Two formulations of the agricultural pesticide adjuvant, Toximul, reduce the glycogen content of HepG2 cells.
Young mice exposed dermally to the Toximul (Tox) class of agricultural pesticide adjuvants have reduced levels of hepatic glycogen, a marker of subclinical toxicity. The present study determined whether these effects on glycogen also occurred in cultured HepG2 cells. Exposure (3 hr) to Tox resulted in significant, concentration-dependent glycogen reductions (up to 70%) relative to control values (76 +/- 3 microg glycogen/mg protein). These reductions did not appear to be due to loss of cell viability, and were reversible with Tox removal. Two different formulations of Tox (3409F and MP-A) differed significantly in the magnitudes of glycogen reduction in the HepG2 cells.


Vasoconstrictor hyporeactivity can be reversed by antioxidants in patients with advanced alcoholic cirrhosis of the liver and ascites.
Hyperdynamic circulation and systemic vasodilation complicate cirrhosis of the liver and are related to vasoconstrictor hyporeactivity. We investigated whether impaired vasoconstrictor responsiveness may be overcome by antioxidants in patients with decompensated alcoholic cirrhosis. Controlled clinical study. University setting. Nine patients with liver cirrhosis Child-Pugh grade C and nine healthy age-matched volunteers. Forearm blood flow responses to intra-arterial norepinephrine, angiotensin II, and the nitric oxide synthase inhibitor N-monomethyl-l-arginine were measured by strain-gauge plethysmography and compared between groups of patients. To assess the role of oxidative stress, the antioxidant vitamin C (24 mg/min) was administered locally into the brachial artery, and forearm blood flow responses were reassessed. Plasma concentrations of vitamin C were lower in patients with cirrhosis (p < .05). In patients with cirrhosis, the reactivity to norepinephrine and angiotensin II was markedly reduced (p < .05 vs. controls). Coadministration of vitamin C completely restored the potency of vasoconstrictors to that in controls but had no effect in healthy subjects. No changes were observed in time-control experiments in cirrhosis patients (n = 3) employing vehicle coinfusion. The response to N-monomethyl-L-arginine was comparable between groups and not affected by vitamin C. Oxidative stress with consumption of antioxidants seems to play an important role in the development of vasoconstrictor hyporeactivity in patients with cirrhosis. Antioxidant therapy may be a promising clinical approach to restore vasoconstrictor hyporeactivity in these patients.


Abdominal pseudocyst as a complication of ventriculoperitoneal shunt placement: Review of the literature and a proposed algorithm for treatment using 4 illustrative cases.
Ventriculoperitoneal (VP) shunt placement is one of the most commonly performed procedures in neurosurgery. One rare complication is the formation of an abdominal pseudocyst, which can cause shunt malfunction. We present four unique cases of abdominal pseudocyst formation. Our first patient initially presented with a right upper quadrant pseudocyst. Shunt was externalized and the distal end was revised with placement of catheter on the opposite side. He developed another pseudocyst within 5 months of shunt revision and developed another shunt failure. Our second patient had a history of shunt revisions and a known pseudocyst, presented with small bowel obstruction, and underwent laparotomy for the lysis of adhesions with improvement in his symptoms. After multiple readmissions for the same problem, it was thought that the pseudocyst was causing gastric outlet obstruction and his VP shunt was converted into a ventriculopleural shunt followed by percutaneous drainage of his pseudocyst. Our third patient developed hydrocephalus secondary to cryptococcal meningitis. He developed abdominal pain secondary to an abdominal pseudocyst, which was drained percutaneously with relief of symptoms. The fourth patient had a history of multiple shunt revisions and a previous percutaneous pseudocyst drainage that recurred with cellulitis and abscess secondary to hardware infection. Abdominal pseudocysts are a rare but important complication of VP shunt placement. Treatment depends on etiology, patient presentation, and clinical manifestations. Techniques for revision include distal repositioning of peritoneal catheter, revision of catheter into pleural space or right atrium, or removal of the shunt completely.


Mitigating human disturbance: can protection influence trajectories of recovery in benthic assemblages?
1. Understanding whether Marine Protected Areas (MPAs) can be considered as a suitable tool for restoring the structure and function of populations and assemblages is urgently needed to achieve an effective policy of mitigation of human impact in coastal management. However, to date, the role played by MPAs in enhancing ecosystems resilience has been more advocated than unambiguously documented. 2. This study was designed to test whether full protection in marine reserves facilitates recovery of benthos impacted by the date mussel Lithophaga lithophaga fishery, one of the most harmful human activities affecting subtidal rocky habitats in the Mediterranean Sea. 3. The effects of this destructive fishery were reproduced at one fully protected location (P) and at two unprotected control locations (Cs) in the SW Mediterranean Sea. At each location, three plots (4 m2) of rocky surface at 4-6 m depth were disturbed experimentally, while another three plots served as reference. In each plot, the species composition and relative cover of the sessile benthic assemblages were sampled photographically on each of five occasions during a period of 20 months. 4. Over and above variation in habitat features among locations, multivariate and univariate analyses revealed significant differences between P-vs.-Cs in patterns of assemblage recovery and showed that, at the fully protected location, recovery was faster than at the unprotected control locations. 5. Our results suggest that MPAs have the potential to change the trajectories of recovery of disturbed assemblages by accelerating the processes of recolonization and call for further investigation to identify the specific mechanisms underlying increased resilience.


Transcriptomic responses of Caco-2 cells to Lactobacillus rhamnosus GG and Lactobacillus plantarum J26 against oxidative stress.
Oxidative stress is the basic reason for aging and age-related diseases. In this study, we investigated the protective effect of 2 strains of lactic acid bacteria (LAB), Lactobacillus rhamnosus GG and L. plantarum J26, against oxidative stress in Caco-2 cells, and gave an overview of the mechanisms of lactic acid bacteria antioxidant activity using digital gene expression profiling. The 2 LAB strains provided significant protection against hydrogen peroxide (H2O2)-induced reduction in superoxide dismutase activity and increase in glutathione peroxidase activity in Caco-2 cells. However, inactive bacteria had little effect on alleviating oxidation stress in Caco-2 cells. Eight genes related to oxidative stress-FOSB, TNF, PPP1R15A, NUAK2, ATF3, TNFAIP3, EGR2, and FBN2-were significantly upregulated in H2O2-induced Caco-2 cells compared with untreated Caco-2 cells. After incubation of the H2O2-induced Caco-2 cells with L. rhamnosus GG and L. plantarum J26, 5 genes (TNF, EGR2, NUAK2, FBN2, and TNFAIP3) and 2 genes (NUAK2 and FBN2) were downregulated, respectively. In addition, the Kyoto Encyclopedia of Genes and Genomes indicated that some signaling pathways associated with inflammation, immune response, and apoptosis, such as Janus kinase/signal transducers and activators of transcription (Jak-STAT), mitogen-activated protein kinase (MAPK), nuclear factor-κB, and tumor necrosis factor, were all negatively modulated by the 2 strains, especially L. rhamnosus GG. In this paper, we reveal the mechanism of LAB in relieving oxidative stress and provide a theoretical basis for the rapid screening and evaluation of new LAB resources.


Self-assembly of silver-aminosilica nanocomposites through silver nanoparticle fusion on hydrophobic surfaces.
Silver-nanoparticle-embedded aminosilica colloids synthesized via aminosilane-induced spontaneous reduction reaction exhibit selective adhesion properties on hydrophobic surfaces and have been utilized as a simple and one-step procedure to create patterned nanocomposite film with silver to aminosilica mole ratio at 0.9:1. Substrates that enable self-assembly of the colloids include silicon wafer, polydimethylsiloxane, and microscope slide, where patterns of hydrophilic surface were either created using oxygen plasma treatment or stamped with chemical ink using microcontact printing. Upon substrates being immersed in a solution containing silver-aminosilica colloids, particles attach to hydrophobic surfaces and continuously self-assemble onto the deposited film, allowing us to fabricate nanocomposite patterns with controllable thickness (approximately 200 nm).


Changes in cardiac sympathetic nerve innervation and activity in pathophysiologic transition from typical to end-stage hypertrophic cardiomyopathy.
Left ventricular (LV) systolic function in hypertrophic cardiomyopathy (HCM) is usually normal. Late in the disease, however, LV systolic dysfunction and dilatation are recognized. Although abnormalities in cardiac sympathetic nerve activity in patients with HCM have been demonstrated using (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, the changes of cardiac sympathetic nerve activity throughout the clinical course from typical to end-stage HCM are unclear. The objective of this study was to evaluate the relationship between abnormalities on (123)I-MIBG myocardial scintigraphy and pathophysiologic changes in patients with HCM. We performed (123)I-MIBG scintigraphy on 46 patients with HCM and 18 age-matched control subjects. The patients were categorized into 3 groups: 28 patients with normal LV systolic function (group A), 9 patients with LV systolic dysfunction (group B), and 9 patients with LV systolic dysfunction and dilatation (group C). With planar (123)I-MIBG imaging, the heart-to-mediastinum ratio for early and delayed acquisitions and the washout rate were calculated. With SPECT, polar maps of the LV myocardium were divided into 20 segments. The regional uptake and washout rate were calculated from semiquantitative 20-segment bull's-eye analysis. The early uptake was significantly lower in group C than in the control group (P < 0.01). The washout rate was progressively higher in group A, group B, and group C (P < 0.01). Reduced regional early uptake was found in 2.9 +/- 3.4 (group A), 4.1 +/- 4.7 (group B), and 7.4 +/- 4.3 (group C) segments, respectively. In group C, regional early uptake was significantly reduced, predominantly in the interventricular septal wall, and regional washout rate was increased in the apex and lateral wall. These results suggest that cardiac sympathetic nerve abnormalities in patients with HCM may advance with development of LV systolic dysfunction and dilatation and that (123)I-MIBG myocardial scintigraphy may be a useful tool for the evaluation of pathophysiologic changes in HCM.


