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Right ventricular thrombus and tricuspid valve dysfunction in a patient with Behcet's syndrome. |
Behcet's syndrome (BS) is a systemic inflammatory disease generally presented with triad of uveitis, oral and genital ulcers. However, it may present with gastrointestinal, central nervous system, skin, vascular disease manifestations. Cardiac involvement like intracardiac thrombus and valvular involvement in BS are rarely seen entities. Here we present the management of a 23-year old male BS patient who had a right ventricular thrombus and tricuspid valve dysfunction which was resistant to immunosuppressive treatment. He has been doing well for 4 years after intraventricular thrombus resection and tricuspid valve replacement with bioprosthesis. |
Behcet's syndrome and pregnancy: course of the disease and pregnancy outcome. |
OBJECTIVES: To review the current available literature on the mutual effect of pregnancy or contraceptives and Behcet's disease (BD) in order to guide our patients more wisely before they take contraceptives or decide to conceive. METHODS: We performed a systematic review of the literature regarding the above issues using PubMed, Cochrane and EMBase databases. RESULTS: We have found 21 case reports and 11 series dealing with the mutual effect of pregnancy or contraceptives and Behcet's disease and 5 case reports dealing with BD and contraceptives. In most cases the course of BD was ameliorated or unchanged during pregnancy. The outcome of pregnancy in BD patients was poorer than that in healthy individuals. Contraceptives have various effects on the course of BD. CONCLUSIONS: Despite the above impression, it is quite difficult to predict the course of the disease during pregnancy in an individual BD patient. Patients with BD and a history of thrombosis are recommended to avoid contraceptive pills. |
Development and validation of an electronic medical record-based disease activity index for Behcet's disease. |
OBJECTIVES: The disease activity of Behcet's disease is inadequately defined, and there is no consensus on how it should be measured. The aim of this study was to verify the usefulness of a simplified electronic medical record (EMR)-based activity index (EMRAI) for Behcet's disease. METHODS: A total of 73 Korean patients with Behcet's disease participated in this study. Two dermatologists interviewed each participant independently using two activity scoring systems: the EMRAI and the Behcet's Disease Current Activity Form (BDCAF). Overall agreement between raters, correlation between activity scoring indices, and total interview run-time were evaluated. RESULTS: The EMRAI significantly correlated with the BDCAF (Spearman's correlation coefficient, r=0.835), physician-assessed overall activity score (r=0.782), erythrocyte sedimentation rate (r=0.520) and C-reactive protein level (r=0.422). The weighted kappa score for inter-rater agreement of EMRAI showed very good reliability compared with that of BDCAF (0.894 and 0.693, respectively). The mean total run-time for the EMRAI was shorter than that required to administer the BDCAF (95 s and 115 s, respectively). CONCLUSIONS: The EMRAI, an EMR-based simplified activity index of Behcet's disease, facilitates rapid and simple gathering of disease activity data and clinical information. |
Vein wall imaging in Behcet's syndrome. |
Self-criticism in Behcet's disease and other autoinflammatory conditions. |
Sulforaphane prevents the development of cardiomyopathy in type 2 diabetic mice probably by reversing oxidative stress-induced inhibition of LKB1/AMPK pathway. |
Type 2 diabetes mellitus (T2DM)-induced cardiomyopathy is associated with cardiac oxidative stress, inflammation, and remodeling. Sulforaphane (SFN), an isothiocyanate naturally presenting in widely consumed vegetables, particularly broccoli, plays an important role in cardiac protection from diabetes. We investigated the effect of SFN on T2DM-induced cardiac lipid accumulation and subsequent cardiomyopathy. Male C57BL/6J mice were fed a high-fat diet for 3months to induce insulin resistance, followed by a treatment with 100mg/kg body-weight streptozotocin to induce hyperglycemia, as T2DM mouse model. Other age-matched mice were fed normal diet as control. T2DM and control mice were treated with or without 4-month SFN at 0.5mg/kg daily five days a week. At the study's end, cardiac function was assessed. SFN treatment significantly attenuated cardiac remodeling and dysfunction induced by T2DM. SFN treatment also significantly inhibited cardiac lipid accumulation, measured by Oil Red O staining, and improved cardiac inflammation oxidative stress and fibrosis, shown by down-regulating diabetes-induced PAI-1, TNF-alpha, CTGF, TGF-beta, 3-NT, and 4-HNE expression. Elevated 4-HNE resulted in the increase of 4-HNE-LKB1 adducts that should inhibit LKB1 and subsequent AMPK activity. SFN upregulated the expression of Nrf2 and its downstream genes, NQO1 and HO-1, decreased 4-HNE-LKB1 adducts and then reversed diabetes-induced inhibition of LKB1/AMPK and its downstream targets, including sirtuin 1, PGC-1alpha, phosphorylated acetyl-CoA carboxylase, carnitine palmitoyl transferase-1, ULK1, and light chain-3 II. These results suggest that SFN treatment to T2DM mice may attenuate the cardiac oxidative stress-induced inhibition of LKB1/AMPK signaling pathway, thereby preventing T2DM-induced lipotoxicity and cardiomyopathy. |
Inflammasome Activation Is Critical to the Protective Immune Response during Chemically Induced Squamous Cell Carcinoma. |
Chronic inflammation affects most stages of tumorigenesis, including initiation, promotion, malignant differentiation, invasion and metastasis. Inflammasomes have been described as involved with persistent inflammation and are known to exert both pro and antitumour effects. We evaluated the influence of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and caspase (CASP)-1 in the antitumor immune response using a multistage model of squamous cell carcinoma (SCC) development. Absence of ASC and CASP-1 resulted in an earlier incidence and increased number of papilloma. Loss of inflammassome function in mice resulted in decreased presence of natural killer (NK), dendritic (DC), CD4+, CD8+ and CD45RB+ T cells in the tumor lesions as well as in lymph nodes (LN) compared with WT mice. Increased percentage of CD4+CD25+Foxp3+ T cells was associated with association with inflammasome loss of function. Moreover, significant differences were also found with neutrophils and macrophage infiltrating the lesions. Myeloperoxidase (MPO), but not elastase (ELA), activity oscillated among the groups during the SCC development. Levels of proinflammatory cytokines IL-1beta, IL-18, Tumor Necrosis Factor (TNF)-alpha and Interferon (IFN)-gamma were decreased in the tumor microenvironment in the absence of inflammasome proteins. These observations suggest a link between inflammasome function and SCC tumorigenesis, indicating an important role for inflammasome activation in the control of SCC development. |
Persistent At-Level Thermal Hyperalgesia and Tactile Allodynia Accompany Chronic Neuronal and Astrocyte Activation in Superficial Dorsal Horn following Mouse Cervical Contusion Spinal Cord Injury. |
In humans, sensory abnormalities, including neuropathic pain, often result from traumatic spinal cord injury (SCI). SCI can induce cellular changes in the CNS, termed central sensitization, that alter excitability of spinal cord neurons, including those in the dorsal horn involved in pain transmission. Persistently elevated levels of neuronal activity, glial activation, and glutamatergic transmission are thought to contribute to the hyperexcitability of these dorsal horn neurons, which can lead to maladaptive circuitry, aberrant pain processing and, ultimately, chronic neuropathic pain. Here we present a mouse model of SCI-induced neuropathic pain that exhibits a persistent pain phenotype accompanied by chronic neuronal hyperexcitability and glial activation in the spinal cord dorsal horn. We generated a unilateral cervical contusion injury at the C5 or C6 level of the adult mouse spinal cord. Following injury, an increase in the number of neurons expressing DeltaFosB (a marker of chronic neuronal activation), persistent astrocyte activation and proliferation (as measured by GFAP and Ki67 expression), and a decrease in the expression of the astrocyte glutamate transporter GLT1 are observed in the ipsilateral superficial dorsal horn of cervical spinal cord. These changes have previously been associated with neuronal hyperexcitability and may contribute to altered pain transmission and chronic neuropathic pain. In our model, they are accompanied by robust at-level hyperaglesia in the ipsilateral forepaw and allodynia in both forepaws that are evident within two weeks following injury and persist for at least six weeks. Furthermore, the pain phenotype occurs in the absence of alterations in forelimb grip strength, suggesting that it represents sensory and not motor abnormalities. Given the importance of transgenic mouse technology, this clinically-relevant model provides a resource that can be used to study the molecular mechanisms contributing to neuropathic pain following SCI and to identify potential therapeutic targets for the treatment of chronic pathological pain. |
