macroautophagy/autophagy-dependent FGF2 (fibroblast growth factor 2) production in tubular cells. Upon induction, FGF2 acts as a key paracrine factor to activate fibroblasts for renal fibrosis. After ischemic AKI in mice, autophagy activation persisted for weeks in renal tubular cells. In inducible, renal tubule-specific atg7 (autophagy related 7) knockout (iRT-atg7-KO) mice, autophagy deficiency induced after AKI suppressed the pro-fibrotic phenotype in tubular cells and reduced fibrosis. Among the major cytokines, tubular autophagy deficiency in iRT-atg7-KO mice specifically diminished FGF2. Autophagy inhibition also attenuated FGF2 expression in TGFB1/TGF-β1 (transforming growth factor, beta 1)-treated renal tubular cells. Consistent with a paracrine action, the culture medium of TGFB1-treated tubular cells stimulated renal fibroblasts, and this effect was suppressed by FGF2 neutralizing antibody and also by fgf2- or atg7-deletion in tubular cells. In human, compared with non-AKI, the renal biopsies from post-AKI patients had higher levels of autophagy and FGF2 in tubular cells, which showed significant correlations with renal fibrosis. These results indicate that persistent autophagy after AKI induces pro-fibrotic phenotype transformation in tubular cells leading to the expression and secretion of FGF2, which activates fibroblasts for renal fibrosis during maladaptive kidney repair.Abbreviations: 3-MA: 3-methyladnine; ACTA2/α-SMA: actin alpha 2, smooth muscle, aorta; ACTB/β-actin: actin, beta; AKI: acute kidney injury; ATG/Atg: autophagy related; BUN: blood urea nitrogen; CCN2/CTGF: cellular communication network factor 2; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CKD: chronic kidney disease; CM: conditioned medium; COL1A1: collagen, type I, alpha 1; COL4A1: collagen, type IV, alpha 1; CQ: chloroquine; ECM: extracellular matrix; eGFR: estimated glomerular filtration rate; ELISA: enzyme-linked immunosorbent assay; FGF2: fibroblast growth factor 2; FN1: fibronectin 1; FOXO3: forkhead box O3; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; HAVCR1/KIM-1: hepatitis A virus cellular receptor 1; IHC: immunohistochemistry; IRI: ischemia-reperfusion injury; ISH: in situ hybridization; LTL: lotus tetragonolobus lectin; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PDGFB: platelet derived growth factor, B polypeptide; PPIB/cyclophilin B: peptidylprolyl isomerase B; RT-qPCR: real time-quantitative PCR; SA-GLB1/β-gal: senescence-associated galactosidase, beta 1; SASP: senescence-associated secretory phenotype; sCr: serum creatinine; SQSTM1/p62: sequestosome 1; TASCC: TOR-autophagy spatial coupling compartment; TGFB1/TGF-β1: transforming growth factor, beta 1; VIM: vimentin.",
"The cause of fibrotic diseases, pathologies characterized by excessive production, deposition, and contraction of extracellular matrix, is unknown. To understand the molecular basis of fibrotic disease, it is essential to appreciate how matrix deposition is normally controlled and how this process is dysregulated in fibrogenesis. This review discusses the current state of knowledge concerning interactions among the profibrotic proteins transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF, CCN2), and ED-A fibronectin (ED-A FN) and the antifibrotic proteins tumor necrosis factor-alpha (TNF-alpha) and gamma-interferon (IFN-gamma).",
"Tubulointerstitial fibrosis is a chronic and progressive process affecting kidneys during aging and in chronic kidney disease (CKD), regardless of cause. CKD and renal fibrosis affect half of adults above age 70 and 10% of the world's population. Although no targeted therapy yet exists to slow renal fibrosis, a number of important recent advances have clarified the cellular and molecular mechanisms underlying the disease. In this review, I highlight these advances with a focus on cells and pathways that may be amenable to therapeutic targeting. I discuss pathologic changes regulating interstitial myofibroblast activation, including profibrotic and proinflammatory paracrine signals secreted by epithelial cells after either acute or chronic injury. I conclude by highlighting novel therapeutic targets and approaches with particular promise for development of new treatments for patients with fibrotic kidney disease.",
"Evidence suggests that autophagy promotes the development of cellular senescence. Because cellular senescence contributes to renal aging and promotes the progression from AKI to CKD, we investigated the potential effect of tubular autophagy on senescence induction. Compared with kidneys from control mice, kidneys from mice with conditional deletion of autophagy-related 5 (Atg5) for selective ablation of autophagy in proximal tubular S3 segments (Atg5(Δ) (flox/) (Δ) (flox)) presented with significantly less tubular senescence, reduced interstitial fibrosis, and superior renal function 30 days after ischemia/reperfusion injury. To correlate this long-term outcome with differences in the early injury process, kidneys were analyzed 2 hours and 3 days after reperfusion. Notably, compared with kidneys of control mice, Atg5(Δ) (flox/) (Δ) (flox) kidneys showed more cell death in outer medullary S3 segments at 2 hours but less tubular damage and inflammation at day 3. These data suggest that the lack of autophagy prevents early survival mechanisms in severely damaged tubular cells. However, if such compromised cells persist, then they may lead to maladaptive repair and proinflammatory changes, thereby facilitating the development of a senescent phenotype and CKD.",
"The transition of AKI to CKD has major clinical significance. As reviewed here, recent studies show that a subpopulation of dedifferentiated, proliferating tubules recovering from AKI undergo pathologic growth arrest, fail to redifferentiate, and become atrophic. These abnormal tubules exhibit persistent, unregulated, and progressively increasing profibrotic signaling along multiple pathways. Paracrine products derived therefrom perturb normal interactions between peritubular capillary endothelium and pericyte-like fibroblasts, leading to myofibroblast transformation, proliferation, and fibrosis as well as capillary disintegration and rarefaction. Although signals from injured endothelium and inflammatory/immune cells also contribute, tubule injury alone is sufficient to produce the interstitial pathology required for fibrosis. Localized hypoxia produced by microvascular pathology may also prevent tubule recovery. However, fibrosis is not intrinsically progressive, and microvascular pathology develops strictly around damaged tubules; thus, additional deterioration of kidney structure after the transition of AKI to CKD requires new acute injury or other mechanisms of progression. Indeed, experiments using an acute-on-chronic injury model suggest that additional loss of parenchyma caused by failed repair of AKI in kidneys with prior renal mass reduction triggers hemodynamically mediated processes that damage glomeruli to cause progression. Continued investigation of these pathologic mechanisms should reveal options for preventing renal disease progression after AKI."
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How does neural activity drive muscles to produce behavior?