Iron chelation therapy in low risk myelodysplastic syndrome.
Anaemia is the commonest cytopenia seen in patients with myelodysplastic syndrome (MDS), and the majority of patients will require transfusion support at some point. Blood transfusions are rich in iron, which leads to the accumulation of body iron over time. It is accepted that this ultimately causes end organ damage and may impact on both morbidity and mortality. In addition, recent data has increased our interest in the subject with regard to the potential impact on stem cell transplant outcome and an anti-leukaemic effect of iron chelation therapy. There is still debate over which patients should receive iron chelation therapy, but the emergence of new diagnostic and prognostic markers in MDS may help decision making in the clinic setting.


Reduced insulin-like growth factor-I after acute feed restriction in lactating dairy cows is independent of changes in growth hormone receptor 1A mRNA.
Growth hormone receptor (GHR) and insulin-like growth factor-I (IGF-I) mRNA decrease in the liver of dairy cows at parturition. Epinephrine is released and feed intake is decreased at the same time. The objective of this study was to determine whether feed restriction and (or) administration of epinephrine could recapitulate the changes in the hepatic GHR 1A and IGF-I mRNA that occur at parturition. Eight lactating cows were randomly assigned to one of two rations (ad libitum or restricted). The cows assigned to the restricted ration were fed 75, 60, 60, and 25% of feed consumed by the ad libitum cows on successive days to mimic the changes in feed intake around parturition. Liver samples were collected by needle biopsy before and after feed restriction. Cows received either 0.02 mg/kg of epinephrine or saline approximately 24 h before the second liver biopsy so that a 2 x 2 factorial arrangement of treatments was created. Feed restriction increased plasma nonesterified fatty acids and liver triglyceride percentages and decreased plasma IGF-I concentrations. The decrease in plasma IGF-I after feed restriction was associated with a decrease in IGF-I mRNA in feed-restricted cows. The amount of GHR 1A mRNA did not change after feed restriction. Epinephrine treatment did not affect the amount of GHR 1A or IGF-I mRNA. We conclude that the decrease in feed intake at parturition may be partially responsible for the decrease in IGF-I but may not cause the decrease in GHR 1A.


Feasibility of Single - Encounter Telemedicine Lung Cancer Screening: A Retrospective Cohort Study in an Underserved Population.
COVID-19 forced a delay of non-essential health services, including lung cancer screening. Our institution developed a single-encounter, telemedicine (SET) lung cancer screening whereby patients receive low-dose CT in-person, but counseling regarding results, coordination of follow-up care and smoking cessation is delivered using telemedicine. This study compares outcomes of SET lung cancer screening to our pre-COVID, single-visit, in-person (SIP) lung cancer screening. A retrospective cohort study was performed we recorded independent variables of gender, race/ethnicity, age, educational attainment, smoking status and dependent variables including cancer diagnosis, stage and treatment between March 2019 to July 2021. Using retrospective analysis, we compared outcomes of SIP lung cancer screening before COVID-19 and SET lung cancer screening amid COVID-19. There was a significant difference in number of patients screened pre- and amid COVID-19.673 people were screened via SIP, while only 440 were screened via SET. SIP screening consisted of 52.5% Black/African American patients, which decreased to 37% with SET lung cancer screening. There was no significant difference in gender, age, or educational attainment. There was also no significant difference in Lung-RADS score between the 2 methods of screening or diagnostic procedures performed. Ultimately telemedicine based screening diagnosed fewer cancers, 1.6% diagnosed via telemedicine vs 3.3% screened by in person. We implemented SET lung cancer screening to continue lung cancer screening during a global pandemic. Our study established feasibility of telemedicine-based lung cancer screening among our predominantly African American/Black population, though fewer patients were screened. We found no difference in distribution between age, or educational attainment suggesting other factors discouraging lung cancer screening amid COVID-19.


Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network.
The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBötzinger Complex (preBötC). To unravel the cellular- and network-level consequences of MOR activation in the preBötC, MOR-expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBötC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: (1) pre-inspiratory spiking is reduced and (2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm-generating network particularly prone to collapse when challenged with exogenous opioids.


Automating cell detection and classification in human brain fluorescent microscopy images using dictionary learning and sparse coding.
Immunofluorescence (IF) plays a major role in quantifying protein expression in situ and understanding cell function. It is widely applied in assessing disease mechanisms and in drug discovery research. Automation of IF analysis can transform studies using experimental cell models. However, IF analysis of postmortem human tissue relies mostly on manual interaction, often subjected to low-throughput and prone to error, leading to low inter and intra-observer reproducibility. Human postmortem brain samples challenges neuroscientists because of the high level of autofluorescence caused by accumulation of lipofuscin pigment during aging, hindering systematic analyses. We propose a method for automating cell counting and classification in IF microscopy of human postmortem brains. Our algorithm speeds up the quantification task while improving reproducibility. Dictionary learning and sparse coding allow for constructing improved cell representations using IF images. These models are input for detection and segmentation methods. Classification occurs by means of color distances between cells and a learned set. Our method successfully detected and classified cells in 49 human brain images. We evaluated our results regarding true positive, false positive, false negative, precision, recall, false positive rate and F1 score metrics. We also measured user-experience and time saved compared to manual countings. We compared our results to four open-access IF-based cell-counting tools available in the literature. Our method showed improved accuracy for all data samples. The proposed method satisfactorily detects and classifies cells from human postmortem brain IF images, with potential to be generalized for applications in other counting tasks.


Why do couples discontinue unlimited free IVF treatments?
Worldwide, IVF is often discontinued before a live birth is achieved due to high costs. Even when partial financial coverage is provided, often medical providers advise treatment discontinuation. In Israel, unlimited IVF is offered free of charge for a couples' first two children. Our objective was to assess the reasons couples discontinue IVF treatments before achieving two children in a completely unlimited cost-free environment. This cohort study included all primary infertile women, <35 years, referred for their first IVF cycle to Sheba IVF unit between 2001 and 2002. Patients were followed until February 2012. Those who ceased treatments for 12 months were interviewed to assess the main reason they ceased treatments. Of the 134 couples included, only 46 ceased IVF treatments without achieving two children, after performing an average of 6.2 IVF cycles to achieve their first birth. The reasons given were: lost hope of success (13), psychological burden (18), divorce (6), medical staff recommendation (5), bureaucratic difficulties (3) and general medical condition (1). The main reasons for "drop out" in our cost-free environment were as follows: psychological burden and lost hope of success. Due to high availability of treatments, medical staff recommendation was a less significant factor in our study.


Identification of phenylcarbamoylazinane-1,3,4-oxadiazole amides as lipoxygenase inhibitors with expression analysis and in silico studies.
In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 µM, respectively, while excellent to moderate inhibitory profiles with IC50 values in the range of 26.13-98.21 µM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5-88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential 'lead' compounds in drug discovery and development.


Evaluation of ocular health among alachlor manufacturing workers.
Earlier toxicology studies found that one strain of rat (Long-Evans) developed severe ocular lesions when fed high doses of alachlor, a chloracetanilide active ingredient in some preemergent herbicides used for corn, soybean, and peanut crops. Because of a lack of eye effects in feeding studies conducted in dogs and other rodent species and strains, the effect was believed to be specific to Long-Evans rats. Nevertheless, to determine whether there were ocular effects among alachlor-exposed workers, we examined a group of the highest exposed alachlor production workers (n = 135) for the presence of a specific eye abnormality, analogous to the initiating lesion in Long-Evans rats, called pigmentary dispersion syndrome. A similar examination was given to unexposed coworkers and relatives (n = 84) to provide comparison rates. None of the exposed workers were found to have pigmentary dispersion syndrome, and prevalence rates for other eye abnormalities were similar for exposed and unexposed study participants. These results suggest that humans exposed to alachlor are not at increased risk of developing ocular disease.


Human microbiome research: Growing pains and future promises.
Human microbiome research is evolving from describing associations to understanding the impact of bioactive strains on humans. Despite challenges, progress is being made to apply data-driven microbiome diagnostics and interventions, potentially leading to precision medicine breakthroughs in the next decade.


Multioverlap simulations for transitions between reference configurations.
We introduce a procedure to construct weight factors, which flatten the probability density of the overlap with respect to some predefined reference configuration. This allows one to overcome free-energy barriers in the overlap variable. Subsequently, we generalize the approach to deal with the overlaps with respect to two reference configurations so that transitions between them are induced. We illustrate our approach by simulations of the brain peptide Met-enkephalin with the ECEPP/2 (Empirical Conformational Energy Program for Peptides) energy function using the global-energy-minimum and the second lowest-energy states as reference configurations. The free energy is obtained as functions of the dihedral and the root-mean-square distances from these two configurations. The latter allows one to identify the transition state and to estimate its associated free-energy barrier.