Unbiased Identification of Patients with Disorders of Sex Development. |
Disorders of sex development (DSD) represent a collection of rare diseases that generate substantial controversy regarding best practices for diagnosis and treatment. A significant barrier preventing a better understanding of how patients with these conditions should be evaluated and treated, especially from a psychological standpoint, is the lack of systematic and standardized approaches to identify cases for study inclusion. Common approaches include "hand-picked" subjects already known to the practice, which could introduce bias. We implemented an informatics-based approach to identify patients with DSD from electronic health records (EHRs) at three large, academic children's hospitals. The informatics approach involved comprehensively searching EHRs at each hospital using a combination of structured billing codes as an initial filtering strategy followed by keywords applied to the free text clinical documentation. The informatics approach was implemented to replicate the functionality of an EHR search engine (EMERSE) available at one of the hospitals. At the two hospitals that did not have EMERSE, we compared case ascertainment using the informatics method to traditional approaches employed for identifying subjects. Potential cases identified using all approaches were manually reviewed by experts in DSD to verify eligibility criteria. At the two institutions where both the informatics and traditional approaches were applied, the informatics approach identified substantially higher numbers of potential study subjects. The traditional approaches yielded 14 and 28 patients with DSD, respectively; the informatics approach yielded 226 and 77 patients, respectively. The informatics approach missed only a few cases that the traditional approaches identified, largely because those cases were known to the study team, but patient data were not in the particular children's hospital EHR. The use of informatics approaches to search electronic documentation can result in substantially larger numbers of subjects identified for studies of rare diseases such as DSD, and these approaches can be applied across hospitals. |
Does oral supplementation of a fermented papaya preparation correct respiratory burst function of innate immune cells in type 2 diabetes mellitus patients? |
Fermented papaya preparation (FPP) is a nutritional supplement reported to act as an antioxidant by scavenging reactive oxygen species (ROS) and removing 'bad ROS', while inducing "respiratory burst" production of necessary 'good ROS'. We sought to investigate the safety of oral administration of FPP (9g/d, 6 weeks) to T2D patients with respect to its effect on the hyperglycemia status of these patients. Peripheral blood was collected during a baseline visit, followed by subsequent collections during and after supplementation. Induced "respiratory burst" ROS production was measured at each visit in addition to fasting blood glucose, lipid profile, glycated hemoglobin (HbA1c), and lipid/protein peroxidation. Oral FPP supplementation induced "respiratory burst" in peripheral blood mononuclear cells while not influencing other blood parameters studied. When human monocytic THP-1 cells were supplemented with sugar-based FPP, cellular ATP and NADPH concentrations were increased while matched glucose alone did not produce similar effects, suggesting a glucose-independent component of FPP to be responsible for increasing cellular energetics. THP-1 cells supplemented with FPP also exhibited higher mitochondrial membrane potential (Deltapsim) and oxygen consumption as compared to cells treated with glucose alone. Taken together, our observations lead to the hypothesis that FPP corrects inducible "respiratory burst" function in type 2 diabetes patients. |
On Naivety of T Cells in Inflammatory Bowel Disease: A Review. |
: Little is known about different phases of T-cell maturation in gut mucosa. Based on current knowledge about the migratory pathways of naive and memory T cells, it is believed that access to peripheral, nonlymphoid tissues is restricted to memory T cells. Surprisingly, there is increasing evidence of high numbers of naive T cells in the chronically inflamed gut tissue of patients with inflammatory bowel disease. This could partially be explained by new formation of ectopic lymphoid organs. Ongoing recruitment of naive T cells at inflammatory sites might play a role in the immunopathogenesis of inflammatory bowel disease. |
Necrotizing Enterocolitis: A Clinical Review on Diagnostic Biomarkers and the Role of the Intestinal Microbiota. |
Necrotizing enterocolitis (NEC) remains one of the most frequent gastrointestinal diseases in the neonatal intensive care unit, with a continuing unacceptable high mortality and morbidity rates. Up to 20% to 40% of infants with NEC will need surgical intervention at some point. Although the exact pathophysiology is not yet elucidated, prematurity, use of formula feeding, and an altered intestinal microbiota are supposed to induce an inflammatory response of the immature intestine. The clinical picture of NEC has been well described. However, an early diagnosis and differentiation against sepsis is challenging. Besides, it is difficult to timely identify NEC cases that will deteriorate and need surgical intervention. This may interfere with the most optimal treatment of infants with NEC. In this review, we discuss the pathogenesis, diagnosis, and treatment of NEC with a focus on the role of microbiota in the development of NEC. An overview of different clinical prediction models and biomarkers is given. Some of these are promising tools for accurate diagnosis of NEC and selection of appropriate therapy. |
Anemia in a Population-based IBD Cohort (ICURE): Still High Prevalence After 1 Year, Especially Among Pediatric Patients. |
BACKGROUND:: Prevalence of anemia in patients with inflammatory bowel disease (IBD) is uncertain because of scarcity of population-based studies. The aim of this study was to evaluate prevalence of anemia in a population-based cohort of newly diagnosed patients with IBD to identify risk factors for anemia and to describe contemporary anemia-specific treatment during the first year. METHODS:: All patients with ulcerative colitis or Crohn's disease in the IBD Cohort of Uppsala Region cohort (n = 790) and hemoglobin levels at the time of diagnosis were eligible for inclusion. The WHO definition of anemia was used. RESULTS:: Seven hundred forty-nine (95%) of the patients with IBD were included. Five hundred eighty of 749 (77%) patients had measured hemoglobin levels at 12-month follow-up. The prevalence of anemia at the time of diagnosis was 227/749 (30%). After 1 year, it was 102/580 (18%). Anemia was more common among newly diagnosed patients with Crohn's disease compared with ulcerative colitis (42% versus 24%, P < 0.0001), but after 1 year, there was no difference (18% versus 18%, P = NS). Children had more often anemia compared with adults, both at diagnosis and after 1 year (diagnosis: 55% versus 27%, P < 0.0001; follow-up: 28% versus 16%, P < 0.05). Anemia was associated with colonic engagement in Crohn's disease and the extent of inflammation in ulcerative colitis. Only 46% of patients with anemia were treated with iron supplementation or blood transfusion. CONCLUSIONS:: The overall prevalence of anemia in patients with IBD at the time of diagnosis was high. A large proportion was still anemic after 1 year. Children were more at risk compared with adults. More efforts are needed to treat patients with anemia. |
Clostridium difficile and Pediatric Inflammatory Bowel Disease: A Prospective, Comparative, Multicenter, ESPGHAN Study. |