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How does neural activity drive muscles to produce behavior? The recent development of genetic lines in
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[
"Glucose-stimulated insulin secretion is associated with transients of intracellular Ca(2+) concentration [Ca(2+)](i) in the pancreatic beta-cell. We identified the expression and function of specific small-conductance Ca(2+)-activated K(+) (SK) channel genes in insulin-secreting cells. The presence of mRNA for SK1, -2, -3, and -4 (intermediate-conductance Ca(2+)-activated K(+) 1 [IK1]) channels was demonstrated by RT-PCR in rodent islets and insulinoma cells. SK2 and -3 proteins in mouse islets were detected by immunoblot and immunocytochemistry. In the tTA-SK3 tet-off mouse, a normal amount of SK3 protein was present in islets, but it became undetectable after exposure to doxycycline (DOX), which inhibits the transcription of the tTA-SK3 gene. The SK/IK channel-blockers apamin, dequalinium, and charybdotoxin caused increases in average [Ca(2+)](i) levels and in frequency of [Ca(2+)](i) oscillations in wild-type mouse islets. In SK3-tTA tet-off mice, the addition of apamin with glucose and tetraethylammonium (TEA) caused a similar elevation in [Ca(2+)](i), which was greatly diminished after DOX suppression of SK3 expression. We conclude that SK1, -2, -3, and IK1 (SK4) are expressed in islet cells and insulin-secreting cells and are able to influence glucose-induced calcium responses, thereby regulating insulin secretion.",
"The octopus arm requires special motor control schemes because it consists almost entirely of muscles and lacks a rigid skeletal support. Here we present a 2D dynamic model of the octopus arm to explore possible strategies of movement control in this muscular hydrostat. The arm is modeled as a multisegment structure, each segment containing longitudinal and transverse muscles and maintaining a constant volume, a prominent feature of muscular hydrostats. The input to the model is the degree of activation of each of its muscles. The model includes the external forces of gravity, buoyancy, and water drag forces (experimentally estimated here). It also includes the internal forces generated by the arm muscles and the forces responsible for maintaining a constant volume. Using this dynamic model to investigate the octopus reaching movement and to explore the mechanisms of bend propagation that characterize this movement, we found the following. 1) A simple command producing a wave of muscle activation moving at a constant velocity is sufficient to replicate the natural reaching movements with similar kinematic features. 2) The biomechanical mechanism that produces the reaching movement is a stiffening wave of muscle contraction that pushes a bend forward along the arm. 3) The perpendicular drag coefficient for an octopus arm is nearly 50 times larger than the tangential drag coefficient. During a reaching movement, only a small portion of the arm is oriented perpendicular to the direction of movement, thus minimizing the drag force.",
"We have applied the perforated patch whole-cell technique to beta cells within intact pancreatic islets to identify the current underlying the glucose-induced rhythmic firing of action potentials. Trains of depolarizations (to simulate glucose-induced electrical activity) resulted in the gradual (time constant: 2.3 s) development of a small (<0.8 nS) K(+) conductance. The current was dependent on Ca(2+) influx but unaffected by apamin and charybdotoxin, two blockers of Ca(2+)-activated K(+) channels, and was insensitive to tolbutamide (a blocker of ATP-regulated K(+) channels) but partially (>60%) blocked by high (10-20 mM) concentrations of tetraethylammonium. Upon cessation of electrical stimulation, the current deactivated exponentially with a time constant of 6.5 s. This is similar to the interval between two successive bursts of action potentials. We propose that this Ca(2+)-activated K(+) current plays an important role in the generation of oscillatory electrical activity in the beta cell.",
"The evolution of vertebrate smooth muscles is obscured by lack of identifiable smooth muscle-like cells in tunicates, the invertebrates most closely related to vertebrates. A recent evolutionary model was proposed in which smooth muscles arose before the last bilaterian common ancestor, and were later diversified, secondarily lost or modified in the branches leading to extant animal taxa. However, there is currently no data from tunicates to support this scenario. Here, we show that the axial columnar cells, a unique cell type in the adhesive larval papillae of the tunicate Ciona, are enriched for orthologs of vertebrate smooth/non-muscle-specific effectors of contractility, in addition to developing from progenitors that express conserved cardiomyocyte regulatory factors. We show that these cells contract during the retraction of the Ciona papillae during larval settlement and metamorphosis. We propose that the axial columnar cells of Ciona are a myoepithelial cell type required for transducing external stimuli into mechanical forces that aid in the attachment of the motile larva to its final substrate. Furthermore, they share developmental and functional features with vertebrate myoepithelial cells, vascular smooth muscle cells, and cardiomyocytes. We discuss these findings in the context of the proposed models of vertebrate smooth muscle and cardiomyocyte evolution.",
"Urinary incontinence is associated with enhanced spontaneous phasic contractions of the detrusor smooth muscle (DSM). Although a complete understanding of the etiology of these spontaneous contractions is not yet established, it is suggested that the spontaneously evoked action potentials (sAPs) in DSM cells initiate and modulate the contractions. In order to further our understanding of the ionic mechanisms underlying sAP generation, we present here a biophysically detailed computational model of a single DSM cell. First, we constructed mathematical models for nine ion channels found in DSM cells based on published experimental data: two voltage gated Ca2+ ion channels, an hyperpolarization-activated ion channel, two voltage-gated K+ ion channels, three Ca2+-activated K+ ion channels and a non-specific background leak ion channel. The ion channels' kinetics were characterized in terms of maximal conductances and differential equations based on voltage or calcium-dependent activation and inactivation. All ion channel models were validated by comparing the simulated currents and current-voltage relations with those reported in experimental work. Incorporating these channels, our DSM model is capable of reproducing experimentally recorded spike-type sAPs of varying configurations, ranging from sAPs displaying after-hyperpolarizations to sAPs displaying after-depolarizations. The contributions of the principal ion channels to spike generation and configuration were also investigated as a means of mimicking the effects of selected pharmacological agents on DSM cell excitability. Additionally, the features of propagation of an AP along a length of electrically continuous smooth muscle tissue were investigated. To date, a biophysically detailed computational model does not exist for DSM cells. Our model, constrained heavily by physiological data, provides a powerful tool to investigate the ionic mechanisms underlying the genesis of DSM electrical activity, which can further shed light on certain aspects of urinary bladder function and dysfunction.",
"We examined the ionic mechanisms mediating depolarization-induced spike activity in pancreatic beta-cells. We formulated a Hodgkin-Huxley-type ionic model for the action potential (AP) in these cells based on voltage- and current-clamp results together with measurements of Ca(2+) dynamics in wild-type and Kv2.1 null mouse islets. The model contains an L-type Ca(2+) current, a \"rapid\" delayed-rectifier K(+) current, a small slowly-activated K(+) current, a Ca(2+)-activated K(+) current, an ATP-sensitive K(+) current, a plasma membrane calcium-pump current and a Na(+) background current. This model, coupled with an equation describing intracellular Ca(2+) homeostasis, replicates beta-cell AP and Ca(2+) changes during one glucose-induced spontaneous spike, the effects of blocking K(+) currents with different inhibitors, and specific complex spike in mouse islets lacking Kv2.1 channels. The currents with voltage-independent gating variables can also be responsible for burst behavior. Original features of this model include new equations for L-type Ca(2+) current, assessment of the role of rapid delayed-rectifier K(+) current, and Ca(2+)-activated K(+) currents, demonstrating the important roles of the Ca(2+)-pump and background currents in the APs and bursts. This model provides acceptable fits to voltage-clamp, AP, and Ca(2+) concentration data based on in silico analysis.",
"Pacemaker neurons exert control over neuronal circuit function by their intrinsic ability to generate rhythmic bursts of action potential. Recent work has identified rhythmic gut contractions in human, mice, and hydra to be dependent on both neurons and the resident microbiota. However, little is known about the evolutionary origin of these neurons and their interaction with microbes. In this study, we identified and functionally characterized prototypical ANO/SCN/TRPM ion channel-expressing pacemaker cells in the basal metazoan Hydra by using a combination of single-cell transcriptomics, immunochemistry, and functional experiments. Unexpectedly, these prototypical pacemaker neurons express a rich set of immune-related genes mediating their interaction with the microbial environment. Furthermore, functional experiments gave a strong support to a model of the evolutionary emergence of pacemaker cells as neurons using components of innate immunity to interact with the microbial environment and ion channels to generate rhythmic contractions.",
"1. Membrane potentials and input resistance were measured in beta-cells from mouse pancreatic islets of Langerhans in the presence or absence of D-glucose. 2. Tetraethylammonium (TEA) (a specific blocker of the K permeability increase induced by shifts in membrane potential from negative to positive values) was externally applied and its effects on potentials and input resistance evaluated. 3. In the absence of glucose, addition of TEA up to 20 mM to the perifusion medium did not affect the resting potential and the input resistance, the selectivity ratio PK/PNa (calculated from the constant field equation) remaining unchanged at about 30. 4. The characteristic response of the beta-cell membrane potential, in the presence of glucose, is a fluctuation between a silent phase at about -50 mV and an active phase at about -40 mV giving rise to a train of spikes. TEA abolishes this pattern and very much reduces the graded response of spike frequency normally seen with different concentrations of glucose. 5. Addition of glucose in the presence of up to 20 mM-TEA induces an increase in membrane resistance of about 4.10(7) omega. 6. TEA lowers the glucose level required to trigger the electrical activity from about 5.6 to about 4.6 mM. 7. TEA blocks the repolarization phase of action potentials induced by the addition of glucose or by depolarizing intracellular current injection. 8. In the presence of 11.1 mM-glucose and 20 mM-TEA the action potentials frequently crossed the zero line, the membrane potential reaching up to 25 mV during the peak of the spikes.",
"A proof of concept for the evaluation of external nerve and muscle fiber excitation with the finite element software COMSOL Multiphysics, formerly known as FEMLAB, is presented. This software allows the simultaneous solution of fiber excitation by 1D models of the Hodgkin-Huxley type which are embedded in a volume conductor where the electric field is mainly dominated by the electrode currents. This way the presented bidomain model includes the interaction between electrode currents and transmembrane currents during the excitation process. Especially for direct muscle fiber stimulation (cardiac muscle, denervated muscle) the effects from secondary currents from large populations of excited fibers seem to be significant. The method has many applications, for example, the relation between stimulus parameters and fiber recruitment can be analyzed.",
"The cardiac cell is a complex biological system where various processes interact to generate electrical excitation (the action potential, AP) and contraction. During AP generation, membrane ion channels interact nonlinearly with dynamically changing ionic concentrations and varying transmembrane voltage, and are subject to regulatory processes. In recent years, a large body of knowledge has accumulated on the molecular structure of cardiac ion channels, their function, and their modification by genetic mutations that are associated with cardiac arrhythmias and sudden death. However, ion channels are typically studied in isolation (in expression systems or isolated membrane patches), away from the physiological environment of the cell where they interact to generate the AP. A major challenge remains the integration of ion-channel properties into the functioning, complex and highly interactive cell system, with the objective to relate molecular-level processes and their modification by disease to whole-cell function and clinical phenotype. In this article we describe how computational biology can be used to achieve such integration. We explain how mathematical (Markov) models of ion-channel kinetics are incorporated into integrated models of cardiac cells to compute the AP. We provide examples of mathematical (computer) simulations of physiological and pathological phenomena, including AP adaptation to changes in heart rate, genetic mutations in SCN5A and HERG genes that are associated with fatal cardiac arrhythmias, and effects of the CaMKII regulatory pathway and beta-adrenergic cascade on the cell electrophysiological function."