Investigation of clinical predictors of survival in idiopathic pulmonary fibrosis patients: A cohort study in Taiwan.
Two antifibrotic medications, pirfenidone and nintedanib, have been approved as treatments for idiopathic pulmonary fibrosis (IPF)-a life-threatening interstitial lung disease. However, there are insufficient current data regarding clinical predictors of survival for patients with IPF in the era of antifibrotics. We retrospectively analyzed the medical records of patients with IPF treated between April 2017 and May 2020. Univariate and multivariate Cox proportional hazard models were used to identify independent predictors of mortality among these patients with IPF. A total of 40 patients with IPF (average age, 75.58 ± 8.34 years) were included in the study, 27 (67.5%) of whom were treated with antifibrotic drugs. In the entire cohort, 14 (35%) patients died, and the overall survival of the study population was 48.52 ± 5 months (median, not applicable [NA] [29-NA] months). The univariate and multivariate Cox proportional hazard models indicated that chest tightness, finger clubbing, acute exacerbation after medication, decreased percentage forced vital capacity (%FVC), and decreased percentage 1-second forced expiratory volume were clinical factors linked to all-cause mortality among all patients, although without statistical significance at the multivariate level. Meanwhile, only finger clubbing was a significant mortality predictor among patients who received antifibrotic medications. A mortality scoring system was built upon the aforementioned risk factors, with the exclusion of %FVC, whose individual mortality score was nearly zero. Chest tightness, finger clubbing, acute exacerbation after medication, and decreased %FVC were clinical factors associated with mortality in patients with IPF, although without statistical significance. A scoring system including these factors can be used to predict all-cause mortality in patients with IPF. The mere intake of antifibrotic medications was not a significant mortality predictor in this study. This might be owed to the retrospective nature of the study, where many patients started the medications after the deterioration of their pulmonary function rather than from the start.


Technical note: Comparison of instantaneous sampling and continuous observation of dairy cattle behavior in freestall housing.
Recording behavior at fixed intervals (instantaneous sampling) can reduce labor relative to observing continuously. However, instantaneous sampling may inaccurately estimate potentially important responses, such as how frequently cows perform a behavior (i.e., the number of bouts). Our objective was to validate the use of instantaneous sampling for capturing how long and how frequently cows in freestall housing lie down or visit the feed bunk and water trough. We predicted that more frequent sampling would be needed to accurately reflect the behaviors that cows spent less time performing. In addition, we predicted that instantaneous sampling would underestimate how often cows engaged in behaviors that they frequently performed in short bouts or with short intervals between bouts, as some of these events may occur between sample intervals. Continuous video observations of 18 lactating Holstein-Friesian dairy cows were conducted for 48-h periods. Instantaneous samples (1 and 30 s, and 1, 3, 5, 10, 15, and 30 min) were generated from continuous data, with the samples recorded at 1-s intervals representing true values. Estimates from each sample interval ≥30 s were compared pairwise to true values with regression analysis. Sample intervals were considered accurate if they met 3 criteria: coefficient of determination ≥0.9 (i.e., strongly related to true values), slope=1, and intercept=0 (i.e., did not over- or underestimate true values). The amount of time cows spent lying (12.1±1.8h/24h, mean ± standard deviation) or visiting the water trough (1.1±0.8h/24h) and feed bunk (5.6±0.8h/24h) were accurately captured using sample intervals ≤30, 10, and 5 min, respectively. In addition, sample intervals ≤3 min accurately estimated the number of lying bouts (10.3±2.4 per 24h), likely because cows were recumbent for long periods (74.0±17.4 min, on average, with <6% of bouts lasting <5 min) and rarely resumed lying soon after standing up (0.4% of intervals between lying bouts were <30 s). However, shorter sample intervals may be needed in situations where cows more frequently transition between lying and standing. In contrast to lying in this study, cows visited the water trough and feed bunk for shorter periods (3.5±1.7 and 25.6±5.8 min, respectively) and frequently returned to these resources soon after leaving (17 and 7% of intervals between visits were <30 s long). As some of these events likely occurred between sample intervals, all sample intervals ≥30 s underestimated the number of times cows visited the water trough and feed bunk (18.5±6.2 and 14.1±4.4 per 24h, respectively). Therefore, continuous observation is needed to determine how often cows visit these resources.


Correlation of pulmonary ACE activity and capillary surface area during postnatal development.
Although a considerable amount of information is available regarding the remodeling and growth of the pulmonary arterial circulation, relatively little is known regarding postnatal development of the pulmonary microcirculation. We hypothesized that the maximal velocity (Vmax) of pulmonary angiotensin-converting enzyme (ACE) activity, measured from indicator-dilution outflow curves using a synthetic substrate, 3H-labeled benzoyl-phenylalanyl-alanyl-proline (BPAP), is directly related to the capillary endothelial cell surface area in the lungs of developing lambs. Accordingly we measured apparent kinetics of pulmonary ACE activity in 22 anesthetized ventilated lambs (2-171 days old) and compared our functional assessment to simultaneous in vivo determinations of CO diffusing capacity (DLCO) and postmortem structural assessment of alveolar septal dimensions using stereology and electron microscopy. There was a progressive increase in Vmax of ACE in this age group, with little change in apparent affinity for BPAP. Similar functional manifestation of growth was noted by an age-dependent increase in DLCO. Neither Vmax nor DLCO was significantly affected by an increase in left atrial pressure to 19 Torr (via inflation of a balloon in the left atrium), suggesting little recruitment of vessels under conditions of the present protocol. A close correlation was observed when either Vmax for ACE activity or DLCO was plotted vs. capillary endothelial cell surface area. Double logarithmic transformation of capillary endothelial cell surface area, Vmax-ACE and DLCO vs. lung volume revealed power functions with slopes all greater than that predicted from isotropic growth, suggesting selective differential postnatal development of the endothelium of the alveolar septum in lambs from 2-171 days of age.


Parasympathetic effects on cardiac electrophysiology during exercise and recovery.
Depressed parasympathetic tone is associated with an increased risk of sudden cardiac death. Exercise and the postexercise recovery period, which are associated with parasympathetic withdrawal, are high risk periods for sudden death. However, parasympathetic effects on cardiac electrophysiology during exercise and recovery have not been described. Electrophysiology studies were performed using noninvasive programmed stimulation (NIPS) in nine subjects (age 59 +/- 18 yr) with implanted dual-chamber devices and normal left ventricular function during multiple bicycle exercise sessions. NIPS was performed at rest, during exercise, and in the early recovery period both before and after parasympathetic blockade with atropine. Parasympathetic effect was defined as the value of the parameter of interest in the absence of atropine minus the value of the parameter in the presence of atropine. During exercise, sinus cycle length, atrioventricular (AV) block cycle length, AV interval, and ventricular effective refractory period shortened; in recovery, the values were intermediate between the rest and exercise values (P < 0.0001 by ANOVA). Parasympathetic effects on sinus cycle length, AV block cycle length, AV interval, and ventricular effective refractory period were 247 +/- 140, 58 +/- 20, 76 +/- 20, and 8.6 +/- 7.5 ms at rest, 106 +/- 20, 37 +/- 14, 24 +/- 13, and 2.6 +/- 7.8 ms during exercise, and 209 +/- 114, 50 +/- 23, 35 +/- 21, and 9.5 +/- 11.8 ms during recovery, respectively. There was poor correlation among the parasympathetic effects noted at the sinus node, AV node, and ventricle. Further work evaluating parasympathetic effects on cardiac electrophysiology during exercise and recovery in patients with heart disease is required to elucidate its role in modulating the risk of sudden cardiac death noted at these times.


Hirschsprung's Disease and Associated Congenital Heart Defects: A Prospective Observational Study from a Single Institution.
To define the prevalence and characteristics of associated congenital heart diseases (CHDs) in patients with Hirschsprung's disease (HSCR). All patients with a histological diagnosis of HSCR admitted to our hospital between January 2010 and December 2013 were included in this prospective observational study and underwent cardiovascular screening. Cardiac anatomy was assessed by a segmental echocardiographic approach. Measurements of aortic root and left ventricular dimensions, wall thickness, and function were obtained. CHDs requiring a percutaneous or surgical intervention were described as major heart diseases. One hundred thirty-three consecutive patients were enrolled at median age of 2.3 years. Eleven patients (8.3%) presented an associated heart disease. Moreover, five patients had mild dilatation of aortic root. Six out of 11 (4.5%) patients had a major CHDs requiring surgical repair. Prevalence of associated CHDs was slightly higher than in previous papers, and mostly represented by septal defects. Four out of six patients with major heart disease had also a chromosomal anomaly. If we do not consider the subpopulation of patients with a chromosomal anomaly, cardiac defects were present in 3.8% of the patients. Based on these results, we suggest to perform routine echocardiogram in all Hirschsprung patients, with or without associated chromosomal syndromes.