BACKGROUND:: Clostridium difficile (C. difficile) infection is associated with pediatric inflammatory bowel disease (IBD) in several ways. We sought to investigate C. difficile infection in pediatric patients with IBD in comparison with a group of children with celiac disease and to evaluate IBD disease course of C. difficile infected patients. METHODS:: In this prospective, comparative, multicenter study, 211 pediatric patients with IBD were enrolled from October 2010 to October 2011 and tested for the presence of C. difficile toxins A and B in their stools at 0, 6, and 12 months. During the same study period, stool specimens for C. difficile toxins analysis were collected from 112 children with celiac disease as controls. RESULTS:: Clostridium difficile occurrence was significantly higher in patients with IBD compared with patients with celiac disease (7.5% versus 0.8%; P = 0.008). Clostridium difficile was associated with active disease in 71.4% of patients with IBD (P = 0.01). Colonic involvement was found in 85.7% of patients with C. difficile. Antibiotics, proton pump inhibitors, hospitalization, and IBD therapies were not associated with increased C. difficile detection. At 12 months, a higher number of C. difficile-positive patients at the enrollment started immunosuppressant/biological therapy compared with patients without C. difficile (P = 0.01). At 6 and 12 months, patients with C. difficile were more frequently in active disease than patients without C. difficile (P = 0.04; P = 0.08, respectively). Hospitalizations were higher at 6 months in C. difficile group (P = 0.05). CONCLUSIONS:: In conclusion, this study demonstrates that pediatric IBD is associated with increased C. difficile detection. Patients with C. difficile tend to have active colonic disease and a more severe disease course. |
Neutrophil/Lymphocyte Ratio Is Associated with Non-Calcified Plaque Burden in Patients with Coronary Artery Disease. |
BACKGROUND: Elevations in soluble markers of inflammation and changes in leukocyte subset distribution are frequently reported in patients with coronary artery disease (CAD). Lately, the neutrophil/lymphocyte ratio has emerged as a potential marker of both CAD severity and cardiovascular prognosis. OBJECTIVES: The aim of the study was to investigate whether neutrophil/lymphocyte ratio and other immune-inflammatory markers were related to plaque burden, as assessed by coronary computed tomography angiography (CCTA), in patients with CAD. METHODS: Twenty patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and 30 patients with stable angina (SA) underwent CCTA at two occasions, immediately prior to coronary angiography and after three months. Atherosclerotic plaques were classified as calcified, mixed and non-calcified. Blood samples were drawn at both occasions. Leukocyte subsets were analyzed by white blood cell differential counts and flow cytometry. Levels of C-reactive protein (CRP) and interleukin(IL)-6 were measured in plasma. Blood analyses were also performed in 37 healthy controls. RESULTS: Plaque variables did not change over 3 months, total plaque burden being similar in NSTE-ACS and SA. However, non-calcified/total plaque ratio was higher in NSTE-ACS, 0.25(0.09-0.44) vs 0.11(0.00-0.25), p<0.05. At admission, levels of monocytes, neutrophils, neutrophil/lymphocyte ratios, CD4+ T cells, CRP and IL-6 were significantly elevated, while levels of NK cells were reduced, in both patient groups as compared to controls. After 3 months, levels of monocytes, neutrophils, neutrophil/lymphocyte ratios and CD4+ T cells remained elevated in patients. Neutrophil/lymphocyte ratios and neutrophil counts correlated significantly with numbers of non-calcified plaques and also with non-calcified/total plaque ratio (r = 0.403, p = 0.010 and r = 0.382, p = 0.024, respectively), but not with total plaque burden. CONCLUSIONS: Among immune-inflammatory markers in NSTE-ACS and SA patients, neutrophil counts and neutrophil/lymphocyte ratios were significantly correlated with non-calcified plaques. Data suggest that these easily measured biomarkers reflect the burden of vulnerable plaques in CAD. |
Dynamic Contrast Enhanced MRI Detects Early Response to Adoptive NK Cellular Immunotherapy Targeting the NG2 Proteoglycan in a Rat Model of Glioblastoma. |
There are currently no established radiological parameters that predict response to immunotherapy. We hypothesised that multiparametric, longitudinal magnetic resonance imaging (MRI) of physiological parameters and pharmacokinetic models might detect early biological responses to immunotherapy for glioblastoma targeting NG2/CSPG4 with mAb9.2.27 combined with natural killer (NK) cells. Contrast enhanced conventional T1-weighted MRI at 7+/-1 and 17+/-2 days post-treatment failed to detect differences in tumour size between the treatment groups, whereas, follow-up scans at 3 months demonstrated diminished signal intensity and tumour volume in the surviving NK+mAb9.2.27 treated animals. Notably, interstitial volume fraction (ve), was significantly increased in the NK+mAb9.2.27 combination therapy group compared mAb9.2.27 and NK cell monotherapy groups (p = 0.002 and p = 0.017 respectively) in cohort 1 animals treated with 1 million NK cells. ve was reproducibly increased in the combination NK+mAb9.2.27 compared to NK cell monotherapy in cohort 2 treated with increased dose of 2 million NK cells (p<0.0001), indicating greater cell death induced by NK+mAb9.2.27 treatment. The interstitial volume fraction in the NK monotherapy group was significantly reduced compared to mAb9.2.27 monotherapy (p<0.0001) and untreated controls (p = 0.014) in the cohort 2 animals. NK cells in monotherapy were unable to kill the U87MG cells that highly expressed class I human leucocyte antigens, and diminished stress ligands for activating receptors. A significant association between apparent diffusion coefficient (ADC) of water and ve in combination NK+mAb9.2.27 and NK monotherapy treated tumours was evident, where increased ADC corresponded to reduced ve in both cases. Collectively, these data support histological measures at end-stage demonstrating diminished tumour cell proliferation and pronounced apoptosis in the NK+mAb9.2.27 treated tumours compared to the other groups. In conclusion, ve was the most reliable radiological parameter for detecting response to intralesional NK cellular therapy. |
POSTOPERATIVE CYSTOGRAM FINDINGS PREDICT INCONTINENCE FOLLOWING ROBOT-ASSISTED RADICAL PROSTATECTOMY. |
Introduction: The factors that contribute to continence following robot-assisted radical prostatectomy (RARP) are currently being investigated. The purpose of this study is to determine the relationship of the bladder neck location on postoperative cystogram to subsequent continence rates following RARP. Materials and Methods: A retrospective review of 611 consecutive RARP patients identified 215 patients with a postoperative cystogram. A ratio was created by measuring the distance from the superior edge of the pubic symphysis to the bladder neck and dividing it by the total pubic symphysis height, termed bladder neck to pubic symphysis ratio (BNPS). Odds ratios with 95% confidence intervals were calculated for the relationship between incontinence and BNPS tertile categories. Results: At 3 month follow-up, continent patients had a mean BNPS ratio of 0.39 (95% C.I. 0.35-0.43), while incontinent patients had a mean BNPS ratio of 0.49 (95% C.I. 0.42-0.56; p=0.01). At 12 months, the mean BNPS ratio was 0.40 (95% C.I. 0.37-0.44) for continent patients, whereas incontinent patients had a mean BNPS ratio of 0.60 (95% C.I. 0.43-0.77; p=0.001). When analyzed as tertile groups, the corresponding incontinence rates at 12 months, were 2.8%, 2.8%, and 19.4% for the lowest, middle and highest BNPS tertiles, respectively. Conclusions: Post-prostatectomy bladder neck location defined by the BNPS ratio on cystogram correlates with continence rates and may predict patients at risk for prolonged incontinence. Efforts designed to preserve support of the bladder neck and sphincteric complex in relation to the pubic symphysis may improve both early and late continence. |
An Image-Based Genetic Assay Identifies Genes in T1D Susceptibility Loci Controlling Cellular Antiviral Immunity in Mouse. |