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Fungal Population and Mycotoxins Level in Loose Tobacco Products
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Smokeless tobacco products (STPs) contain several microbial communities which are responsible for the formation of carcinogens, like tobacco-specific nitrosamine (TSNAs). A majority of STPs are sold in loose/unpackaged form which can be loaded with a diverse microbial population. Here, the fungal population and mycotoxins level of three popular Indian loose STPs, Dohra, Mainpuri Kapoori (MK), and loose leaf-chewing tobacco (LCT) was examined using metagenomic sequencing of ITS1 DNA segment of the fungal genome and LC-MS/MS, respectively. We observed that Ascomycota was the most abundant phylum and Sterigmatomyces and Pichia were the predominant fungal genera in loose STPs. MK displayed the highest α-diversity being enriched with pathogenic fungi Apiotrichum, Aspergillus, Candida, Fusarium, Trichosporon, and Wallemia. Further, FUNGuild analysis revealed an abundance of saprotrophs in MK, while pathogen-saprotroph-symbiotroph were abundant in Dohra and LCT. The level of a fungal toxin (ochratoxins A) was high in the MK product. This study caution that loose STPs harbor various harmful fungi that can infect their users and deliver fungal toxins or disrupt the oral microbiome of SLT users which can contribute to several oral pathologies.
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"\"Cherry-red\" tobacco is the superior variant of tobacco, appearing with the apperance of red dapples on cured leaves due to the demethylation of nicotine to nornicotine during maturation and curing. Fungi are known to have the capacity to convert nicotine to nornicotine. However, an endophytic fungal community of \"cherry-red\" tobacco has never been reported to our best knowledge. Here, we sampled mature leaves from both \"cherry-red\" and ordinary tobacco at lower, center, and upper plant sections, and we analyzed the ITS diversity using high-throughput sequencing. Results revealed a significantly different fungal community of foliar endophyte in \"cherry-red\" and ordinary tobacco. In comparison to the ordinary control, higher diversity and a co-occurrence network complex were found in \"cherry-red\" samples, especially in the center and upper leaves, where the red dapples mainly emerged. More taxa were enriched in the \"cherry-red\" than ordinary tobacco leaves at all plant sections. In particular, Aspergillus, some strains of which are reported capable of converting nicotine to nornicotine, was specifically enriched in upper \"cherry-red\" tobacco leaves, which showed most red dapples after curing. A less robust network structure was detected in the \"cherry-red\" tobacco compared to ordinary tobacco. The nearest taxon index (NTI) and β NTI indicated that the local community structuration of tobacco endophytic fungi mainly driven by deterministic process, while the community turnover among plant sections was stochastic. In conclusion, our study provides the earliest information of endophytic fungal community in \"cherry-red\" tobacco leaf, and the community diversity, composition, and network features are synchronously varied with the appearance of red dapples, which is suggestive of their relationship to the formation of \"cherry-red\" tobacco.",
"The Ribosomal Database Project (RDP) Classifier, a naïve Bayesian classifier, can rapidly and accurately classify bacterial 16S rRNA sequences into the new higher-order taxonomy proposed in Bergey's Taxonomic Outline of the Prokaryotes (2nd ed., release 5.0, Springer-Verlag, New York, NY, 2004). It provides taxonomic assignments from domain to genus, with confidence estimates for each assignment. The majority of classifications (98%) were of high estimated confidence (> or = 95%) and high accuracy (98%). In addition to being tested with the corpus of 5,014 type strain sequences from Bergey's outline, the RDP Classifier was tested with a corpus of 23,095 rRNA sequences as assigned by the NCBI into their alternative higher-order taxonomy. The results from leave-one-out testing on both corpora show that the overall accuracies at all levels of confidence for near-full-length and 400-base segments were 89% or above down to the genus level, and the majority of the classification errors appear to be due to anomalies in the current taxonomies. For shorter rRNA segments, such as those that might be generated by pyrosequencing, the error rate varied greatly over the length of the 16S rRNA gene, with segments around the V2 and V4 variable regions giving the lowest error rates. The RDP Classifier is suitable both for the analysis of single rRNA sequences and for the analysis of libraries of thousands of sequences. Another related tool, RDP Library Compare, was developed to facilitate microbial-community comparison based on 16S rRNA gene sequence libraries. It combines the RDP Classifier with a statistical test to flag taxa differentially represented between samples. The RDP Classifier and RDP Library Compare are available online at http://rdp.cme.msu.edu/.",
"Plants, including cannabis (Cannabis sativa subsp. sativa), host distinct beneficial microbial communities on and inside their tissues and organs, including seeds. They contribute to plant growth, facilitating mineral nutrient uptake, inducing defence resistance against pathogens, and modulating the production of plant secondary metabolites. Understanding the microbial partnerships with cannabis has the potential to affect the agricultural practices by improving plant fitness and the yield of cannabinoids. Little is known about this beneficial cannabis-microbe partnership, and the complex relationship between the endogenous microbes associated with various tissues of the plant, and the role that cannabis may play in supporting or enhancing them. This review will consider cannabis microbiota studies and the effects of endophytes on the elicitation of secondary metabolite production in cannabis plants. The review aims to shed light on the importance of the cannabis microbiome and how cannabinoid compound concentrations can be stimulated through symbiotic and/or mutualistic relationships with endophytes.",
"The Italian Toscano cigar production includes a fermentation step that starts when dark fire-cured tobacco leaves are moistened and mixed with ca. 20% prefermented tobacco to form a 500-kg bulk. The dynamics of the process, lasting ca. 18 days, has never been investigated in detail, and limited information is available on microbiota involved. Here we show that Toscano fermentation is invariably associated with the following: (i) an increase in temperature, pH, and total microbial population; (ii) a decrease in reducing sugars, citric and malic acids, and nitrate content; and (iii) an increase in oxalic acid, nitrite, and tobacco-specific nitrosamine content. The microbial community structure and dynamics were investigated by culture-based and culture-independent approaches, including denaturing gradient gel electrophoresis and single-strand conformational polymorphism. Results demonstrate that fermentation is assisted by a complex microbial community, changing in structure and composition during the process. During the early phase, the moderately acidic and mesophilic environment supports the rapid growth of a yeast population predominated by Debaryomyces hansenii. At this stage, Staphylococcaceae (Jeotgalicoccus and Staphylococcus) and Lactobacillales (Aerococcus, Lactobacillus, and Weissella) are the most commonly detected bacteria. When temperature and pH increase, endospore-forming low-G+C content gram-positive bacilli (Bacillus spp.) become evident. This leads to a further pH increase and promotes growth of moderately halotolerant and alkaliphilic Actinomycetales (Corynebacterium and Yania) during the late phase. To postulate a functional role for individual microbial species assisting the fermentation process, a preliminary physiological and biochemical characterization of representative isolates was performed.",
"Causative linkages of tobacco use with oral potentially malignant disorders and cancers of oral cavity have been studied. Oral squamous cell carcinoma is one of the most common cancers in India. The International Agency for Research on Cancer (IARC) monograph found a significant association between smokeless tobacco (SLT) use and oral cancer. However, only a few limited studies have been represented on the IARC monograph. Published meta-analyses have provided pooled risk estimates for oral cancers caused by tobacco, both on global and regional levels. This systematic review was aimed at summarizing all the available studies exclusively in India by collecting data from PubMed and Medline. Emphasis was laid on cohort and case-control studies, and a few cross-sectional studies for premalignant lesions were also discussed. A significant association was noticed on SLT and premalignant and malignant oral cavity lesions.",
"Smokeless tobacco product (STP) consumption is a significant public health threat across the globe. STPs are not only a storehouse of carcinogens and toxicants but also harbor microbes that aid in the conversion of tobacco alkaloids to carcinogenic tobacco-specific nitrosamines (TSNAs), thereby posing a further threat to the health of its consumers. The present study analyzed the bacterial diversity of popular dry and loose STPs by 16S rRNA gene sequencing. This NGS-based investigation revealed four dominant phyla Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria and identified 549 genera, Prevotella, Bacteroides, and Lactobacillus constituting the core bacteriome of these STPs. The most significantly diverse bacteriome profile was displayed by the loose STP Mainpuri kapoori. The study further predicted the functional attributes of the prevalent genera by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) algorithm. Genes encoding for nitrate and nitrite reduction and transport enzymes, antibiotic resistance, multi-drug transporters and efflux pumps, secretion of endo- and exotoxin, and other pro-inflammatory molecules were identified. The loose STPs showed the highest level of nitrogen metabolism genes which can contribute to the synthesis of TSNAs. This study reveals the bacteriome of Indian domestic loose STPs that stagger behind in manufacturing and storage stringencies. Our results raise an alarm that the consumption of STPs harboring pathogenic genera can potentially lead to the onset of several oral and systemic diseases. Nevertheless, an in-depth correlation analysis of the microbial diversity of STPs and their elicit impact on consumer health is warranted. KEY POINTS: • Smokeless tobacco harbors bacteria that aid in synthesis of carcinogenic nitrosamines. • Most diverse bacteriome profile was displayed by loose smokeless tobacco products. • Pathogenic genera in these products can harm the oral and systemic health of users."