Neurotoxic Concentration of Piperacillin during Continuous Infusion in Critically Ill Patients.
This retrospective cohort study included 53 patients admitted to the intensive care unit (ICU), with an average age of 69 years, without neurologic disorder before initiation of a continuous piperacillin infusion at the standard dose and who underwent piperacillin serum concentration monitoring. Among them, 23 developed a neurologic disorder for which the piperacillin causality was chronologically and semiologically suggestive. A concentration threshold of 157.2 mg/liter independently predicted neurotoxicity with 96.7% specificity and 52.2% sensitivity and may constitute a limitation when targeting less susceptible pathogens.


Two new records of deep sea shrimp under the genus Parapontocaris (Crustacea: Decapoda: Crangonidae) from the southwestern coast of India.
This paper reports the occurrence of two species of the crangonid genus Parapontocaris Alcock, 1901 in waters off Kerala from the southwestern coast of India, viz. P. levigata (Chace 1984) and P. bengalensis (Wood-Mason Alcock 1891). Although P. bengalensis was reported off Bay of Bengal in India, after 121 years this species was now recorded off Kerala, Arabian Sea. Specimens were obtained at a depth of 250-300 m from Kalamuku (9°59'02.91"N /76°14'33.14"E) and Sakthikulangara (8°56'60.78"N /76°32'34.27"E) fish landing centres. Interspecies genetic divergence (COI: 8.8-9.1% 16S DNA: 2.1-6.2 %) was recorded in the present specimen P. bengalensis and NCBI sequences.


[Screening of short peptides binding to StxB by phage-display library].
Under induction with 41 degrees C, pBV220-stxb/DH5alpha expressed the recombinant protein Shiga Toxin B Subunit (StxB), which was purified by centrifugation, salting out and ion exchange chromatography. As a target, the purified-protein-coated ELISA plate was used to screen phages able to bind onto it from a random 12-mer peptide library. After 4 rounds of affinity screening, a group of clones were isolated from the peptide library. ELISA assay detected their binding activity with the target. 27 clones showed the specific binding activity. The peptide sequences of these positive phage clones were analyzed. 16 of them had the same sequence named A6, 2 clones had the A9 sequence, and 3 clones had the A3 sequence. To evaluate the neutralization effect of A6 phage, animal test was carried out. The Shiga Toxin was incubated with A6 phage clone, then used to attack the Balb/C mice. As a control, the toxin was incubated with negative phage. In the control group, no mice survived. Comparing with it, the survival rate of the mice in neutralization group could reach to a level of 33.3%. It showed that the toxicity of Shiga Toxin was partly inhibited. The A6 peptide could be developed as an inhibitor of Shiga Toxin to cure the diseases caused by Shiga Toxin.


Population dynamics of type I and II methanotrophic bacteria in rice soils.
Methane-oxidizing bacteria (methanotrophs) consume a significant but variable fraction of greenhouse-active methane gas produced in wetlands and rice paddies before it can be emitted to the atmosphere. Temporal and spatial dynamics of methanotroph populations in California rice paddies were quantified using phospholipid biomarker analyses in order to evaluate the relative importance of type I and type II methanotrophs with depth and in relation to rice roots. Methanotroph population fluctuations occurred primarily within the top 0-2 cm of soil, where methanotroph cells increased by a factor of 3-5 over the flooded rice-growing season. The results indicate that rice roots and rhizospheres were less important than the soil-water interface in supporting methanotroph growth. Both type I and type II methanotrophs were abundant throughout the year. However, only type II populations were strongly correlated with soil porewater methane concentrations and rice growth.


[Argyrophilic nucleolar organizers in squamous changes in bronchial epithelium].
Argyrophil technique for presentation of interphase nucleolar organiser regions (AgNOR) is becoming an important method in tumour pathology which is used in diagnosis and prognosis. The number of interphase AgNOR is in the strict correlation with the degree of cell proliferation. We have used this technique in evaluation of degree of differentiation and proliferation of squamous changes of the epithelium of the bronchial mucosa. The statistically significant differences were found (p < 0.01) in the number of AgNOR by nucleus in cells of benignant squamous metaplasia (3.31) and epidermoid bronchial carcinoma (5.34). On the basis of numerical values of AgNOR epidermoid bronchial carcinomas could be divided into the group with low proliferative capability (AgNOR < 5.34) and in the group with high degree of proliferation (AgNOR > 5.34). Prognosis of patients with tumours with the high AgNOR value is poorer and they require additional systemic chemotherapy regardless of the clinical state of the disease at the moment of surgical intervention.


A case of Guillain-Barré syndrome with focal segmental glomerulosclerosis.
Acute inflammatory polyneuropathy or Guillain-Barré syndrome may be associated with glomerulonephritis, especially membranous nephropathy. This paper details the case of a 73-year-old woman presenting with acute onset of Guillain-Barré syndrome associated with an abnormal urinary sediment and significant proteinuria. Renal biopsy was consistent with focal segmental glomerulosclerosis. Despite an initial response to plasmapheresis, the patient's polyneuropathy deteriorated and subsequently improved with corticosteroid therapy. Simultaneously, her proteinuria and urinary sediment also improved. This implies that this was not a chance association. A brief discussion of the association between Guillain-Barré syndrome and glomerulopathies is undertaken.


Learning to distinguish progressive and non-progressive ductal carcinoma in situ.
Ductal carcinoma in situ (DCIS) is a non-invasive breast neoplasia that accounts for 25% of all screen-detected breast cancers diagnosed annually. Neoplastic cells in DCIS are confined to the ductal system of the breast, although they can escape and progress to invasive breast cancer in a subset of patients. A key concern of DCIS is overtreatment, as most patients screened for DCIS and in whom DCIS is diagnosed will not go on to exhibit symptoms or die of breast cancer, even if left untreated. However, differentiating low-risk, indolent DCIS from potentially progressive DCIS remains challenging. In this Review, we summarize our current knowledge of DCIS and explore open questions about the basic biology of DCIS, including those regarding how genomic events in neoplastic cells and the surrounding microenvironment contribute to the progression of DCIS to invasive breast cancer. Further, we discuss what information will be needed to prevent overtreatment of indolent DCIS lesions without compromising adequate treatment for high-risk patients.


Magnetoelectroluminescence in organic light-emitting diodes.
The magnetoelectroluminescence of conjugated organic polymer films is widely accepted to arise from a polaron pair mechanism, but their magnetoconductance is less well understood. Here we derive a new relationship between the experimentally measurable magnetoelectroluminescence and magnetoconductance and the theoretically calculable singlet yield of the polaron pair recombination reaction. This relationship is expected to be valid regardless of the mechanism of the magnetoconductance, provided the mobilities of the free polarons are independent of the applied magnetic field (i.e., provided one discounts the possibility of spin-dependent transport). We also discuss the semiclassical calculation of the singlet yield of the polaron pair recombination reaction for materials such as poly(2,5-dioctyloxy-paraphenylene vinylene) (DOO-PPV), the hyperfine fields in the polarons of which can be extracted from light-induced electron spin resonance measurements. The resulting theory is shown to give good agreement with experimental data for both normal (H-) and deuterated (D-) DOO-PPV over a wide range of magnetic field strengths once singlet-triplet dephasing is taken into account. Without this effect, which has not been included in any previous simulation of magnetoelectroluminescence, it is not possible to reproduce the experimental data for both isotopologues in a consistent fashion. Our results also indicate that the magnetoconductance of DOO-PPV cannot be solely due to the effect of the magnetic field on the dissociation of polaron pairs.


Functional Expression of the Clostridium ljungdahlii Acetyl-Coenzyme A Synthase in Clostridium acetobutylicum as Demonstrated by a Novel In Vivo CO Exchange Activity En Route to Heterologous Installation of a Functional Wood-Ljungdahl Pathway.
Engineering the Wood-Ljungdahl pathway (WLP) in the established industrial organism Clostridium acetobutylicum would allow for the conversion of carbohydrates into butanol, acetone, and other metabolites at higher yields than are currently possible, while minimizing CO2 and H2 release. To this effect, we expressed 11 Clostridium ljungdahlii core genes coding for enzymes and accessory proteins of the WLP in Clostridium acetobutylicum The engineered WLP in C. acetobutylicum showed functionality of the eastern branch of the pathway based on the formation of labeled 5,10-methylenetetrahydrofolate from 13C-labeled formate, as well as functionality of the western branch as evidenced by the formation of CO from CO2 However, the lack of labeling in acetate and butyrate pools indicated that the connection between the two branches is not functional. The focus of our investigation then centered on the functional expression of the acetyl-coenzyme A (CoA) synthase (ACS), which forms a complex with the CO dehydrogenase (CODH) and serves to link the two branches of the WLP. The CODH/ACS complex catalyzes the reduction of CO2 to CO and the condensation of CO with a methyl group to form acetyl-CoA, respectively. Here, we show the simultaneous activities of the two recombinant enzymes. We demonstrate in vivo the classical in vitro ACS carbonyl carbon exchange assay, whereby the carbonyl carbon of acetyl-CoA is exchanged with the CO carbon. Our data suggest that the low heterologous expression of ACS may limit the functionality of the heterologous WLP in C. acetobutylicumIMPORTANCE The bifunctional carbon monoxide dehydrogenase/acetyl-CoA synthase (CODH/ACS) from C. ljungdahlii was heterologously expressed in the obligate heterotroph C. acetobutylicum The functional activity of the CODH was confirmed through both the oxidation and reduction of CO, as had previously been shown for the heterologous CODH from Clostridium carboxidivorans Significantly, a novel in vivo assay for ACS exchange activity using 13C-tracers was developed and used to confirm functional ACS expression.