The pathogenesis of complex diseases, such as type 1 diabetes (T1D), derives from interactions between host genetics and environmental factors. Previous studies have suggested that viral infection plays a significant role in initiation of T1D in genetically predisposed individuals. T1D susceptibility loci may therefore be enriched in previously uncharacterized genes functioning in antiviral defense pathways. To identify genes involved in antiviral immunity, we performed an image-based high-throughput genetic screen using short hairpin RNAs (shRNAs) against 161 genes within T1D susceptibility loci. RAW 264.7 cells transduced with shRNAs were infected with GFP-expressing herpes simplex virus type 1 (HSV-1) and fluorescent microscopy was performed to assess the viral infectivity by fluorescence reporter activity. Of the 14 candidates identified with high confidence, two candidates were selected for further investigation, Il27 and Tagap. Administration of recombinant IL-27 during viral infection was found to act synergistically with interferon gamma (IFN-gamma) to activate expression of type I IFNs and proinflammatory cytokines, and to enhance the activities of interferon regulatory factor 3 (IRF3). Consistent with a role in antiviral immunity, Tagap-deficient macrophages demonstrated increased viral replication, reduced expression of proinflammatory chemokines and cytokines, and decreased production of IFN-beta. Taken together, our unbiased loss-of-function genetic screen identifies genes that play a role in host antiviral immunity and delineates roles for IL-27 and Tagap in the production of antiviral cytokines. |
Right or Left: The Role of Nanoparticles in Pulmonary Diseases. |
Due to the rapid development of the nanotechnology industry in the last decade, nanoparticles (NPs) are omnipresent in our everyday life today. Many nanomaterials have been engineered for medical purposes. These purposes include therapy for pulmonary diseases. On other hand, people are endeavoring to develop nanomaterials for improvement or replacement of traditional therapies. On the other hand, nanoparticles, as foreign material in human bodies, are reported to have potential adverse effects on the lung, including oxidase stress, inflammation, fibrosis and genotoxicity. Further, these damages could induce pulmonary diseases and even injuries in other tissues. It seems that nanoparticles may exert two-sided effects. Toxic effects of nanomaterials should be considered when their use is developed for therapies. Hence this review will attempt to summarize the two-side roles of nanoparticles in both therapies for pulmonary diseases and initiation of lung diseases and even secondary diseases caused by lung injuries. Determinants of these effects such as physicochemical properties of nanoparticles will also be discussed. |
Discovery and in Vivo Evaluation of Novel RGD-Modified Lipid-Polymer Hybrid Nanoparticles for Targeted Drug Delivery. |
In the current study, the lipid-shell and polymer-core hybrid nanoparticles (lpNPs) modified by Arg-Gly-Asp(RGD) peptide, loaded with curcumin (Cur), were developed by emulsification-solvent volatilization method. The RGD-modified hybrid nanoparticles (RGD-lpNPs) could overcome the poor water solubility of Cur to meet the requirement of intravenous administration and tumor active targeting. The obtained optimal RGD-lpNPs, composed of PLGA (poly(lactic-co-glycolic acid))-mPEG (methoxyl poly(ethylene- glycol)), RGD-polyethylene glycol (PEG)-cholesterol (Chol) copolymers and lipids, had good entrapment efficiency, submicron size and negatively neutral surface charge. The core-shell structure of RGD-lpNPs was verified by TEM. Cytotoxicity analysis demonstrated that the RGD-lpNPs encapsulated Cur retained potent anti-tumor effects. Flow cytometry analysis revealed the cellular uptake of Cur encapsulated in the RGD-lpNPs was increased for human umbilical vein endothelial cells (HUVEC). Furthermore, Cur loaded RGD-lpNPs were more effective in inhibiting tumor growth in a subcutaneous B16 melanoma tumor model. The results of immunofluorescent and immunohistochemical studies by Cur loaded RGD-lpNPs therapies indicated that more apoptotic cells, fewer microvessels, and fewer proliferation-positive cells were observed. In conclusion, RGD-lpNPs encapsulating Cur were developed with enhanced anti-tumor activity in melanoma, and Cur loaded RGD-lpNPs represent an excellent tumor targeted formulation of Cur which might be an attractive candidate for cancer therapy. |
A Proteomic Analysis of Human Follicular Fluid: Comparison between Younger and Older Women with Normal FSH Levels. |
The follicular fluid (FF) is produced during folliculogenesis and contains a variety of proteins that play important roles in follicle development and oocyte maturation. Age-related infertility is usually considered as a problem that can be solved by assisted reproduction technology. Therefore, the identi fi cation of novel biomarkers that are linked to reproductive aging is the subject of this study. FF was obtained from healthy younger (20-32 years old) and older (38-42 years old) women undergoing intracytoplasmic sperm injection (ICSI) due to male factor infertility. The FF was analyzed by two-dimensional gel electrophoresis (2-DE). The power of two-dimensional gel electrophoresis and the identi fi cation of proteins were exploited using matrix-assisted laser desorption-ionization time-of-flight/time-of-flight (MALDI-TOF-TOF) mass spectrometry. Twenty three protein spots showed reproducible and significant changes in the aged compared to the young group. Of these, 19 protein spots could be identified using MALDI-TOF-TOF-MS. As a result of MASCOT search, five unique downregulated proteins were identified in the older group. These were identified as serotransferrin, hemopexin precursor, complement C3, C4 and kininogen. A number of protein markers were found that may help develop diagnostic methods of infertility. |
A Functional Polymorphism in the 3'-UTR of PXR Interacts with Smoking to Increase Lung Cancer Risk in Southern and Eastern Chinese Smoker. |
Pregnane X receptor (PXR) is an important member of the nuclear receptor superfamily that copes with various endobiotic and xenobiotic stimuli, such as carcinogens by regulating an array of environmental response genes. Low PXR expression has been shown to promote tumor initiation and metastasis. The aim of the current study was to investigate whether the single nucleotide polymorphisms (SNPs) of PXR could alter lung cancer susceptibility in Chinese by affecting the function or expression of PXR. We genotyped three putatively functional SNPs of PXR (i.e., rs3814055C>T, rs3732360C>T, and rs3814058C>T) and analyzed their associations with lung cancer risk in a two-stage case-control study with a total of 1559 lung cancer cases and 1679 controls in the southern and eastern Chinese population. We found that in comparison to the rs3814058CC common genotype, the rs3814058T variants (TC/TT) which is located in the 3'-untranslated region (3'-UTR) of PXR conferred a consistently increased risk of lung cancer in both the southern Chinese (odd ratios (OR) = 1.24, 95% confidence interval (CI) = 1.03-1.49) and the eastern Chinese (OR = 1.33, 95% CI = 1.02-1.75). The variants also significantly interacted with smoking on increasing cancer risk (p = 0.023). Moreover, lung cancer tissues with the rs3814058T variants showed significantly lower PXR expression than those with rs3814058CC genotype in the smokers (p = 0.041). These results suggested that the rs3814058C>T polymorphism of PXR interacts with smoking on increasing lung cancer risk in Chinese smokers, which might be a functional genetic biomarker for lung cancer. |
The Biological Function and Clinical Utilization of CD147 in Human Diseases: A Review of the Current Scientific Literature. |
CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions. CD147 is also important to many organ systems. This review will provide a detailed overview of the discovery, characterization, molecular structure, diverse biological functions and regulatory mechanisms of CD147 in human physiological and pathological processes. In particular, recent studies have demonstrated the potential application of CD147 not only as a phenotypic marker of activated regulatory T cells but also as a potential diagnostic marker for early-stage disease. Moreover, CD147 is recognized as an effective therapeutic target for hepatocellular carcinoma (HCC) and other cancers, and exciting clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies. |
Gender-Associated Genomic Differences in Colorectal Cancer: Clinical Insight from Feminization of Male Cancer Cells. |
Gender-related differences in colorectal cancer (CRC) are not fully understood. Recent studies have shown that CRC arising in females are significantly associated with CpG island methylator phenotype (CIMP-high). Using array comparative genomic hybridization, we analyzed a cohort of 116 CRCs (57 males, 59 females) for chromosomal copy number aberrations (CNA) and found that CRC in females had significantly higher numbers of gains involving chromosome arms 1q21.2-q21.3, 4q13.2, 6p21.1 and 16p11.2 and copy number losses of chromosome arm 11q25 compared to males. Interestingly, a subset of male CRCs (46%) exhibited a "feminization" phenomenon in the form of gains of X chromosomes (or an arm of X) and/or losses of the Y chromosome. Feminization of cancer cells was significantly associated with microsatellite-stable CRCs (p-value 0.003) and wild-type BRAF gene status (p-value 0.009). No significant association with other clinicopathological parameters was identified including disease-free survival. In summary, our data show that some CNAs in CRC may be gender specific and that male cancers characterized by feminization may constitute a specific subset of CRCs that warrants further investigation. |