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Performance of virtual monochromatic images with the same dose and iodine contrast
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To investigate the performance of virtual monochromatic (VM) images with the same dose and iodine contrast as those for single-energy (SE) images using five dual-energy (DE) scanners with DE techniques: two generations of fast kV switching (FKS), two generations of dual source (DS), and one split filter (SF).
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"Recent technologic advances have markedly enhanced the clinical applications of computed tomography (CT). While the benefits of CT exceed the harmful effects of radiation exposure in patients, increasing radiation doses to the population have raised a compelling case for reduction of radiation exposure from CT. Strategies for radiation dose reduction are difficult to devise, however, because of a lack of guidelines regarding CT examination and scanning techniques. Various methods and strategies based on individual patient attributes and CT technology have been explored for dose optimization. It is the purpose of this review article to outline basic principles of CT radiation exposure and emphasize the need for CT radiation dose optimization based on modification of scanning parameters and application of recent technologic innovations.",
"To assess image quality of virtual monochromatic spectral (VMS) images, compared to single-energy (SE) CT, and to evaluate the feasibility of material density imaging in abdominal aortic disease. In this retrospective study, single-source (ss) dual-energy (DE) CT of the aorto-iliac system in 35 patients (32 male, mean age 76.5 years) was compared to SE-CT. By post-processing the data from ssDECT, VMS images at different energies and material density water (WD) images were generated. The image quality parameters were rated on 5-point scales. The aorto-iliac attenuation and contrast-to-noise ratio (CNR) were recorded. Quality of WD images was compared to true unenhanced (TNE) images. Radiation dose was recorded and statistical analysis was performed. Image quality and noise were better at 70 keV (P < 0.01). Renal artery branch visualisation was better at 50 keV (P < 0.005). Attenuation and CNR were higher at 50 and 70 keV (P < 0.0001). The WD images had diagnostic quality but higher noise than TNE images (P < 0.0001). Radiation dose was lower using single-phase ssDECT compared to dual-phase SE-CT (P < 0.0001). 70-keV images from ssDECT provide higher contrast enhancement and improved image quality for aorto-iliac CT when compared to SE-CT at 120 kVp. WD images are an effective substitute for TNE images with a potential for dose reduction.",
"The purpose of this study was to evaluate the impact of attenuation-based kilovoltage (kV) pair selection in dual source dual energy (DSDE)-pulmonary embolism (PE) protocol examinations on radiation dose savings and image quality. A prospective study was carried out on 118 patients with suspected PE. In patients in whom attenuation-based kV pair selection selected the 80/140Sn kV pair, the pre-scan 100/140Sn CTDIvol (computed tomography dose index volume) values were compared with the pre-scan 80/140Sn CTDIvol values. Subjective and objective image quality parameters were assessed. Attenuation-based kV pair selection switched to the 80/140Sn kV pair (\"switched\" cohort) in 63 out of 118 patients (53%). The mean 100/140Sn pre-scan CTDIvol was 8.8 mGy, while the mean 80/140Sn pre-scan CTDIvol was 7.5 mGy. The average estimated dose reduction for the \"switched\" cohort was 1.3 mGy (95% CI 1.2, 1.4; p < 0.001), representing a 15% reduction in dose. After adjusting for patient weight, mean attenuation was significantly higher in the \"switched\" vs. \"non-switched\" cohorts in all five pulmonary arteries and in all lobes on iodine maps. This study demonstrates that attenuation-based kV pair selection in DSDE examination is feasible and can offer radiation dose reduction without compromising image quality. • Attenuation-based kV pair selection in dual energy examination is feasible. • It can offer radiation dose reduction to approximately 50% of patients. • Approximate 15% reduction in radiation dose was achieved using this technique. • The image quality is not compromised by use of attenuation-based kV pair selection.",
"To reduce radiation dose from abdominal computed tomography (CT) without degradation of low-contrast detectability by using a technique with low tube voltage (90 kV). The institutional review board approved the participation of the radiologists in the observer performance test, and informed consent was obtained from all participating radiologists. A phantom for measurement of the radiation dose and a phantom containing low-contrast objects were scanned with a 16-detector row CT scanner at 120 kV and 90 kV. For determination of the radiation dose at both 90 kV and 120 kV, the tube current-time product settings were 100-560 mAs, and the doses at the center and periphery of the phantom were measured. To assess low-contrast detectability, we used a 300-mAs setting at 120 kV and 250-560-mAs settings at 90 kV. Five observers participated in the receiver operating characteristic analysis. Area under the receiver operating characteristic curve (A(z)) values were calculated in each observer. A(z) values obtained with each of the scanning techniques were recorded, and differences were examined for significance by using the Dunnet method. The mean A(z) value was 0.951 at 120 kV and 300 mAs. A(z) values were 0.927-0.973 at 90 kV and 450-560 mAs, and the differences between those values and values obtained at 120 kV and 300 mAs were not significant (P = .937-.952). A value of 100% was assigned to the radiation dose delivered to the center of the phantom at 120 kV and 300 mAs. The relative dose delivered at 90 kV ranged from 65% at 450 mAs to 79% at 560 mAs. A reduction from 120 kV to 90 kV led to as much as a 35% reduction in the radiation dose, without sacrifice of low-contrast detectability, at CT.",
"Single-source dual-energy (DE) computed tomography (CT) with fast switching of tube voltage allows projection-based image reconstruction, substantial reduction of beam-hardening effects, reconstruction of accurate monochromatic images and material decomposition images (MDIs), and detailing of material composition by using x-ray spectral information. In vascular applications, DE CT is expected to overcome limitations of standard single-energy CT angiography, including patient exposure to nephrotoxic contrast medium and carcinogenic radiation, insufficient contrast vascular enhancement, interference from metallic and beam-hardening artifacts and severe vessel calcification, and limited tissue characterization and perfusion assessment. Acquisition of low-energy monochromatic images and iodine/water MDIs can reasonably reduce contrast agent dose and improve vessel enhancement. Acquisition of virtual noncontrast images, such as water/iodine MDIs, can reduce overall radiation exposure by replacing true noncontrast CT in each examination. Acquisition of monochromatic images by using metal artifact reduction software or acquisition of iodine/water MDIs can reduce metal artifacts with preserved or increased vessel contrast, and subtraction of monochromatic images between two energy levels can subtract coils composed of dense metallic materials. Acquisition of iodine/calcium (ie, hydroxyapatite) MDIs permits subtraction of vessel calcification and improves vessel lumen delineation. Sensitive detection of lipid-rich plaque can be achieved by using fat/water MDIs, the spectral Hounsfield unit curve (energy level vs CT attenuation), and a histogram of effective atomic numbers included in an image. Various MDIs are useful for accurate differentiation among materials with high attenuation values, including contrast medium, calcification, and fresh hematoma. Iodine/water MDIs are used to assess organ perfusion, such as in the lungs and myocardium. Understanding these DE CT techniques enhances the value of CT for vascular applications. (©)RSNA, 2016.",
"To investigate and compare the use of automated tube potential selection (ATPS) with automated tube current modulation (ATCM) in high-pitch dual-source computed tomographic angiography (CTA) for imaging the whole aorta without electrocardiogram synchronization. Two groups of 60 patients underwent CTA on a dual-source computed tomographic device in high-pitch mode: ATCM (with 100-kV fixed tube potential) was used in group 1 and ATPS (with the same image quality options) in group 2. For the evaluation of radiation exposure, CT dose index and dose-length product were analyzed. Contrast and image quality were assessed by 2 independent observers. The ATPS group received a higher radiation dose than the ATCM group (P < 0.001) because in 80% of patients, the software switched to use of a 120-kV tube potential. In all cases, images of the aorta were of sufficient quality. High-pitch dual-source CTA of the aorta using ATPS is feasible in clinical routine, but is associated with higher radiation exposure than the ATCM protocol. This finding contradicts previously evaluations of ATPS based on single-source techniques."
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Plasma gelsolin levels and extracellular vesicles in type 2 diabetes mellitus
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The growing epidemic of the inflammation-related metabolic disease, type 2 diabetes mellitus, presents a challenge to improve our understanding of potential mechanisms or biomarkers to prevent or better control this age-associated disease. A gelsolin isoform is secreted into the plasma as part of the extracellular actin scavenger system which serves a protective role by digesting and removing actin filaments released from damaged cells. Recent data indicate a role for decreased plasma gelsolin (pGSN) levels as a biomarker of inflammatory conditions. Extracellular vesicles (EVs), a heterogeneous group of cell-derived membranous structures involved in intercellular signaling, have been implicated in metabolic and inflammatory diseases including type 2 diabetes mellitus. We examined whether pGSN levels were associated with EV concentration and inflammatory plasma proteins in individuals with or without diabetes.