Salivary microbiome of healthy women of reproductive age.
The human salivary microbial community plays a crucial role in local and systemic diseases. Biological and lifestyle factors such as menstrual cycle, oral hygiene, and smoking have been documented to impact this community. However, while hormonal contraceptives are the most prescribed drug in healthy women and intimate partners play key roles in microbial exchange between humans, their impact on the salivary microbiome of women of reproductive age have been understudied. Additionally, the role of other lifestyle factors such as diet, allergies, age, and stress on the saliva microbiome of the general population is not well understood. Here, we studied the salivary microbiome of 255 healthy women of reproductive age using self-sampling kits and 16S rRNA amplicon sequencing combined with questionnaires on lifestyle and host-related parameters. A preserved salivary bacterial community of 12 genera (Actinobacillus, Actinomyces, Alloprevotella, Campylobacter, Fusobacterium, Gemella, Granulicatella, Leptotrichia, Neisseria, Prevotella, Streptococcus, and Veillonella) was identified. Contrary to what we expected, the number of intimate partners or specific contraceptive use did not have a major impact on these bacterial communities. However, recent use of oral antibiotics was associated with a significant decrease in richness at genus level and increase in mean relative abundances of several taxa. Being stressed or nervous was associated with a significantly increased richness of the salivary microbiome at the level of amplicon sequencing variants . Nevertheless, these associations with host-related and lifestyle variables only appeared to be subtle, suggesting that the salivary microbiome is mainly driven by the buccal environment and health status of an individual. IMPORTANCE The salivary microbiome has been proven to play a crucial role in local and systemic diseases. Moreover, the effects of biological and lifestyle factors such as oral hygiene and smoking on this microbial community have already been explored. However, what was not yet well understood was the natural variation of the saliva microbiome in healthy women and how this is associated with specific use of hormonal contraception and with the number of different sexual partners with whom microbiome exchange is expected regularly. In this paper, we characterized the salivary microbiome of 255 healthy women of reproductive age using an in-depth questionnaire and self-sampling kits. Using the large metadata set, we were able to investigate the associations of several host-related and lifestyle variables with the salivary microbiome profiles. Our study shows a high preservation between individuals.


Assessing the Readiness of Rural Public Health Agencies for Facilitating a School-based Intervention.
Partnerships are best positioned for success when the readiness of those engaged is assessed and discussed from the outset. Doing so requires an approach to readiness that is responsive to the particular context of the partnership. This study contributes to the topic of partnership readiness through a readiness assessment used with rural local public health agencies (LPHAs) to partner with a university research team on implementing a Kindergarten to 12th-grade school-based health intervention called Assess, Identify, Make it happen. Through case study methodology, we explored the readiness of LPHAs to partner with a university on this initiative as well as the role the readiness assessment played in facilitating this partnership. We conducted semistructured interviews with directors and agency staff in five rural LPHAs before (n = 8) and after (n = 5) they implemented Assess, Identify, Make it happen. We also documented their work with Kindergarten to 12th-grade schools and in partnership with us throughout the initiative. The findings of this study are presented in three phases. Phase 1 outlines the results from the initial readiness assessment interviews as aligned with select constructs of readiness. Phase 2 recounts how these constructs materialized through partnership between LPHAs and the university. Phase 3 includes findings from a postintervention interview focused on readiness for partnership. Collectively, these findings portray prospective, operational, and retrospective perspectives on LPHA readiness for partnership. This study contributes to the constructs of readiness for partnership, highlights the distinction between assessing and cultivating readiness, and demonstrates the benefits of a multiphase approach to readiness for partnership.


Pathology of nasopharyngeal carcinoma. Proposal of a new histologic classification correlated with prognosis.
To establish a new histologic classification with better correlation with patient prognosis, the histologic features of nasopharyngeal carcinoma (NPC) were correlated with prognosis and clinical stage among 494 patients who had been followed a minimum of 5 years after initial radiotherapy. A slight modification of World Health Organization (WHO) classification by the separation of spindle cell variant from the nonkeratinizing (NK) and undifferentiated carcinomas (UD) provided a better prognostic correlation: keratinizing squamous cell carcinoma (KS), spindle cell carcinoma (SP), round cell carcinoma (RC), and mixed cell carcinoma (Mix, or NK); 5-year survival rates were 21%, 41%, 51.8%, and 54%, respectively. This prognostic distinction was further improved by dividing the three nonkeratinizing carcinomas (SP, RC, and Mix) into two subtypes each, according to the degree of cell anaplasia and pleomorphism: Type A (with marked anaplasia and/or pleomorphism), and Type B (with moderate or little anaplasia). The three Type A carcinomas had very similar 5-year survival rates (33.3 to 38.6%), as did the three Type B carcinomas (60% to 71.8%). Therefore, a working formulation for the malignancy of NPC emerged: high-grade malignancy (KS; 5-year survival, 21%), intermediate malignancy (Type A carcinomas, 5-year survival, 30%-40%), and low-grade malignancy (Type B carcinomas, 5-year survival rate, 60%-72%). The prognostic distinction remained true after stratification by clinical stage. Therefore, the histologic condition of the tumor of NPC correlated with patient's prognosis.


mirPRo-a novel standalone program for differential expression and variation analysis of miRNAs.
Being involved in many important biological processes, miRNAs can regulate gene expression by targeting mRNAs to facilitate their degradation or translational inhibition. Many miRNA sequencing studies reveal that miRNA variations such as isomiRs and "arm switching" are biologically relevant. However, existing standalone tools usually do not provide comprehensive, detailed information on miRNA variations. To deepen our understanding of miRNA variability, we developed a new standalone tool called "mirPRo" to quantify known miRNAs and predict novel miRNAs. Compared with the most widely used standalone program, miRDeep2, mirPRo offers several new functions including read cataloging based on genome annotation, optional seed region check, miRNA family expression quantification, isomiR identification and categorization, and "arm switching" detection. Our comparative data analyses using three datasets from mouse, human and chicken demonstrate that mirPRo is more accurate than miRDeep2 by avoiding over-counting of sequence reads and by implementing different approaches in adapter trimming, mapping and quantification. mirPRo is an open-source standalone program (https://sourceforge.net/projects/mirpro/).


Who affiliates with SMART recovery? A comparison of individuals attending SMART recovery, alcoholics anonymous, both, or neither.
Mutual-help organizations (MHOs) play a crucial role for many individuals with alcohol use disorder (AUD) or other substance use disorders in achieving stable remission. While there is now substantial research characterizing who uses 12-step MHOs, very little is known about who becomes affiliated with newer and rapidly growing MHOs, such as Self-Management and Recovery Training ("SMART" Recovery). More research could inform knowledge regarding who may be best engaged by these differing pathways. We conducted a cross-sectional analysis of participants (N = 361) with AUD recruited mostly from the community who were starting a new recovery attempt and self-selected into one of four different recovery paths: (1) SMART Recovery ("SMART-only"; n = 75); (2) Alcoholics Anonymous ("AA-only"; n = 73); (3) Both SMART and AA ("Both"; n = 53); and (4) Neither SMART nor AA ("Neither"; n = 160). We compared the groups on demographics, clinical history, treatment and recovery support service use, and indices of functioning and well-being. We computed descriptives and conducted inferential analyses according to the data structure. Compared to study participants choosing AA-only or Both, SMART-only participants were more likely to be White, married, have higher income and more education, be full-time employed, and evince a pattern of lower clinical severity characterized by less lifetime and recent treatment and recovery support services usage, lower alcohol use intensity and fewer consequences, and less legal involvement. AUD symptom levels, lifetime psychiatric diagnoses, psychiatric distress, and functioning were similar across MHO-engaged groups. SMART Recovery appears to attract individuals with greater psychosocial stability and economic advantage and less severe histories of alcohol-related impairment and legal involvement. Findings suggest that certain aspects specific to the SMART Recovery group approach, format, and/or contents may appeal to individuals exhibiting this type of profile. As such, SMART appears to provide an additional resource that expands the repertoire of options for individuals with AUD who seek recovery.


[Hereditary periodic fever].
Familial Mediterranean fever (FMF), hyperimmunoglobulinemia D periodic fever syndrome (HIDS), and tumor necrosis factor receptor-associated periodic syndrome (TRAPS) are hereditary periodic fever syndromes. FMF is caused by mutations in the Mediterranean fever gene, HIDS by mutations in the mevalonat-kinase gene, and TRAPS by mutations in the TNF-receptor superfamily 1A gene. Impaired function of the encoded proteins, i.e. pyrin in FMF, mevalonat-kinase in HIDS, and the p55 TNF-receptor in TRAPS, induces a dysregulated cytokine balance. Clinical manifestations are relapsing fever, serositis, arthralgia, myalgia, and miscellaneous forms of rash. The diagnosis is made through moleculargenetic analysis of mutations of the MEFV-gene (FMF), MVK-gene (HIDS), or TNFRSF1A-gene (TRAPS). Colchicine is the therapy of choice in FMF. HIDS is treated symptomatically. Impaired TNF-alpha regulation in TRAPS can be treated with etanercept.