Effect of APE1 T2197G (Asp148Glu) Polymorphism on APE1, XRCC1, PARP1 and OGG1 Expression in Patients with Colorectal Cancer. |
It has been hypothesized that genetic variation in base excision repair (BER) might modify colorectal adenoma risk. Thus, we evaluated the influence of APE1 T2197G (Asp148Glu) polymorphism on APE1, XRCC1, PARP1 and OGG1 expression in normal and tumor samples from patients with colorectal cancer. The results indicate a downregulation of OGG1 and an upregulation of XRCC1 expression in tumor tissue. Regarding the anatomical location of APE1, OGG1 and PARP-1, a decrease in gene expression was observed among patients with cancer in the rectum. In patients with or without some degree of tumor invasion, a significant downregulation in OGG1 was observed in tumor tissue. Interestingly, when taking into account the tumor stage, patients with more advanced grades (III and IV) showed a significant repression for APE1, OGG1 and PARP-1. XRCC1 expression levels were significantly enhanced in tumor samples and were correlated with all clinical and histopathological data. Concerning the polymorphism T2197G, GG genotype carriers exhibited a significantly reduced expression of genes of the BER repair system (APE1, XRCC1 and PARP1). In summary, our data show that patients with colorectal cancer present expression changes in several BER genes, suggesting a role for APE1, XRCC1, PARP1 and OGG1 and APE1 polymorphism in colorectal carcinogenesis. |
Correcting Age-Related Changes in the Face by Use of Injectable Fillers and Neurotoxins. |
Many patients seeking rejuvenation treatment have readily apparent age-related changes in facial features. Others exhibit more subtle changes that nonetheless can be corrected to achieve a more youthful appearance. In the following article, four specialists in aesthetic dermatology discuss how injectable hyaluronic acid-based fillers and neurotoxins can achieve rejuvenation without surgery. |
Data on the Safety of Psoriasis Therapies. |
Safety remains paramount to the clinical utility of a therapy. Evaluation of safety is an ongoing process that does not end when a therapy becomes commercially available. This article reviews recent data pertaining to the safety profile of two therapeutic classes widely used in the treatment of psoriasis: inhibitors of tumor necrosis factor-alpha and agents that target interleukin-12/23. |
Therapeutic Development in Psoriasis. |
Advances in molecular biology have provided the basis for development of new therapeutic approaches to psoriasis. New, more effective therapies target specific molecules in the inflammatory cascade involved in the pathogenesis of psoriasis.The biologic era of psoriasis therapy began with inhibitors of T-cell activation, tumor necrosis factor-alpha, and interleukin (IL)-12/23. Continued investigation has led to therapies and therapeutic candidates that target IL-17, IL-23, phosphodiesterase-4, and isomers of Janus kinase. |
The Role of TNF Inhibitors in Psoriatic Disease. |
In contrast to many other diseases, modern psoriasis therapy has a fairly brief history. Until about 15 years ago, clinicians and their patients had few options, with limited ability to rein in the disease process.The success of antifolate methotrexate in the treatment of rheumatoid arthritis (RA) led to clinical evaluation and adoption of the agent, a principal form of treatment for psoriasis, which, like RA, has its origin based in inflammation. The introduction of tumor necrosis factor-alpha inhibitors marked the beginning of the biologic era of psoriasis therapy. Also borrowed from the field of rheumatology, biologic therapy has evolved from improved understanding of the molecular basis of the disease process. An increased recognition of comorbid conditions that often accompany psoriasis, particularly psoriatic arthritis, can complicate clin-ical management. Dermatologists and other clinicians who treat psoriasis continue to benefit from insights gained in the field of rheumatology. |
ZFC3H1, a Zinc Finger Protein, Modulates IL-8 Transcription by Binding with Celastramycin A, a Potential Immune Suppressor. |
Celastramycin A, a small molecule that inhibits the production of antibacterial peptides in an ex vivo culture system of Drosophila, suppresses the TNFalpha-mediated induction of IL-8 in mammalian cells. To understand its molecular mechanism, we examined Celastramycin A binding proteins and investigated their biological functions. Our screening and subsequent pull-down assay revealed ZFC3H1 (also known as CCDC131 or CSRC2), an uncharacterized zinc finger protein, as a Celastramycin A binding protein. The knockdown of ZFC3H1 reduced IL-8 expression levels in the TNFalpha-stimulated lung carcinoma cell line, LU99, and UV-irradiated HeLa cells. Based on reporter assay results, we concluded that ZFC3H1 participates in the transcriptional activation of IL-8. The findings of our UV-irradiation experiments implied that ZFC3H1 may indirectly interact with ERCC1 in an activated DNA repair complex. Thus, we designated ZFC3H1 as a mammalian target of Celastramycin A (mTOC). |
Glioma: Application of Whole-Tumor Texture Analysis of Diffusion-Weighted Imaging for the Evaluation of Tumor Heterogeneity. |
BACKGROUND AND PURPOSE: To apply a texture analysis of apparent diffusion coefficient (ADC) maps to evaluate glioma heterogeneity, which was correlated with tumor grade. MATERIALS AND METHODS: Forty patients with glioma (WHO grade II (n = 8), grade III (n = 10) and grade IV (n = 22)) underwent diffusion-weighted imaging (DWI), and the corresponding ADC maps were obtained. Regions of interest containing the lesions were drawn on every section of the ADC map containing the tumor, and volume-based data of the entire tumor were constructed. Texture and first order features including entropy, skewness and kurtosis were derived from the ADC map using in-house software. A histogram analysis of the ADC map was also performed. The texture and histogram parameters were compared between low-grade and high-grade gliomas using an unpaired student's t-test. Additionally, a one-way analysis of variance analysis with a post-hoc test was performed to compare the parameters of each grade. RESULTS: Entropy was observed to be significantly higher in high-grade gliomas than low-grade tumors (6.861+/-0.539 vs. 6.261+/-0.412, P = 0.006). The fifth percentiles of the ADC cumulative histogram also showed a significant difference between high and low grade gliomas (836+/-235 vs. 1030+/-185, P = 0.037). Only entropy proved to be significantly different between grades III and IV (6.295+/-0.4963 vs. 7.119+/-0.3165, P<0.001). The diagnostic accuracy of ADC entropy was significantly higher than that of the fifth percentile of the ADC histogram (P = 0.0034) in distinguishing high- from low-grade glioma. CONCLUSION: A texture analysis of the ADC map based on the entire tumor volume can be useful for evaluating glioma grade, which provides tumor heterogeneity. |
IgM-Antibodies against Phosphorylcholine in Mothers and Normal or Low Birth Weight Term Newborn Infants. |
OBJECTIVE: To determine levels of athero-protective IgM antibodies against phosphorylcholine in mothers and term-born normal or low birth weight infants. APPROACH: Twenty three mother-infant pairs were studied, of whom 16 infants were within the normal weight range for gestational age (NGA; 3652[504] g) and 7 were small for gestational age (SGA; birth weight: 2715[255] g), the latter <2SD below the Swedish reference data mean for normal fetal growth. All infants were born at term (mean+/-SD 40.5+/-1.1 weeks). Serum was available from 6 mothers with SGA and 14 with NGA infants. Participating mothers were aged 34.0+/-3.9 years (no difference between groups). Fourteen neonates were boys and seven were girls. Levels of anti-PC IgM were determined by ELISA. RESULTS: Neonatal IgM anti-PC levels were low (undetectable in 8 infants out of which 3 were SGA) with a median of 76[range 0-2.51] U/ml. Maternal IgM anti-PC levels were significantly higher (median 7198[range: 25.32-656.0]) U/ml) and the proportion of mothers in highest quartile (>75th percentile) was larger in mothers of NGA-infants (43%) vs. those of SGA-infants (0%, p = 0.032). CONCLUSIONS: IgM anti-PC levels are low at birth, which suggests that these antibodies do not play a "housekeeping" role in immune function during fetal life/development, but arise predominately on exposure to external antigens after birth. Furthermore, low maternal IgM anti-PC levels may play a role in placental insufficiency, contributing to poor fetal growth and a small-for-date baby. This preliminary observation may have implications for the future risk of atherosclerosis/cardiovascular disease development in pregnant women and their offspring. |