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"The discovery that submicron-sized extracellular vesicles (EVs) are generated by both prokaryotic and eukaryotic cells might have a profound effect on experimental and clinical sciences, and could pave the way for new strategies to combat various diseases. EVs are carriers of pathogen-associated and damage-associated molecular patterns, cytokines, autoantigens and tissue-degrading enzymes. In addition to a possible role in the pathogenesis of a number of inflammatory conditions, such as infections and autoimmune diseases, EVs, including microvesicles (also known as microparticles), exosomes and apoptotic vesicles, have therapeutic potential and might be used as biomarkers for inflammatory diseases. Therefore, molecular diagnostics and targeted therapy could benefit from expanding knowledge in the field. In this Review, we summarize important developments and propose that extracellular vesicles could be used as therapeutic vehicles and as targets for the treatment and prevention of inflammatory diseases.",
"The global epidemic of obesity is accompanied by an increased prevalence of cardiovascular disease (CVD), in particular stroke and heart attack. Dysfunctional adipose tissue links obesity to CVD by secreting a multitude of bioactive lipids and pro-inflammatory factors (adipokines) with detrimental effects on the cardiovascular system. Adiponectin is one of the few adipokines that possesses multiple salutary effects on insulin sensitivity and cardiovascular health. Clinical investigations have identified adiponectin deficiency (hypoadiponectinaemia) as an independent risk factor for CVD. In animals, elevation of plasma adiponectin by either pharmacological or genetic approaches alleviates obesity-induced endothelial dysfunction and hypertension, and also prevents atherosclerosis, myocardial infarction and diabetic cardiomyopathy. Furthermore, many therapeutic benefits of the peroxisome-proliferator activated receptor gamma agonists, the thiazolidinediones, are mediated by induction of adiponectin. Adiponectin protects cardiovascular health through its vasodilator, anti-apoptotic, anti-inflammatory and anti-oxidative activities in both cardiac and vascular cells. This review summarizes recent findings in the understanding of the physiological role and clinical relevance of adiponectin in cardiovascular health, and in the identification of the receptor and postreceptor signalling events that mediate the cardiovascular actions of adiponectin. It also discusses adiponectin-targeted drug discovery strategies for treating obesity, diabetes and CVD. This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.",
"The adipocyte-derived hormone adiponectin seems to protect from insulin resistance, a key factor in the pathogenesis of type 2 diabetes. Genome-wide scans have mapped a susceptibility locus for type 2 diabetes and the metabolic syndrome to chromosome 3q27, where the adiponectin gene is located. A common silent T-G exchange in nucleotide 94 (exon 2) of the adiponectin gene has been associated with increased circulating adiponectin levels. Metabolic abnormalities associated with the G allele have not been reported. We therefore assessed whether this polymorphism alters insulin sensitivity and/or measures of obesity using the Tübingen Family Study database (prevalence of the G allele, 28%). In 371 nondiabetic individuals, we found a significantly greater BMI in GG + GT (25.5 +/- 0.7 kg/m(2)) compared with TT (24.1 +/- 0.3 kg/m(2); P = 0.02). Insulin sensitivity (determined by euglycemic clamp, n = 209) was significantly lower in GG + GT (0.089 +/- 0.007 units) compared with TT (0.112 +/- 0.005 units; P = 0.02). This difference disappeared completely on adjustment for BMI. Because our population contains a relatively high proportion of first-degree relatives of patients with type 2 diabetes, we stratified by family history (FHD). Much to our surprise, the genotype differences in BMI and insulin sensitivity in the whole population were attributable entirely to differences in the subgroup without FHD, whereas in the subgroup with FHD, the G allele had absolutely no effect. Moreover, individuals without FHD had a significantly lower BMI than individuals with FHD (25.2 +/- 0.4 vs. 26.2 +/- 0.5 kg/m(2); P = 0.01), which was not the case for the GG + GT subgroup without FHD (27.0 +/- 0.9 kg/m(2); NS). This suggests that in individuals without familial predisposition for type 2 diabetes, the adiponectin polymorphism may mildly increase the obesity risk (and secondarily insulin resistance). In contrast, in individuals who are already burdened by other genetic factors, this small effect may be very hard to detect.",
"Adiponectin is a novel, adipose-specific protein abundantly present in the circulation, and it has antiatherogenic properties. We analyzed the plasma adiponectin concentrations in age- and body mass index (BMI)-matched nondiabetic and type 2 diabetic subjects with and without coronary artery disease (CAD). Plasma levels of adiponectin in the diabetic subjects without CAD were lower than those in nondiabetic subjects (6.6+/-0.4 versus 7.9+/-0.5 microg/mL in men, 7.6+/-0.7 versus 11.7+/-1.0 microg/mL in women; P<0.001). The plasma adiponectin concentrations of diabetic patients with CAD were lower than those of diabetic patients without CAD (4.0+/-0.4 versus 6.6+/-0.4 microg/mL, P<0.001 in men; 6.3+/-0.8 versus 7.6+/-0. 7 microg/mL in women). In contrast, plasma levels of leptin did not differ between diabetic patients with and without CAD. The presence of microangiopathy did not affect the plasma adiponectin levels in diabetic patients. Significant, univariate, inverse correlations were observed between adiponectin levels and fasting plasma insulin (r=-0.18, P<0.01) and glucose (r=-0.26, P<0.001) levels. In multivariate analysis, plasma insulin did not independently affect the plasma adiponectin levels. BMI, serum triglyceride concentration, and the presence of diabetes or CAD remained significantly related to plasma adiponectin concentrations. Weight reduction significantly elevated plasma adiponectin levels in the diabetic subjects as well as the nondiabetic subjects. These results suggest that the decreased plasma adiponectin concentrations in diabetes may be an indicator of macroangiopathy.",
"Extracellular vesicles (EVs) have emerged in the last decade as critical cell-to-cell communication devices used to carry nucleic acids and proteins between cells. EV cargo includes plasma membrane and endosomal proteins, but EVs also contain material from other cellular compartments, including mitochondria. Within cells, mitochondria are responsible for a large range of metabolic reactions, but they can also produce damaging levels of reactive oxygen species and induce inflammation when damaged. Consistent with this, recent evidence suggests that EV-mediated transfer of mitochondrial content alters metabolic and inflammatory responses of recipient cells. As EV mitochondrial content is also altered in some pathologies, this could have important implications for their diagnosis and treatment. In this review, we will discuss the nature and roles of mitochondrial EVs, with a special emphasis on the nervous system.",
"Adiponectin is the most abundant peptide secreted by adipocytes, being a key component in the interrelationship between adiposity, insulin resistance and inflammation. Central obesity accompanied by insulin resistance is a key factor in the development of metabolic syndrome (MS) and future macrovascular complications. Moreover, the remarkable correlation between coronary artery disease (CAD) and alterations in glucose metabolism has raised the likelihood that atherosclerosis and type 2 diabetes mellitus (T2DM) may share a common biological background. We summarize here the current knowledge about the influence of adiponectin on insulin sensitivity and endothelial function, discussing its forthcoming prospects and potential role as a therapeutic target for MS, T2DM, and cardiovascular disease. Adiponectin is present in the circulation as a dimer, trimer or protein complex of high molecular weight hexamers, >400 kDa. AdipoR1 and AdipoR2 are its major receptors in vivo mediating the metabolic actions. Adiponectin stimulates phosphorylation and AMP (adenosin mono phosphate) kinase activation, exerting direct effects on vascular endothelium, diminishing the inflammatory response to mechanical injury and enhancing endothelium protection in cases of apolipoprotein E deficiency. Hypoadiponectinemia is consistently associated with obesity, MS, atherosclerosis, CAD, T2DM. Lifestyle correction helps to favorably modify plasma adiponectin levels. Low adiponectinemia in obese patients is raised via continued weight loss programs in both diabetic and nondiabetic individuals and is also accompanied by reductions in pro-inflammatory factors. Diet modifications, like intake of fish, omega-3 supplementation, adherence to a Mediterranean dietary pattern and coffee consumption also increase adiponectin levels. Antidiabetic and cardiovascular pharmacological agents, like glitazones, glimepiride, angiotensin converting enzyme inhibitors and angiotensin receptor blockers are also able to improve adiponectin concentration. Fibric acid derivatives, like bezafibrate and fenofibrate, have been reported to enhance adiponectin levels as well. T-cadherin, a membrane-associated adiponectin-binding protein lacking intracellular domain seems to be a main mediator of the antiatherogenic adiponectin actions. The finding of novel pharmacologic agents proficient to improve adiponectin plasma levels should be target of exhaustive research. Interesting future approaches could be the development of adiponectin-targeted drugs chemically designed to induce the activaton of its receptors and/or postreceptor signaling pathways, or the development of specific adiponectin agonists.",
"Accumulating evidence indicates the impact of endothelial progenitor cells (EPCs) in vascular repair. In patients, the number of EPCs is negatively correlated with the severity of atherosclerosis. In various animal models, transplantation of bone marrow-derived progenitor cells could sufficiently rescue organ function and enhance vascular repair and tissue regeneration. Increase in the number of circulating progenitors, induced by cell transfusion or enhanced mobilization, can also enhance restoration and integrity of the endothelial lining, suppress neointimal formation, and increase blood flow to ischaemic sites. However, the beneficial outcome of EPC infusion very much depends on the growth and differentiation factors within the tissue, cell-to-cell interactions, and the degree of injury. As highlighted by several studies, EPCs derive from different sources including bone marrow and non-bone marrow organs such as the spleen, the functional repair properties of which may vary with the maturation state of the cell. Thus, understanding the molecular mechanisms involved in EPC-repairing processes is essential. In the present review we focus on the role of EPCs in vascular diseases, and we provide an update on the mechanisms of EPC mobilization, homing, and differentiation."