Radiographic comparison of apical root resorption after orthodontic treatment between bidimensional and Roth straight-wire techniques.
The aim of this study was to compare the amount of root resorption after orthodontic treatment between the bidimensional and the Roth straight-wire techniques. Another objective was to compare the amount of root resorption in the whole sample studied and record the prevalence of root resorption. The sample consisted of 40 patients (age ranged between 11 and 18 years) with Angle Class II division 1 malocclusions, treated nonextraction. Twenty patients were treated with bidimensional technique and 20 with a 0.018-inch Roth straight-wire technique. Root lengths of the maxillary incisors were measured on pre- and post-treatment periapical radiographs. The results demonstrated that the bidimensional and Roth straight-wire groups showed significant root resorption after treatment, 1.11 (0.17) and 0.86 (0.05), respectively, P < 0.001. When comparing the amount of root shortening between the bidimensional and Roth straight-wire groups, there was no significant difference between the mean change from pre- to post-treatment between bidimensional group (mean = 1.00 ± 1.34) and Roth straight-wire group (mean = 0.88 ± 0.86), P = 0.63. Considering the whole sample, there was no root resoprtion in 32.5% of the analysed teeth. There was only mild resorption in 56.2%, moderate in 8.8% and severe in only 2.5% of the teeth. Treatment with the bidimensional technique did not produce an increase in the amount of root resorption. The prevalence and amount of root resorption was similar between bidimensional and Roth straight-wire techniques.


Formal analyses are fundamental for the definition of honey, a product representing specific territories and their changes: the case of North Tyrrhenian dunes (Italy).
Honey is a variegate matrix depending significantly on the floral origin, and it could become an important agri-food product to valorise specific territories. Being so diverse, different analytical techniques are necessary for its description. Herein we characterized the honey produced in one of the Italian sand dunes systems hosting beekeeping activities. In terms of floristic origin, phytochemical characterization, and sensory and colour analysis, honey collected in 2021 and 2022 was comparable. Honey was polyfloral, with several pollens from dune habitat plants classified as minor. The presence of the allochthonous Amorpha fruticosa L. and the ruderal Rubus fruticosus L. pollens in the category of the secondary pollens testifies the alteration of the park vegetation. The phytochemical profile was rich in polyphenols. Other interesting compounds were coumarine derivatives, likely attributable to resin-laden plants as rockroses, long chain hydroxyacids typical of royal jelly and nicotinic acid and its analogues (2-hydroxynicotinic acid and 2-hydroxyquinoline). The above-mentioned honey showed interesting features and was a good representation of the vegetation of this area. Our study pointed out the importance of relying on multiple analytical techniques for the characterization of honey and the advisability of a technical support toward beekeepers to correctly describe and valorise their product.


Nitric oxide synthesis and biological functions of nitric oxide released from ruthenium compounds.
During three decades, an enormous number of studies have demonstrated the critical role of nitric oxide (NO) as a second messenger engaged in the activation of many systems including vascular smooth muscle relaxation. The underlying cellular mechanisms involved in vasodilatation are essentially due to soluble guanylyl-cyclase (sGC) modulation in the cytoplasm of vascular smooth cells. sGC activation culminates in cyclic GMP (cGMP) production, which in turn leads to protein kinase G (PKG) activation. NO binds to the sGC heme moiety, thereby activating this enzyme. Activation of the NO-sGC-cGMP-PKG pathway entails Ca(2+) signaling reduction and vasodilatation. Endothelium dysfunction leads to decreased production or bioavailability of endogenous NO that could contribute to vascular diseases. Nitrosyl ruthenium complexes have been studied as a new class of NO donors with potential therapeutic use in order to supply the NO deficiency. In this context, this article shall provide a brief review of the effects exerted by the NO that is enzymatically produced via endothelial NO-synthase (eNOS) activation and by the NO released from NO donor compounds in the vascular smooth muscle cells on both conduit and resistance arteries, as well as veins. In addition, the involvement of the nitrite molecule as an endogenous NO reservoir engaged in vasodilatation will be described.


[Carbohydrate tolerance and behavior of insulin in the glucose infusion test in persons with normal weight with prediabetic suspicion].
In altogether 289 persons with normal weight with suspicion of the existence of a prestage of diabetes the 2 hour's glucose infusion test was carried out. In these cases 61% of the test persons showed a normal, 8% a critical, 26% a pathological and 5% a manifest diabetic metabolic condition. A reduction of the initial and late phase of the insulin secretion provable with deterioration of the carbohydrate tolerance must be regarded as cause of metabolic disturbances. The lack of a significant relation between diabetic heredofamiliality and carbohydrate tolerance indirectly refers to the importance of the environmental factors which on the basis of a genetic defect have a decisive influence of the morbidity caused by diabetes. The reduction of the initial phase which is provable already in potential diabetes, particularly clearly it is to be demonstrated in pathological and manifest diabetic metabolic situation, may be regarded as an early symptom of diabetes. Carbohydrate tolerance and preparation of insulin were reduced in decenniums of older age.


Laparoscopic or open distal gastrectomy after neoadjuvant chemotherapy for advanced gastric cancer: study protocol for a randomised phase II trial.
Current guidelines recommend open gastrectomy with D2 lymph node dissection and adjuvant chemotherapy as the standard treatment for advanced gastric cancer. However, the prognosis is not satisfactory. Perioperative chemotherapy has been proposed to improve survival. Although still in debate, the efficacy of laparoscopic distal gastrectomy (LDG) in patients with advanced gastric cancer has been demonstrated in a few trials. Therefore, LDG after neoadjuvant chemotherapy can be a candidate for future standard treatment on advanced distal gastric cancer. We propose a randomised phase II trial to compare LDG and open distal gastrectomy (ODG) after neoadjuvant chemotherapy for advanced gastric cancer. To test the efficacy and safety, a randomised, open-label, single-centre, phase II trial was designed to evaluate the non-inferiority of LDG compared with ODG after neoadjuvant chemotherapy, with 3-year recurrence-free survival as the primary endpoint. The chosen critical value of a non-inferiority margin was an increase of <8%. The study started in 2015 and enrolled 96 patients according to a prior sample size calculation. Intention-to-treat and per-protocol approach will be used for efficacy analysis, and as-treated analysis will be applied for safety analysis. The survival curves will be constructed as time-to-event plots using the Kaplan-Meier method and compared using log-rank tests and Cox proportional hazards model. All statistical analyses will be conducted in standard statistical software with a significance level of 0.05. This study was approved by the Peking University Cancer Hospital Ethics Committee. The results will be submitted for publication in peer-reviewed journals. NCT02404753; Pre-results.


Antiviral activities of hybrids of two major human leukocyte interferons.
Four hybrid human leukocyte interferon (LeIF or IFN-alpha) genes have been constructed by in vitro recombination of LeIF-A (IFN-alpha 2) and LeIF-D (IFN-alpha 1) genes at common restriction endonuclease sites located within their coding regions. These hybrid genes have been expressed in E. coli under trp promoter control. The interferons produced [LeIF-AD (BglII), -AD (PvuII), -DA (BglII), -DA (PvuII)] have antiviral properties distinct from the parental molecules LeIF-A and -D, varying considerably in their abilities to inhibit plaque formation by different viruses in a range of mammalian cells. All six of the cloned LeIFs exhibit the heat stability, pH 2 stability and antigenic specificity of natural leukocyte interferons.


Tumor necrosis factor alpha-238G/A polymorphism and risk of breast cancer: An update by meta-analysis.
The association between the tumor necrosis factor-alpha gene (TNF-a) -238G/A polymorphism and the breast cancer has been analyzed in several studies, but the results have been inconclusive. We then performed a meta-analysis to get a precise estimation of the association. Eight case-control studies with a total of 37,257 cases and 39,564 controls were identified by searching the ISI Web of Knowledge database and the PubMed database up to August 2014. Overall, no association was found between TNF-alpha-238G/A polymorphism and breast cancer in any of genetic model (additive model OR = 1.06, 95%CI: 0.94-1.21, Pheterogeneity = .02; homozygous model OR = 1.04, 95%CI: 0.83-1.30, Pheterogeneity = .98; dominant model OR = 1.06, 95%CI: 0.92-1.21, Pheterogeneity = .01; recessive model OR = 1.04, 95%CI: 0.83-1.30, Pheterogeneity = .98). Furthermore, no significant association was identified when stratified by ethnicity (Caucasian, Asian). This meta-analysis indicated that the TNF-alpha-238G/A polymorphism is not associated with breast cancer risk in the overall population.


Epithelial cell apoptosis by fas ligand-positive myofibroblasts in lung fibrosis.
The Fas/Fas ligand (FasL) apoptotic pathway has been shown to be involved in bleomycin-induced lung fibrosis. We examined the hypothesis that myofibroblasts from fibrotic lungs possess a cytotoxic phenotype that causes apoptosis of epithelial cells via the Fas/FasL pathway. We show in vivo epithelial cell apoptosis and associated upregulation of Fas and apoptotic Fas pathway genes in epithelial cells of lungs with bleomycin-induced fibrosis. In addition, we show that FasL surface molecules are overexpressed on alpha-SMA-positive cells in mice with bleomycin-induced fibrosis, and in humans with idiopathic pulmonary fibrosis. This enables the molecules to kill Fas-positive epithelial cells. In contrast, FasL-deficient myofibroblasts lose this myofibroblast cytotoxic phenotype, both in vivo and in vitro. In vivo, there was no bleomycin-induced epithelial cell apoptosis, as assessed by specific M30 staining in chimeric FasL-deficient mice that lacked FasL-positive myofibroblasts. In vitro, FasL-positive, but not FasL-negative myofibroblasts, induce mouse lung epithelial cell apoptosis. Thus myofibroblast cytotoxicity may underlie the absence of re-epithelialization, resulting in persistent lung fibrosis.