Psoriatic Inflammation Facilitates the Onset of Arthritis in a Mouse Model. |
Psoriatic arthritis (PsA) is a seronegative, inflammatory joint disease associated with psoriasis. In most patients with PsA, skin lesions precede arthritis; however, the causality of skin inflammation for the development of arthritis remains unclear. Gp130F759/F759 knock-in (F759) mice develop autoimmune arthritis after 1 year of age through persistent Stat3 activation due to impairment in SOCS3-dependent negative regulation. Here, we crossed F759 mice with K5.Stat3C transgenic mice, in which keratinocytes express constitutive active Stat3 (Stat3C) leading to generation of psoriasis-like skin change. F759 mice harboring the K5.Stat3C transgene not only had aggravated skin lesions but also spontaneously developed arthritis with high penetrance in adjacent paws as early as 3 weeks of age. The joint lesions included swelling of the peripheral paws and nail deformities contiguous with the skin lesions, closely resembling PsA. Histopathologic study revealed enthesitis and bone erosions, with mononuclear cell infiltrates. qRT-PCR, immunohistochemical analyses, and flow cytometry showed up-regulation of the IL-23/Th17 pathway in affected joints. Furthermore, enforced generation of psoriasis-like skin inflammation by topical treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) in F759 mice induced swelling of the underlying joints. This animal model renders psoriatic inflammation as the driver of arthritis and helps to further understand the pathogenesis of PsA.Journal of Investigative Dermatology accepted article preview online, 30 September 2014; doi:10.1038/jid.2014.426. |
CisMiner: Genome-Wide In-Silico Cis-Regulatory Module Prediction by Fuzzy Itemset Mining. |
Eukaryotic gene control regions are known to be spread throughout non-coding DNA sequences which may appear distant from the gene promoter. Transcription factors are proteins that coordinately bind to these regions at transcription factor binding sites to regulate gene expression. Several tools allow to detect significant co-occurrences of closely located binding sites (cis-regulatory modules, CRMs). However, these tools present at least one of the following limitations: 1) scope limited to promoter or conserved regions of the genome; 2) do not allow to identify combinations involving more than two motifs; 3) require prior information about target motifs. In this work we present CisMiner, a novel methodology to detect putative CRMs by means of a fuzzy itemset mining approach able to operate at genome-wide scale. CisMiner allows to perform a blind search of CRMs without any prior information about target CRMs nor limitation in the number of motifs. CisMiner tackles the combinatorial complexity of genome-wide cis-regulatory module extraction using a natural representation of motif combinations as itemsets and applying the Top-Down Fuzzy Frequent- Pattern Tree algorithm to identify significant itemsets. Fuzzy technology allows CisMiner to better handle the imprecision and noise inherent to regulatory processes. Results obtained for a set of well-known binding sites in the S. cerevisiae genome show that our method yields highly reliable predictions. Furthermore, CisMiner was also applied to putative in-silico predicted transcription factor binding sites to identify significant combinations in S. cerevisiae and D. melanogaster, proving that our approach can be further applied genome-wide to more complex genomes. CisMiner is freely accesible at: http://genome2.ugr.es/cisminer. CisMiner can be queried for the results presented in this work and can also perform a customized cis-regulatory module prediction on a query set of transcription factor binding sites provided by the user. |
CD4+ T Cells Expressing Latency-Associated Peptide and Foxp3 Are an Activated Subgroup of Regulatory T Cells Enriched in Patients with Colorectal Cancer. |
Latency-associated peptide (LAP) - expressing regulatory T cells (Tregs) are important for immunological self-tolerance and immune homeostasis. In order to investigate the role of LAP in human CD4+Foxp3+ Tregs, we designed a cross-sectional study that involved 42 colorectal cancer (CRC) patients. The phenotypes, cytokine-release patterns, and suppressive ability of Tregs isolated from peripheral blood and tumor tissues were analyzed. We found that the population of LAP-positive CD4+Foxp3+ Tregs significantly increased in peripheral blood and cancer tissues of CRC patients as compared to that in the peripheral blood and tissues of healthy subjects. Both LAP+ and LAP- Tregs had a similar effector/memory phenotype. However, LAP+ Tregs expressed more effector molecules, including tumor necrosis factor receptor II, granzyme B, perforin, Ki67, and CCR5, than their LAP- negative counterparts. The in vitro immunosuppressive activity of LAP+ Tregs, exerted via a transforming growth factor-beta-mediated mechanism, was more potent than that of LAP- Tregs. Furthermore, the enrichment of LAP+ Treg population in peripheral blood mononuclear cells (PBMCs) of CRC patients correlated with cancer metastases. In conclusion, we found that LAP+ Foxp3+ CD4+ Treg cells represented an activated subgroup of Tregs having more potent regulatory activity in CRC patients. The increased frequency of LAP+ Tregs in PBMCs of CRC patients suggests their potential role in controlling immune response to cancer and presents LAP as a marker of tumor-specific Tregs in CRC patients. |
Characteristics of nonylphenol and bisphenol A accumulation by fish and implications for ecological and human health. |
Fish populations constitute an important part of aquatic ecosystems. Thus, their accumulation of nonylphenol (NP) and bisphenol A (BPA) may pose risks to ecosystems and human health. This study analyzed the concentrations of NP and BPA in four types of fishes (i.e., wild/farmed freshwater fishes and wild/farmed marine fishes). Wild freshwater fishes contained higher concentrations of NP and BPA than the other three types of fishes. The concentrations of NP in the wild freshwater fishes ranged from 1.01 to 277mug/kg ww, with bioconcentration factors (BCFs) and biota-sediment accumulation factors (BSAFs) ranging from 74.0 to 2.60x104L/kg and from 0.003 to 18.3, respectively. The wild freshwater fishes contained relatively low amounts of BPA, varying from ND to 25.2mug/kg ww, with the BCFs and BSAFs ranging from 1.00 to 274L/kg and from 0.003 to 3.40, respectively. Five fish species particularly showed high BCFs and BSAFs, indicating that they could be an important source of NP for higher trophic levels, most likely resulting in ecological risks. The demersal fishes showed a greater ability to accumulate NP than the pelagic ones. The fact that the 95th percentile values of the risk quotient (RQ) for NP and BPA were higher than the acceptable threshold indicated that these two compounds would have adverse effects on aquatic organisms in Taiwanese rivers. The consumption of wild marine fishes had the highest 95th percentile values of hazard quotient (HQ) for NP and BPA among the four types of fishes, particularly for the population aged 0-3years. However, the 95th percentile values of HQ for NP and BPA were all less than 1, suggesting that exposure to NP and BPA through fish consumption posed no remarkable risk to human health in Taiwan. |
Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial. |