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Moral views on non-treatment decisions in Norway
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Decisions about appropriate treatment at the end of life are common in modern healthcare. Non-treatment decisions (NTDs), comprising both withdrawal and withholding of (potentially) life-prolonging treatment are in principle accepted in Norway. However, in practice they may give rise to significant moral problems for health professionals, patients and next of kin. Here, patient values must be considered. It is relevant to study the moral views and intuitions of the general population on NTDs and special areas of contention such as the role of next of kin in decision-making.
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"Our objective was to investigate whether a consensus exists between the general public and health care providers regarding the reasoning and values at stake on the subject of life-sustaining treatment. A postal questionnaire was sent to a random sample of members of the adult population (n = 989) and to a random sample of intensive care doctors and neurosurgeons (n = 410) practicing in Sweden in 2004. The questionnaire was based on a case involving a severely ill patient and presented arguments for and against withholding and withdrawing treatment, and providing treatment that might hasten death. Approximately 70% of the physicians and 51% of the general public responded. A majority of doctors (82.3%) stated that they would withhold treatment, whereas a minority of the general public (40.2%) would do so; the arguments forwarded (for instance, belief that the first task of health care is to save life) and considerations regarding quality of life differed significantly between the two groups. Most physicians (94.1%) and members of the general public (77.7%) were prepared to withdraw treatment, and most (95.1% of physicians and 82% of members of the general public) agreed that sedation should be provided. There are indeed considerable differences in how physicians and the general public assess and reason in critical care situations, but the more hopelessly ill the patient became the more the groups' assessments tended to converge, although they prioritized different arguments. In order to avoid unnecessary dispute and miscommunication, it is important that health care providers be aware of the public's views, expectations, and preferences.",
"A careful examination of our attitudes toward end-of-life care is critical to our understanding of where change is needed to improve patient outcomes. The objectives of our narrative review are 1) to review why the intensive care unit setting presents particular challenges for the delivery of optimal end-of-life care, 2) to outline how four different research methods can provide insights into our understanding of attitudes about withdrawal of life support, and 3) to suggest seven different approaches to changing prevailing attitudes toward withdrawal of life support in the intensive care unit. To better understand attitudes about end-of-life care in general and withdrawal of life support in particular, we reviewed four different sources of data: 1) decision support tools, 2) qualitative research, 3) surveys, and 4) observational studies. Understanding these attitudes offers valuable insights about strategies that may help to improve the care of dying patients and their families. There are several ways to change attitudes; the approaches we reviewed are 1) promoting social change professionally, 2) legitimizing end-of-life research, 3) determining what families of dying patients need, 4) initiating quality improvement locally, 5) evaluating the benefits and harms of new initiatives, 6) modeling quality end-of-life care for future clinicians, and 7) using narratives. Attitudes toward end-of-life care are influenced by many factors and change slowly. Our attitudes have social and personal origins; they are grounded in values that are collective and community based. Different research methods provide insights into attitudes toward death in the intensive care unit and withdrawal of life support in particular. Understanding these attitudes may offer valuable insights about strategies that should help improve the care for dying patients and their families.",
"The purpose was to investigate physicians' perceptions of the role of European intensive care nurses in end-of-life decision making. This study was part of a larger study sponsored by the Ethics Section of the European Society of Intensive Care Medicine, the ETHICUS Study. Physicians described whether they thought nurses were involved in such decisions, whether nurses initiated such a discussion and whether there was agreement between physicians and nurses. The items were analyzed and comparisons were made between different regions within Europe. The study took place in 37 intensive care units in 17 European countries. Physician investigators reported data related to patients from 37 centers in 17 European countries. None. Physicians perceived nurses as involved in 2,412 (78.3%) of the 3,086 end-of-life decisions (EOLD) made. Nurses were thought to initiate the discussion in 66 cases (2.1%), while ICU physicians were cited in 2,438 cases (79.3%), the primary physician in 328 cases (10.7%), the consulting physician in 105 cases (3.4%), the family in 119 cases (3.9%) and the patient in 19 cases (0.6%). In only 20 responses (0.6%) did physicians report disagreement between physicians and nurses related to EOLD. A significant association was found between the region and responses to the items related to nursing. Physicians in more northern regions reported more nurse involvement. Physicians perceive nurses as involved to a large extent in EOLDs, but not as initiating the discussion. Once a decision is made, there is a sense of agreement. The level of perceived participation is different for different regions."
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LibGuides: COVID19: Mental Health and Wellbeing
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COVID19, and associated lockdown restrictions, have impacted on people's daily lives. Understanding the mental health and wellbeing implications of these impacts has been identified as a public health research priority.
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"Environmental stressors such as mass disasters may contribute to an increased prevalence of depression within the population affected. We examined the prevalence of probable major depression and risk factors for depression in the 6-month period after the September 11, 2001, attacks on the World Trade Center among New York City (NYC) metropolitan residents. A total of 2700 persons who were representative of the NYC metropolitan area were included in this cross-sectional telephone survey. The prevalence of probable major depression in the 6 months after the attacks was 9.4%. Multivariate logistic regression covariates associated with the likelihood of probable major depression included being directly affected by the attacks, having a perievent panic attack, experiencing multiple life stressors, and having been exposed to previous traumatic events. Mass traumatic event exposure appears to be an independent environmental risk factor for depression in the postdisaster context; specific reactions such as perievent panic attacks may have prognostic value.",
"Research on the psychological toll of the COVID-19 pandemic is being conducted in various countries. This study aimed to examine risk factors for mental health problems among Israeli adults during this crisis. A total of 204 participants took part in the study. They completed self-report questionnaires assessing perceived stress, anxiety, quality of life, and various questions related to quarantine, pre-existing health issues, and worries related to the virus. The study took place during the last two weeks of March 2020. The majority of participants reported relatively high levels of perceived stress and corona-related worries, but low levels of anxiety. Female gender, younger age, corona-related loneliness, and pre-existing chronic illness were all related to higher levels of psychological distress and lower levels of quality of life. While considering the preliminary nature of these results, the current study highlights risk factors for psychological distress in light of the corona pandemic. Attention should be given to sociodemographic variables that were identified as related to psychological distress, as well as to the important role of loneliness, when screening and treating people during this crisis. More research is needed in order to fully understand the scope and correlates of psychological difficulties during these challenging times.",
"There is major concern about the impact of the global COVID-19 outbreak on mental health. Several studies suggest that mental health deteriorated in many countries before and during enforced isolation (ie, lockdown), but it remains unknown how mental health has changed week by week over the course of the COVID-19 pandemic. This study aimed to explore the trajectories of anxiety and depression over the 20 weeks after lockdown was announced in England, and compare the growth trajectories by individual characteristics. In this prospective longitudinal observational study, we analysed data from the UCL COVID-19 Social Study, a panel study weighted to population proportions, which collects information on anxiety (using the Generalised Anxiety Disorder assessment) and depressive symptoms (using the Patient Health Questionnaire) weekly in the UK since March 21, 2020. We included data from adults living in England who had at least three repeated measures between March 23 and Aug 9, 2020. Analyses were done using latent growth models, which were fitted to account for sociodemographic and health covariates. Between March 23, and Aug 9, data from over 70 000 adults were collected in the UCL COVID-19 Social Study. When including participants living in England with three follow-up measures and no missing values, our analytic sample consisted of 36 520 participants. The average depression score was 6·6 (SD=6·0, range 0-27) and the average anxiety score 5·7 (SD=5·6, range 0-21) in week 1. Anxiety and depression levels both declined across the first 20 weeks following the introduction of lockdown in England (b=-1·93, SE=0·26, p<0·0001 for anxiety; b=-2·52, SE=0·28, p<0·0001 for depressive symptoms). The fastest decreases were seen across the strict lockdown period (between weeks 2 and 5), with symptoms plateauing as further lockdown easing measures were introduced (between weeks 16 and 20). Being a woman or younger, having lower educational attainment, lower income, or pre-existing mental health conditions, and living alone or with children were all risk factors for higher levels of anxiety and depression at the start of lockdown. Many of these inequalities in experiences were reduced as lockdown continued, but differences were still evident 20 weeks after the start of lockdown. These data suggest that the highest levels of depression and anxiety occurred in the early stages of lockdown but declined fairly rapidly, possibly because individuals adapted to circumstances. Our findings emphasise the importance of supporting individuals in the lead-up to future lockdowns to try to reduce distress, and highlight that groups already at risk for poor mental health before the pandemic have remained at risk throughout lockdown and its aftermath. Nuffield Foundation, UK Research and Innovation, Wellcome Trust.",
"The paper reports on the development of the WHOQOL-BREF, an abbreyiated version of the WHOQOL-100 quality of life assessment. The WHOQOL-BREF was derived from data collected using the WHOQOL-100. It produces scores for four domains related to quality of life: physical health, psychological, social relationships and environment. It also includes one facet on overall quality of life and general health. Domain scores produced by the WHOQOL-BREF correlate highly (0.89 or above) with WHOQOL-100 domain scores (calculated on a four domain structure). WHOQOL-BREF domain scores demonstrated good discriminant validity, content validity, internal consistency and test-retest reliability. These data suggest that the WHOQOL-BREF provides a valid and reliable alternative to the assessment of domain profiles using the WHOQOL-100. It is envisaged that the WHOQOL-BREF will be most useful in studies that require a brief assessment of quality of life, for example, in large epidemiological studies and clinical trials where quality of life is of interest. In addition, the WHOQOL-BREF may be of use to health professionals in the assessment and evaluation of treatment efficacy."