Maxillary distomolars: case reports, differential diagnosis and literature review.
Supernumerary teeth can be found anywhere in the oral cavity, during deciduous or permanent dentition, in males and females. They are rare, owned to various genetic or environmental factors and usually impacted. This article first reports three cases of young adult patients coming to the office for other reasons than their maxillary distomolars and without any pathology caused by them. The decision of keeping or removing these teeth was made based on other associated factors. The fourth case is one of a 40-year-old partially edentulous male patient, also with a good general health and no other associated condition, having a unilateral maxillary fourth molar; it was small, only partially erupted, with a normal morphology with crown and root and an impacted perpendicular position on the distal face of the third molar. It was extracted because of the periodontal and carious complications that it caused to the third molar facing it. The last reported case is a 64-year-old partially edentulous female patient with a maxillary tooth very similar to a distomolar because of its form and position; it was extracted because it interfered with the new removable partial denture treatment plan. The differential diagnosis between a distomolar and an anatomical variant of a third molar was difficult to make even using panoramic X-ray, also because of a very small inferior third molar. In young patients, distomolars are rather accidentally discovered during radiographic examination; later in life, they can cause both pathological issues and difficulties in diagnosis and prosthetic treatment.


Role of mitofusin 2 in the protective effect of breviscapine against hepatic ischemia/reperfusion injury in rats.
The purpose of the present study was to investigate the effect of breviscapine injection on hepatic ischemia/reperfusion (I/R) injury in rats. To explore the relevance and discuss the underlying mechanism of mitofusin 2 (Mfn2) in hepatic I/R injury, 40 Sprague-Dawley male rats were randomly and equally divided into five groups (n=8 per group) as follows: Sham, I/R + normal saline 1 (NS1), I/R + breviscapine 1 (Bre1), I/R + NS2 and I/R + Bre2 groups. Groups 1 and 2 represented ischemia for 20 and 60 min, respectively. Breviscapine or normal saline was injected via the tail vein (single dose of 10 mg/kg) 1 h prior to surgery and immediately postoperatively. The classical model of hepatic I/R injury was used in the present study. The blood and liver samples of different groups were collected following reperfusion to observe serum transaminases and histopathological changes. Alterations in Mfn2, cytosolic cytochrome c and cleaved caspase-3 were additionally assessed. The results demonstrated that breviscapine improved liver function, based on histopathological analysis, and decreased levels of the liver enzymes aspartate and alanine aminotransferase in the I/R + Bre groups compared with the I/R + NS group (P<0.05). The expression of Mfn2 was significantly increased in the I/R + Bre groups (P<0.05), whereas the expression of caspase-3 and cytosolic cytochrome c protein was decreased in the I/R + Bre groups (P<0.05) compared with the I/R + NS group. These data provided substantial evidence that breviscapine treatment exerted a protective effect against damage induced by hepatic I/R. This protective effect was possibly due to its ability to inhibit I/R-induced apoptosis and promote the expression of Mfn2.


Diagnosis of an intracranial arteriovenous malformation using extracranial carotid Doppler sonography.
Carotid sonography is a well-established technique in the evaluation of patients with neurologic symptoms. We describe the case of a woman in whom duplex Doppler sonography of the extracranial carotid circulation showed high-velocity diastolic flow and a low resistance index without turbulence or morphologic abnormality of the artery. A suspected cause of this finding was low-resistance distal circulation secondary to low-resistance intracranial circulation due to an arteriovenous malformation. This diagnosis was later confirmed by CT. Because of the significant risk of bleeding associated with an asymptomatic intracranial arteriovenous malformation, duplex Doppler sonographic findings suggesting a low-resistance waveform in the presence of a morphologically normal carotid artery should prompt further imaging.


Does cholecystectomy always resolve biliary disease?
To evaluate long-term effects of cholecystectomy on typical gallstone symptoms and associated digestive syndrome. Clinical prospective study on selected patients. First Surgical Clinic--Catania University. 143 gallstone patients, divided in highly symptomatic Group 1 (79) and mild symptomatic Group 2 (64), who underwent cholecystectomy during period 1991/92. 125/143 patients compiled a set questionnaire to detect any subjective postoperative disorders and to evaluate whether they were similar to preoperative symptoms or were new ones. 125/143 patients completed the 12-month follow-up programme, which revealed a 30% (38/125) with postcholecystectomy symptoms and 13.4% (17) with a postcholecystectomy syndrome. Moreover, 10% (13) of the patients reported the same digestive symptoms as before treatment. Statistical analysis confirmed that cholecystectomy was efficacious in curing gallstone related symptoms and digestive disorders in both Groups with a general improvement in clinical picture (p > 0.01). No significant statistical difference in the incidence of postcholecystectomy dyspeptic symptoms was found between the 2 Groups. Cholecystectomy is often efficacious in curing both typical gallstone related symptoms and digestive syndrome. Cholecystectomy patterns of failure in curing digestive disorders is unpredictable preoperatively on the basis of clinical features of the disease.


Longevity pathways and maintenance of the proteome: the role of autophagy and mitophagy during yeast ageing.
Ageing is a complex and multi-factorial process that results in the progressive accumulation of molecular alterations that disrupt different cellular functions. The budding yeast Saccharomyces cerevisiae is an important model organism that has significantly contributed to the identification of conserved molecular and cellular determinants of ageing. The nutrient-sensing pathways are well-recognized modulators of longevity from yeast to mammals, but their downstream effectors and outcomes on different features of ageing process are still poorly understood. A hypothesis that is attracting increased interest is that one of the major functions of these "longevity pathways" is to contribute to the maintenance of the proteome during ageing. In support of this hypothesis, evidence shows that TOR/Sch9 and Ras/PKA pathways are important regulators of autophagy that in turn are essential for healthy cellular ageing. It is also well known that mitochondria homeostasis and function regulate lifespan, but how mitochondrial dynamics, mitophagy and biogenesis are regulated during ageing remains to be elucidated. This review describes recent findings that shed light on how longevity pathways and metabolic status impact maintenance of the proteome in both yeast ageing paradigms. These findings demonstrate that yeast remain a powerful model system for elucidating these relationships and their influence on ageing regulation.


Out-of-pocket health care expenditures among older Americans with dementia.
The number of older individuals with dementia will likely increase significantly in the next decades, but there is currently limited information regarding the out-of-pocket expenditures (OOPE) for medical care made by cognitively impaired individuals and their families. We used data from the 1993 and 1995 Asset and Health Dynamics Study, a nationally representative longitudinal survey of older Americans, to determine the OOPE for individuals with and without dementia. Dementia was identified in 1993 using a modified version of the Telephone Interview for Cognitive Status for self-respondents, and proxy assessment of memory and judgment for proxy respondents. In 1995, respondents reported OOPE over the prior 2 years for: 1) hospital and nursing home stays, 2) outpatient services, 3) home care, and 4) prescription medications. The adjusted mean annual OOPE was 1,350 US dollars for those without dementia, 2,150 US dollars for those with mild/moderate dementia, and 3,010 US dollars for those with severe dementia (p < 0.01). Expenditures for hospital/nursing home care (1,770 per year US dollars) and prescription medications (800 per year US dollars) were the largest OOPE components for those with severe dementia. We conclude that dementia is independently associated with significantly higher OOPE for medical care compared with those with normal cognitive function. Severe dementia is associated with a doubling of OOPE, mainly due to higher payments for long-term care. Given that the number of older Americans with dementia will likely increase significantly in the coming decades, changes in public funding aimed at reducing OOPE for both long-term care and prescription medications would have considerable impact on individuals with dementia and their families.


Nanoporous hollow transition metal chalcogenide nanosheets synthesized via the anion-exchange reaction of metal hydroxides with chalcogenide ions.
Nanoporous hollow transition metal chalcogenides are of special interest for a variety of promising applications. Although some advanced synthetic methods have been reported, the development of a facile and general strategy to fabricate porous hollow nanostructures of transition metal chalcogenides, especially with enhanced electrocatalytic performance, still remains highly challenged. Herein, we report a facile chemical transformation strategy to prepare nanoporous hollow Co3S4 nanosheets via the anion exchange reaction of Co(OH)2 with sulfide ions. The chemical transformation mechanism involves the as-formed layer of nanoporous cobalt sulfide on Co(OH)2 driven by the anion-exchange-reaction and lattice mismatch induced quick strain release, a following diffusion-effect-dominated core-shell hollow intermediate with hollow interiors, and subsequent Ostwald ripening growth of hollow nanosheets at elevated temperatures. This anion-exchange strategy of transition metal hydroxides with chalcogenide ions is also suitable for fabricating nanoporous hollow nanosheets of other metal chalcogenides (e.g., CoSe2, CoTe2, CdS, and NiS). The as-prepared nanoporous hollow Co3S4 nanosheets are found to be highly active and stable for electrocatalytic oxygen evolution reaction.