Abstract In vitro fertilization (IVF) cycles generate abnormalities in luteal-phase sex steroid concentrations and this represent an important limiting factor to achieve a good pregnancy rate. Although there are evidences about the usefulness of luteal phase support (LPS) after IVF cycles, no consensus exist about the best dose and way of progesterone (PG) administration, the advantages of estradiol (E2) supplementation and which IVF protocol could benefit from one more than other LPS scheme. Aim of the study was to assess the best LPS (low-dose PG, high-dose PG, high-dose PG and E2 supplementation) to achieve the highest clinical/ongoing pregnancy rate according to stimulation protocol, E2 at ovulation induction, endometrial thickness at pick-up and women's age. We conducted a randomized trial on 360 women undergoing IVF (180 treated by long-GnRH agonist, 90 by short-GnRH agonist and 90 by short-GnRH antagonist protocol) and stimulated by recombinant follicle-stimulating hormone alone. Our data demonstrated that high-dose PG is better than low-dose to increase both clinical and ongoing pregnancy rate. E2 supplementation are mandatory in case of short-GnRH antagonist protocol and strongly suggested in all protocols when E2max <5 nmol/l and endometrial thickness <10 mm. In long-GnRH agonist protocols, as well as in patients >35 years, the real advantages of E2 supplementation remain debatable and require further confirmation. |
The menstrual cycle regularization following d-chiro-inositol treatment in PCOS women: a retrospective study. |
Abstract Polycystic ovary syndrome is characterized by irregular cycles, hyperandrogenism, polycystic ovary at ultrasound and insulin resistance. The effectiveness of d-chiro-inositol (DCI) treatment in improving insulin resistance in PCOS patients has been confirmed in several reports. The objective of this study was to retrospectively analyze the effect of DCI on menstrual cycle regularity in PCOS women. This was a retrospective study of patients with irregular cycles who were treated with DCI. Of all PCOS women admitted to our centre, 47 were treated with DCI and had complete medical charts. The percentage of women reporting regular menstrual cycles significantly increased with increasing duration of DCI treatment (24% and 51.6% at a mean of 6 and 15 months of treatment, respectively). Serum AMH levels and indexes of insulin resistance significantly decreased during the treatment. Low AMH levels, high HOMA index, and the presence of oligomenorrhea at the first visit were the independent predictors of obtaining regular menstrual cycle with DCI. In conclusion, the use of DCI is associated to clinical benefits for many women affected by PCOS including the improvement in insulin resistance and menstrual cycle regularity. Responders to the treatment may be identified on the basis of menstrual irregularity and hormonal or metabolic markers. |
The role of free triiodothyronine in pathogenesis of infertility in levothyroxine-treated women with thyroid autoimmunity - a preliminary observational study. |
Abstract Introduction: The aim of this study was to analyze the possible role of free triiodothyronine (FT3) in infertility and in levothyroxine-treated (LT4) euthyroid women with Hashimoto thyroiditis (HT). Methods: It is an observational retrospective case control study. Twenty one euthyroid women with HT on LT4 replacement therapy and a medical history of idiopathic infertility were included into the study. To achieve higher FT3 level, the dose of LT4 was increased in every patient. Fifteen fertile women with HT on LT4 replacement therapy served as a control group. Results: At baseline in the study group mean thyroid stimulating hormone (TSH) level was 1.96 muU/ml +/- 0.84 muU/ml and mean FT3 was 4.07 pmol/l +/- 0.78 pmol/l. The mean TSH level after the increase of LT4 was 0.60 muU/ml +/- 0.45 muU/ml (p < 0.0001), and the mean FT3 was 5.12 pmol/l +/- 0.77 pmol/l (p = 0.0001). Baseline TSH in the study group was higher than in controls (p < 0.0001) and baseline FT3 in the study group was lower than in controls (p = 0.0003). Conclusions: Relatively low levels of FT3 in women with HT on LT4 replacement therapy may contribute to higher infertility rates. |
Trehalose- and glucose-derived glycoamphiphiles: small-molecule and nanoparticle Toll-like Receptor 4 (TLR4) modulators. |
An increasing number of pathologies have been linked to Toll-like Receptor 4 (TLR4) activation and signaling. New hit and lead compounds that target the TLR4 activation process are urgently needed. We report on the synthesis and biological properties of protonatable glycolipids based on glucose and trehalose scaffolds. Some of these compounds potently inhibit TLR4 activation and signaling in cells transfected with human and mouse variants of TLR4, MD-2 and CD14 receptors and are active in inhibiting TLR4-dependent cytokine production in vivo. Structure-activity relationship studies indicate that the presence of fatty ester chains in the molecule is a primary prerequisite for biological activity in this family of compounds and points to facial amphiphilicity as a preferred architecture for TLR4 antagonist design. Experimental data also support that single molecules, and not micellar aggregates, are the active species. Because the cationic glycolipids here presented exhibit negligible toxicity at their active concentrations, they can be considered as new lead compounds for the development of drugs targeting TLR4 activation and signaling in infectious, inflammatory and autoimmune diseases. Interestingly, the biological activity of the best drug candidate was retained after adsorption at the surface of colloidal gold nanoparticles, broadening the options for clinical development. |
Lexical tone and stuttering loci in Mandarin: Evidence from preschool children who stutter. |
Abstract The purpose of this study was to examine the relationship between stuttering loci and lexical tone in Mandarin-speaking preschoolers. Conversational samples from 20 Taiwanese children who stutter (CWS; M = 4:9; range = 3:2-6:4) were analysed for frequency and type of speech disfluency and lexical tone associated with stuttering-like disfluencies (SLDs). Results indicated that SLDs were significantly more likely to be produced on Mandarin syllables carrying Tone 3 and Tone 4 syllables compared to syllables carrying either Tone 1 or Tone 2. Post-hoc analyses revealed: (1) no significant differences in the stuttering frequencies between Tone 1 and Tone 2, or between Tone 3 and Tone 4, and (2) a higher incidence of stuttering on syllables carrying Tone 3 and Tone 4 embedded in conflicting (as opposed to compatible) tonal contexts. Results suggest that the higher incidence of stuttering on Mandarin syllables carrying either Tone 3 or 4 may be attributed to the increased level of speech motor demand underlying rapid F0 change both within and across syllables. |
The Postconcussion Symptom Scale: Utility of a Three-Factor Structure. |
PURPOSE: To determine the factor structure of a 19-item Post-Concussion Symptom Scale (PCSS) and examine associations between factor scores and gender, previous history of concussion, and length of time since injury. METHODS: Retrospective medical record review of pediatric patients with concussion seen in a sports medicine clinic from April 2008 to September 2012. We performed an exploratory factor analysis (EFA) followed by a confirmatory factor analysis (CFA). Analysis of variance (ANOVA) and regression analysis were used to examine associations between factor scores and gender, previous history of concussion, mood disorder, anxiety disorder or attention deficit disorder (ADD), and length of time since injury. RESULTS: EFA supported a 3-factor solution for post-concussive symptoms employing 18 of the original 19 scale items. Factor 1 consisted of eight cognition-related items, factor 2 consisted of six somatic-related items, and factor 3 consisted of four emotional-related items. CFA results confirmed the unidimensionality of factors 1 (neurocognitive), 2 (somatic) and 3 (emotional), with factor 3 being considered borderline. Females and patients with anxiety disorders had significantly worse (higher) scores on all three factors. Patients seen more than 14 days following the concussive injury had worse (higher) factor 3 (emotional) scores than those seen fewer than 14 days after the injury. There was no significant difference in post-concussion symptom factor structures between those with and without a previous history of concussion. CONCLUSION: Our investigation demonstrates a consistent symptom 3-factor structure of the PCSS in pediatric patients with concussions. Females and patients with anxiety disorders had higher scores than males for all 3 factors. Patients seen more than 14 days following concussive injury had higher scores for emotional symptoms, suggesting that prolonged concussion symptoms may affect emotional health. |
Using Motivational Interviewing: Through Evidence-Based Health Coaching. |
To enhance compliance and achieve better outcomes, providers must actively engage their patients and caregivers in different ways than in the past. One strategy that has gained national attention is motivational interviewing through evidence-based health coaching. A closer look at this exciting new clinical skill reveals what it is, how it works, why it is so successful, and why our traditional patient approach has fallen short. |