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Human milk banks in Italy: a tool to standardize the organization, management and procedures
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In Europe, an increasing number of human milk banks (HMBs) collect donor human milk to feed preterm infants when their mother's milk is not available or not enough. Moreover, donor milk is a bridge to breastfeeding, with positive clinical and psychological advantages for both mother and infant. Italy, with 41 HMBs actively operating in 2022, has the highest number of HMBs in Europe. The process of human milk donation is complex, so activity of HMBs must be regulated according to well-established rules. The present recommendations have been prepared as a tool to standardize the organization, management, and procedures of HMBs operating in Italy and to determine the minimal essential requirements to establish new HMBs. This article covers all the aspects of human milk donation and human milk banking, including general recommendations, donor recruitment and screening, expression, handling and storage of donor human milk, milk screening, and milk treatment (pasteurization). A pragmatic approach was taken to drafting the recommendations. Items for which there was consensus or robust published evidence on which to base recommendations were included. When there were differences that could not be resolved by reference to published research, a statement of explanation based on the expert opinion of the authors (all members of the Italian Association of Human Milk Banks) was included. Implementation of these recommendations can contribute to promotion of breastfeeding.
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"Mother's own milk has long been accepted as the best source of nutrition for the newborn. In those cases where mother's milk is not available, the best choice is the human milk provided by selected donors. Human milk banks are the most institutionalized method of milk sharing and play a vital role for neonates that cannot be breastfed. This study aims at systematically reviewing factors influencing donation to human milk banks. A systematic review of the literature was performed on authentic electronic resources, including PubMed, Scopus, Embase, ScienceDirect, and Web of Science with no time limitation. To increase the sensitivity and to find additional studies for systematic review, the reference list of the published studies was examined as well. Data extraction and quality appraisal were carried out by two independent reviewers. The study was qualitatively summarized to generate descriptive and explanatory themes that emerged from the literature. From a total of 1,157 articles, 31 met the inclusion criteria in which 64 factors are extracted. From these, 26 factors act as barriers and 38 factors act as facilitators of milk donation. Having excess milk, altruism, and helping other babies are found to be the most important facilitators of milk donation, while the most important barriers are religious and cultural concerns. Developing practical strategies to attract milk donors are crucial for successfully establishing human milk banks. These include providing reliable information regarding the milk bank goals and functions and developing breastfeeding polices with regard to differences in countries' contexts and trying to resolve any uncertainties regarding milk donation, especially those arising for religious concerns.",
"A variety of methods are in use for decontaminating breast pump milk collection kits and related items associated with infant feeding. This paper aims to provide best practice guidance for decontamination of this equipment at home and in hospital. It has been compiled by a Joint Working Group of the Healthcare Infection Society and the Infection Prevention Society. The guidance has been informed by a search of the literature in Medline, the British Nursing Index, the Cumulative Index to Nursing and Allied Health Literature, Midwifery and Infant Care, and the results of two surveys of UK neonatal units in 2002/3 and 2006, and of members of the Infection Prevention Society in 2014. Since limited good quality evidence was available from these sources, much of the guidance represents good practice based on the consensus view of the Working Group. This guidance provides practical recommendations to support the safe decontamination of breast pump milk collection kits for healthcare professionals to use and communicate to other groups such as parents and carers.",
"Breast milk is the best food for preterm infants. Due to their inadequate suction- swallowing action, the administration of expressed breast milk should be done with an orogastric tube. There is little information available regarding the microbiological safety of expressed breast milk. The aim of this article was to evaluate if there were any differences regarding the contamination of breast milk obtained at a healthcare facility versus at home. Cross-sectional study that analyzed pairs of breast milk samples (one obtained at home and the other one at a healthcare facility, the same day) from mothers of hospitalized newborn infants with a gestational age =35 weeks. Samples with over 105CFU/mL of mesophilic aerobic bacteria, or with the presence of Escherichia coli, Staphylococcus aureus, Streptococcus faecalis, enterobacterias, Pseudomonas, Salmonella, fungi, and yeast were considered contaminated. A total of 280 breast milk samples (140 pairs) from 53 mothers were analyzed; 139 samples (49.6%; 95% CI: 43.6 to 55.6) were contaminated; contamination was significantly more frequent in the samples obtained at home than in those obtained at a healthcare facility (59.6% versus 39.6%; p = 0.0008; OR 2.25; 95% IC: 1.36 to 3.7). Half of the breast milk samples had bacterial growth, which was more frequent in the samples obtained at home than those obtained at a healthcare facility.",
"The Committee on Nutrition of the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition aims to document the existing evidence of the benefits and common concerns deriving from the use of donor human milk (DHM) in preterm infants. The comment also outlines gaps in knowledge and gives recommendations for practice and suggestions for future research directions. Protection against necrotizing enterocolitis is the major clinical benefit deriving from the use of DHM when compared with formula. Limited data also suggest unfortified DHM to be associated with improved feeding tolerance and with reduced cardiovascular risk factors during adolescence. Presence of a human milk bank (HMB) does not decrease breast-feeding rates at discharge, but decreases the use of formula during the first weeks of life. This commentary emphasizes that fresh own mother's milk (OMM) is the first choice in preterm infant feeding and strong efforts should be made to promote lactation. When OMM is not available, DHM is the recommended alternative. When neither OMM nor DHM is available, preterm formula should be used. DHM should be provided from an established HMB, which follows specific safety guidelines. Storage and processing of human milk reduces some biological components, which may diminish its health benefits. From a nutritional point of view, DHM, like HM, does not meet the requirements of preterm infants, necessitating a specific fortification regimen to optimize growth. Future research should focus on the improvement of milk processing in HMB, particularly of heat treatment; on the optimization of HM fortification; and on further evaluation of the potential clinical benefits of processed and fortified DHM.",
"Although the habits of cigarette smoking and associated coffee drinking are generally ceased during pregnancy, they are often reinitiated after delivery when the breastfeeding period starts. This is a case report of a 32-year-old lactating smoker mother who consumed caffeinated drinks and who agreed to donate breast milk after smoking one cigarette (containing 0.6 mg of nicotine) and drinking one cup of espresso (containing 80 mg of caffeine) for an investigation of the excretion of nicotine, its major metabolite cotinine and caffeine into the breast milk and subsequent transfer to the infant. Nicotine and its metabolite cotinine peaked in the breast milk at 0.5 h after the cigarette smoking, and caffeine peaked 2 h after drinking coffee. Moreover, the nicotine disappeared from the milk by 3 h, the caffeine required 24 h and the cotinine required 72 h. The relative infant doses of caffeine, nicotine and cotinine were found to be 8.9, 12.8 and 77.6%, respectively. In the light of these results obtained after the mother smoked only one cigarette and consumed one cup of espresso, if a lactating mother cannot refrain from smoking cigarettes, she should extend the time between the last smoked cigarette and breastfeeding to at least 3 h when the nicotine has been completely eliminated from the milk. Similarly, nursing mothers should also drink coffee sparingly and immediately after nursing and avoid coffee or caffeinated beverages for at least 4 h prior to breastfeeding to minimize the infant's exposure to caffeine.",
"The bacteriology of 20 paired samples of breast milk was analysed to find out if discarding the first few millilitres would reduce the amount of bacterial contamination in breast milk donated to a hospital milk bank. The first sample was the initial 2-3 ml collected from the opposite breast to that first suckled by the baby, and the second was a midstream sample from the same breast. There was no significant difference in the colony counts between the paired samples, and in no instance did the bacterial flora of the second sample differ from that of the first.",
"This study explored whether donor-milk supplementation increases breastfeeding exclusivity at 6 months of life. In 10/2015, we implemented donor milk for breastfed newborns who needed nutritional supplements for hypoglycemia, hyperbilirubinemia, and >8% weight loss at 40 h of life. We conducted a retrospective chart review on 122 qualified neonates admitted to newborn nursery at University of Florida Jacksonville 4 months before donor-milk implementation and 6 months after. 73 (60%) of the neonates received formula and 49 (40%) received donor milk. 39 (54%) in the formula group and 33 (46%) in the donor-milk group were surveyed after 6 months of life. Multivariate logistic regression showed that newborns who received donor milk had five times greater odds of being exclusively breastfed at 6 months of life. Donor milk as feeding supplementation for newborns is associated with increased exclusive breastfeeding at 6 months of life.",
"On the basis of this study, IgA was best preserved in frozen human milk by thawing either overnight in the refrigerator or under warm running water. If either of those procedures are to be used, it is suggested that bacterial monitoring should be performed. Because current technology does not allow for accurate low internal temperature monitoring of liquids, it is concluded that use of the microwave oven for the treatment of human milk is inappropriate. However, because microwaving is as effective as holder pasteurization in killing bacteria, and because it would be less expensive and is faster, this process should be further investigated.",
"It is widely agreed that the best source of nutrition for the newborn is the milk of their own mothers. In those cases where it is not available, especially in very premature and/or very low birth weight infants, as well as other sick newborns, the preferred choice before formula is the human milk provided by selected donors. This indication is supported by the highest international bodies dedicated to the health of the child population, including the World Health Organisation as well as the main national and international scientific societies in the field of Paediatrics. Milk banks are health institutions responsible for the collection, processing and distribution of donated human milk. Currently, there are 14 human milk banks operating in Spain, grouped in the Spanish Association of Human Milk Banks, created in September 2008. In order to homogenise the criteria and to unify the working methods of the different milk banks, the Spanish Association of Human Milk Banks has developed standards to harmonise the protocols, and to serve as a guide for the start-up of new milk banks in the Spanish territory. These standards, set out in the present article, range from the donor selection and the evaluation process to the collection, processing, storage, and distribution of donor human milk.",
"In Italy, the use of nucleic acid testing for hepatitis B virus (HBV) in donor screening has allowed the detection of infections in the window phase, as well as the presence of occult infections which could potentially be transmitted. The aim of this study was to analyse the trends of epidemiological data focused on HBV infection in blood donors and to estimate the residual risk of transmitting HBV from both the window phase and occult infection over a 10-year period in Italy. Data were obtained from the Italian Haemovigilance System which includes the results of screening tests for transfusion transmissible infections. During the period of this survey (2009-2018), the molecular methods used for HBV screening were transcription-mediated amplification and polymerase chain reaction tests. Prevalence and incidence were calculated. The residual risk was estimated by applying the incidence-window period model for acute cases and a more recently reported model for estimating the risk due to occult infections. A total of 17,424,535 blood donors and 30,842,794 donations were tested for HBV. Altogether, 6,250 donors tested positive for HBV markers: 4,782 (175.6×105) were first time donors and 1,468 (10.0×105) were repeat donors. The prevalence of HBV markers in first time donors was 275.9×105 in 2009, declining to 143.6×105 in 2018. The incidence of new infections was 3.37×105 in 2009 and 2.17×105 in 2018. The overall residual risk for HBV amounted to 1 in 2,566,854 donations calculated as the sum of risks of both acute infections in the window period (1 in 5,835,306 donations) and occult infections (1 in 4,582,270 blood units). In Italy, the residual risk of transfusing a blood unit infected with HBV, both from window phase and occult infections, is currently very low, amounting to levels that can be considered tolerable."
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Early tumor recurrence in pilocytic astrocytomas.
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Pilocytic astrocytomas (PAs) are benign tumors. However, clinically aggressive PAs despite benign histology have been reported, and histological and molecular risk factors for prognosis have not been elucidated. 38 PAs were studied for clinical, histological, and molecular factors, including tumor location, extent of resection, post-operative treatment, glioma-associated molecules (IDH1/2, ATRX, BRAF, FGFR1, PIK3CA, H3F3A, p53, VEGF, Nestin, PD-1/PD-L1), CDKN2A/B deletion, and chromosomal number aberrations, to see if there is any correlation with patient's progression-free survival (PFS). Brainstem/spinal location, extent of resection and post-operative treatment, and VEGF-A, Nestin and PD-L1 expression, copy number gain of chromosome 7q or 19, TP53 mutation were significantly associated with shorter PFS. None of the histological parameters was associated with PFS. Multivariate analyses demonstrated that high Nestin expression, gain of 7q or 19, and extent of removal were independently predictive for early tumor recurrence. The brainstem/spinal PAs appeared distinct from those in the other sites in terms of molecular characteristics. Clinically aggressive PAs despite benign histology exhibited high Nestin expression. Brainstem/spinal location, extent of resection and some molecular factors including Nestin expression and gains of 7q and 19, rather than histological parameters, may be associated with early tumor recurrence in PAs.
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"Pilocytic astrocytoma (PA) is one of the most common glial neoplasms in the pediatric population, and its gross total resection can be curative. Treatment of partially resected or recurrent tumors is challenging, and the factors associated with increased recurrence risk are not well defined. Identification of favorable and unfavorable factors can lead to a better understanding and management of patients with PA. We studied the pathologic characteristics of 116 intracranial PAs from 4 institutions representing 3 distinct geographic regions to identify factors that may be associated with biological behavior. The study included 65 boys and 51 girls with a median age of 6 years. Median follow-up for all patients was 101 months, during which time 38 patients had recurrence. Progression-free and overall survivals were better in patients who underwent gross total resection. We were not able to identify any differences in pathologic and molecular markers among the 4 institutions from 3 different countries. However, progression-free survival varied significantly among institutions. Sox-2 was the most prevalent stem cell marker in PA, and many tumors showed synaptophysin positivity. BRAF immunostaining was not useful in determining BRAF duplication. BRAF duplication was more typical of posterior fossa tumors. There was a strong correlation between BRAF duplication and pERK immunostaining, suggesting that the RAF/MEK/ERK pathway is active in these tumors. This finding has significant implications given its role in oncogen-induced senescence and possible influence on treatment decisions of subtotally resected tumors.",
"We report the first case of a child with a H3F3A K27M mutated pilocytic astrocytoma, who presented with a 10 years survival, and underwent spontaneous malignant transformation. The complex tumoral chromosomal rearrangements were consistent for genomic instability and for the histopathological features of malignant transformation into glioblastoma. H3F3A K27M mutations are rarely observed in benign neoplasms and may be associated with an adverse outcome. This mutation might not be the major driver that led to the onset of tumorigenesis, and we could consider that the associated TP53 mutation, would be required for malignant transformation.",
"The p53 gene was examined in a series of formalin-fixed paraffin-embedded astrocytic neoplasms of various types by polymerase chain reaction (PCR), single-strand conformation polymorphism analysis (SSCP), and direct sequencing of amplified DNA. PCR primers were designed to amplify three DNA fragments encompassing exons 5, 7, and 8 with splice sites, including all four mutational \"hot spots\" within this gene. SSCP was performed in a polyacrylamide gel containing 10% glycerol. Two mutations were found among the 20 high and intermediate grade adult astrocytomas studied by this sensitive screening technique and confirmed by sequencing of the PCR product. (1) An anaplastic astrocytoma disclosed a T-A transversion in Codon 246 giving rise to a methionine to lysine amino acid substitution. (2) A giant cell glioblastoma disclosed a G to A transition in Codon 285 resulting in a glutamic acid to lysine substitution. Both mutations were associated with loss of the normal allele. Twenty-three DNA fragments that disclosed no mutation by SSCP analysis were confirmed to be negative by direct sequencing of amplified DNA. No mutations were detected in a series of eight juvenile cerebellar astrocytomas, a biologically distinct form of low-grade astrocytoma. Mutations of the p53 gene may play an important pathogenetic role in a subset of human astrocytomas.",
"In adults, the TP53 tumor suppressor gene is frequently mutated in astrocytic brain tumors which is supposed to represent an early event in their development. In juvenile pilocytic and low-grade astrocytomas, however, TP53 mutations have until now been reported as rare, which has led to the suggestion that these tumors may follow a different molecular pathogenesis with an involvement of genes other than TP53. Our analysis of 20 pilocytic and two low-grade astrocytomas of childhood, based on a comprehensive denaturing gradient gel electrophoresis (DGGE) mutation detection assay of the entire coding region, including all splice site junctions of TP53, showed mutations considered as causative in 7 of the 20 (35%) pilocytic astrocytomas and in one of the two low-grade astrocytomas. Our finding is significantly different from the mutation frequency of 1.3% (2/155) previously reported for these tumor types. This may be attributed to the mutation detection system used, which also detects mutations occurring outside the evolutionary conserved region of TP53. Our results suggest that, contrary to the present notion, TP53 mutations may well play a role in the development of juvenile astrocytomas. Furthermore, no mutations were found in tumors of patients with progression of residual tumor after postoperative follow-up. This suggests that TP53 mutations may be associated with less aggressive forms of juvenile astrocytomas, analogous to the situation in adult astrocytomas."
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