Nfluenza 101: What You Need to Know. |
Each year, 5% to 20% of the U.S. population is infected with the influenza virus. The influenza season occurs annually between the months of October and May, with 3,000 to 49,000 influenza-related deaths each year. Since complications delay recuperation, those in high-risk groups need to be monitored carefully. High-risk groups are more vulnerable to severe illness and complications of the disease and include: people older than 65 years of age, children under 2 years of age, pregnant women, obese patients, and patients with other serious comorbid conditions. This article provides home healthcare clinicians with important information on influenza, how it is transmitted, influenza virus types and changes in the virus, signs and symptoms of complications, and measures to prevent the occurrence and transmission of influenza. |
Synthesis and Characterization of Novel 2-Amino-Chromene-Nitriles that Target Bcl-2 in Acute Myeloid Leukemia Cell Lines. |
The anti-apoptotic protein Bcl-2 is a well-known and attractive therapeutic target for cancer. In the present study the solution-phase T3P-DMSO mediated efficient synthesis of 2-amino-chromene-3-carbonitriles from alcohols, malanonitrile and phenols is reported. These novel 2-amino-chromene-3-carbonitriles showed cytotoxicity in human acute myeloid leukemia (AML) cell lines. Compound 4g was found to be the most bioactive, decreasing growth and increasing apoptosis of AML cells. Moreover, compound 4g (at a concentration of 5 microM) increased the G2/M and sub-G1 (apoptosis) phases of AML cells. The AML cells treated with compound 4g exhibited decreased levels of Bcl-2 and increased levels of caspase-9. In silico molecular interaction analysis showed that compound 4g shared a similar global binding motif with navitoclax (another small molecule that binds Bcl-2), however compound 4g occupies a smaller volume within the P2 hot spot of Bcl-2. The intermolecular pi-stacking interaction, direct electrostatic interactions, and docking energy predicted for 4g in complex with Bcl-2 suggest a strong affinity of the complex, rendering 4g as a promising Bcl-2 inhibitor for evaluation as a new anticancer agent. |
Simvastatin in the Acute Respiratory Distress Syndrome. |
Background Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS. Methods In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety. Results The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (+/-SD) number of ventilator-free days (12.6+/-9.9 with simvastatin and 11.5+/-10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4+/-11.1 and 17.8+/-11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug. Conclusions Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364 .). |
Chromium in Drinking Water: Association with Biomarkers of Exposure and Effect. |
An epidemiological cross-sectional study was conducted in Greece to investigate health outcomes associated with long-term exposure to chromium via drinking water. The study population consisted of 304 participants. Socio-demographics, lifestyle, drinking water intake, dietary habits, occupational and medical history data were recorded through a personal interview. Physical examination and a motor test were carried out on the individuals. Total chromium concentrations were measured in blood and hair of the study subjects. Hematological, biochemical and inflammatory parameters were determined in blood. Chromium in drinking water ranged from <0.5 to 90 mug.L-1 in all samples but one (220 mug.L-1), with a median concentration of 21.2 mug.L-1. Chromium levels in blood (median 0.32 mug.L-1, range <0.18-0.92 mug.L-1) and hair (median 0.22 mug.g-1, range 0.03-1.26 mug.g-1) were found within "normal range" according to the literature. Personal lifetime chromium exposure dose via drinking water, calculated from the results of the water analyses and the questionnaire data, showed associations with blood and hair chromium levels and certain hematological and biochemical parameters. Groups of subjects whose hematological or biochemical parameters were outside the normal range were not correlated with chromium exposure dose, except for groups of subjects with high triglycerides or low sodium. Motor impairment score was not associated with exposure to chromium. |
Impact of a collaborative interprofessional learning experience upon medical and social work students in geriatric health care. |
Abstract Interprofessional collaborative practice is increasingly recognized as an essential model in health care. This study lends preliminary support to the notion that medical students (including residents) and social work students develop a broader understanding of one another's roles and contributions to enhancing community-dwelling geriatric patients' health, and develop a more thorough understanding of the inherent complexities and unique aspects of geriatric health care. Wilcoxon Signed Rank Tests of participants' scores on the Index of Interdisciplinary Collaboration (IIC) indicated the training made significant changes to the students' perception of interprofessional collaboration. Qualitative analysis of participants' statements illustrated (1) benefits of the IPE experience, including complementary roles in holistic interventions; and (2) challenges to collaboration. The findings suggest that interprofessional educational experiences have a positive impact upon students' learning and strategies for enhanced care of geriatric patients. |
Effects of Home-Based Interval Walking Training on Thigh Muscle Strength and Aerobic Capacity in Female Total Hip Arthroplasty Patients: A Randomized, Controlled Pilot Study. |
Due to the reduced physical activity of patients who have undergone total hip arthroplasty (THA), there are no home-based exercise training regimens for preventing muscle atrophy and aerobic capacity impairment in these patients. We examined whether interval walking training (IWT) could prevented these issues. Twenty-eight female patients ( approximately 60 years of age) who had undergone THA more than 2 months prior were randomly divided into IWT (n = 14) and control (CNT, n = 14) groups. The IWT subjects trained at a target of 60 min of fast walking at >70% peak aerobic capacity for walking ([Formula: see text]O2peak) per wk for 12 wk, while those in the CNT maintained their previous sedentary life during the same period. We measured the energy expenditure of the daily physical activity, except during sleeping and bathing, every minute and every day during the intervention. We also measured the isometric knee extension (FEXT) and flexion (FFLX) forces, [Formula: see text]O2peak, and anaerobic threshold during the graded cycling exercise ([Formula: see text]O2AT) before and after the intervention. All subjects, except for one in IWT, completed the protocol. FFLX increased by 23% on the operated side (P = 0.003) and 14% on the non-operated side of IWT (P = 0.006), while it only increased on the operated side of CNT (P = 0.03). The [Formula: see text]O2peak and [Formula: see text]O2AT in IWT increased by 8% (P = 0.08) and 13% (P = 0.002), respectively, and these changes were significantly higher in the IWT than in CNT group (both, P<0.05). In conclusion, IWT might be an effective home-based training regimen for preventing the muscle atrophy from reduced daily physical activity in THA patients. TRIAL REGISTRATION: UMIN-CTR UMIN000013172. |
Nanoblinker: Brownian Motion Powered Bio-Nanomachine for FRET Detection of Phagocytic Phase of Apoptosis. |
We describe a new type of bio-nanomachine which runs on thermal noise. The machine is solely powered by the random motion of water molecules in its environment and does not ever require re-fuelling. The construct, which is made of DNA and vaccinia virus topoisomerase protein, can detect DNA damage by employing fluorescence. It uses Brownian motion as a cyclic motor to continually separate and bring together two types of fluorescent hairpins participating in FRET. This bio-molecular oscillator is a fast and specific sensor of 5'OH double-strand DNA breaks present in phagocytic phase of apoptosis. The detection takes 30 s in solution and 3 min in cell suspensions. The phagocytic phase is critical for the effective execution of apoptosis as it ensures complete degradation of the dying cells' DNA, preventing release of pathological, viral and tumor DNA and self-immunization. The construct can be used as a smart FRET probe in studies of cell death and phagocytosis. |