Autophagy in neural stem cells and glia for brain health and diseases.
Autophagy is a multifaceted cellular process that not only maintains the homeostatic and adaptive responses of the brain but is also dynamically involved in the regulation of neural cell generation, maturation, and survival. Autophagy facilities the utilization of energy and the microenvironment for developing neural stem cells. Autophagy arbitrates structural and functional remodeling during the cell differentiation process. Autophagy also plays an indispensable role in the maintenance of stemness and homeostasis in neural stem cells during essential brain physiology and also in the instigation and progression of diseases. Only recently, studies have begun to shed light on autophagy regulation in glia (microglia, astrocyte, and oligodendrocyte) in the brain. Glial cells have attained relatively less consideration despite their unquestioned influence on various aspects of neural development, synaptic function, brain metabolism, cellular debris clearing, and restoration of damaged or injured tissues. Thus, this review composes pertinent information regarding the involvement of autophagy in neural stem cells and glial regulation and the role of this connexion in normal brain functions, neurodevelopmental disorders, and neurodegenerative diseases. This review will provide insight into establishing a concrete strategic approach for investigating pathological mechanisms and developing therapies for brain diseases.


An examination of "nonleadership": from laissez-faire leadership to leader reward omission and punishment omission.
Laissez-faire leadership has received much less attention than have the 3 transactional leadership dimensions of the Multifactor Leadership Questionnaire (MLQ). However, laissez-faire leadership has shown strong negative relationships with various leadership criteria, and the absence of leadership (laissez-faire leadership) may be just as important as is the presence of other types of leadership. This article focuses on a single type of laissez-faire leadership (i.e., the lack of response to subordinate performance). Using a reinforcement perspective, the authors developed measures and examined the effects of the lack of performance-contingent reinforcement in 2 forms: reward omission (leader nonreinforcement of good subordinate performance) and punishment omission (leader nonreinforcement of poor subordinate performance). They found strong evidence in support of the construct validity of the new measures and found that omission was related to follower satisfaction with the leader, subordinate-rated leader effectiveness, subordinate-perceived role clarity, and supervisor-rated subordinate performance. (PsycINFO Database Record (c) 2008 APA, all rights reserved).


Decriminalizing LGBTQ+: Reproducing and resisting mental health inequities.
Secure settings are not queer because lesbian, gay, bisexual, transgender, queer, questioning, Two Spirit, and asexual (LGBTQ+) people populate them, and neither are LGBTQ+ people inherently criminal because they are found in those spaces. Queer people bear disproportionate health, mental health, and social inequities that have had, historically and currently, the effect to criminalize them. This review discusses effective language and ideologies when working with LGBTQ+ people in secure settings. Major health, mental health, and social inequities are reviewed, along with the applied framework of minority stress. Then, the process of criminalization is diagrammed across the phases of predetainment, being in the system, and through re-entering the community. Finally, multilevel strategies are offered to decriminalize LGBTQ+ people ideologically and in practice.


A chemical compound from fruit extract of Juglans mandshurica inhibits melanogenesis through p-ERK-associated MITF degradation.
Trials for regulation of abnormal hyperpigmentation from the use of natural products have been going on for years. Leaf and root extracts from Juglans mandshurica are reported to function as antioxidants and to suppress allergic dermatitis. However, studies evaluating its fruit extract and the chemical compounds from the fruit extract are lacking in dermatology fields, including melanogenesis. The aim of this study is to understand the effect of the fruit extract from J. mandshurica on pigmentation and to search for specific chemical compounds that affect melanogenesis. After screening out any anti-melanotic effects of the fruit extract from J. mandshurica in B16F10 melanoma cells, three major phenolic compounds isolated from the fruit extract were tested by western blot analysis for expression of microphthalmia-associated transcription factor (MITF) and tyrosinase. Their effect on B16F10 melanoma cells with regard to melanogenesis was also confirmed in primary human epidermal melanocytes (PHEMs). PD98059 was tested to observe the compounds' signaling role in the extracellular signal-regulated protein kinase (ERK)-pathway. Fruit extract from J. mandshurica showed anti-melanotic effects in B16F10 melanoma cells. After chemical compounds were isolated from the fruit extracts, three phenolic compounds were evaluated for anti-melanotic effects. 2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-propanediol (compound 1) showed the highest suppression effect among the three compounds. In B16F10 melanoma cells and PHEMs, reduced melanin contents were observed after treatment with the compound (1). Experiments using a blocker of ERK showed that the inhibitory effect of the compound (1) on melanogenesis was dependent on ERK-associated MITF degradation. A chemical constituent of Juglans mandshurica Maxim. induces an inhibitory mechanism to melanogenesis. It has the potential to become a whitening agent in the medical field, though this requires further clinical investigation.


[Postmortem detection of accidental methadone intoxication in a 10-year-old girl].
Intoxications in children still account for a large part of the cases reported to poison control centres. Among drug intoxications, substitution drugs have gained in importance lately. Careless storage of take-home medications puts children living in the same household at risk. The authors report on a fatal case of a 10-year-old girl who died from intoxication with methadone belonging to a carer. The accidental intoxication had not been diagnosed at the hospital where the girl was treated for suspected meningitis. The question of medical malpractice is discussed.


Targeted mutation of the calbindin D28K gene disrupts circadian rhythmicity and entrainment.
The suprachiasmatic nucleus (SCN) is the principal circadian pacemaker in mammals. A salient feature of the SCN is that cells of a particular phenotype are topographically organized; this organization defines functionally distinct subregions that interact to generate coherent rhythmicity. In Syrian hamsters (Mesocricetus auratus), a dense population of directly retinorecipient calbindin D(28K) (CalB) neurons in the caudal SCN marks a subregion critical for circadian rhythmicity. In mouse SCN, a dense cluster of CalB neurons occurs during early postnatal development, but in the adult CalB neurons are dispersed through the SCN. In the adult retina CalB colocalizes with melanopsin-expressing ganglion cells. In the present study, we explored the role of CalB in modulating circadian function and photic entrainment by investigating mice with a targeted mutation of the CalB gene (CalB-/- mice). In constant darkness (DD), CalB-/- animals either become arrhythmic (40%) or exhibit low-amplitude locomotor rhythms with marked activity during subjective day (60%). Rhythmic clock gene expression is blunted in these latter animals. Importantly, CalB-/- mice exhibit anomalies in entrainment revealed following transfer from a light : dark cycle to DD. Paradoxically, responses to acute light pulses measured by behavioral phase shifts, SCN FOS protein and Period1 mRNA expression are normal. Together, the developmental pattern of CalB expression in mouse SCN, the presence of CalB in photoresponsive ganglion cells and the abnormalities seen in CalB-/- mice suggest an important role for CalB in mouse circadian function.


Antibody responses to early antigens of varicella-zoster virus (VZV) during varicella and zoster.
The antibody responses to membrane and early antigens and thymidine kinase of varicella-zoster virus (VZV) were studied in sera during both varicella and zoster by a test with fluorescent antibody to membrane antigen (FAMA), staining the biochemically transformed cells by the immunofluorescent technique and neutralization of virus-specific thymidine kinase activity, respectively. Similar increases in FAMA antibody titers were demonstrated in sera from patients with varicella and zoster. IgM was detected in both groups, but appeared earlier during varicella than during zoster. Furthermore, the antibody titers to early antigens and virus-specific thymidine kinase were higher in patients with zoster than in those with varicella. These data suggest that different types of antibody responses occur during varicella and zoster.


[Should elderly hypertensive patients be treated with a beta-blocker-diuretic combination?].
30 hypertensive patients aged over 60 years underwent an antihypertensive treatment for a time of 3 months with Viskaldix . There was an excellent hypotensive effect in supine and standing position and no bradycardia or orthostatic dysregulation occurred. Metabolic parameters were not influenced, and this is of great importance in elderly patients. It seems notable that elderly patients may benefit from a beta-blocker therapy, as there is clinical or subclinical coronary heart disease.


Regulation of parathyroid hormone-related protein secretion and mRNA expression in normal human keratinocytes and a squamous carcinoma cell line.
Parathyroid hormone-related protein (PTHrP) has been identified as a causative factor in the pathogenesis of humoral hypercalcemia of malignancy (HHM). The regulation and mechanisms of PTHrP secretion in most normal and malignant cells are unknown. PTHrP secretion, mRNA expression, and transcription were measured in neoplastic human squamous carcinoma cells (A253) and normal human foreskin keratinocytes (NHFK) by radioimmunoassay, RNase protection assay, and transient transfections of the 5'-flanking region of human PTHrP in a luciferase expression vector. Mechanisms of PTHrP secretion were investigated using chemicals (monensin, colchicine, cytochalasin B, guanosine 5'-[gamma-thio]triphosphate (GTPgammaS)) that interfere with or facilitate intracellular transport. Monensin inhibited PTHrP secretion in both NHFK and A253 cells. Ultrastructurally, monensin caused dilatation of rough endoplasmic reticulum and the formation of numerous cytoplasmic secretory vacuoles in both cell lines. Colchicine decreased PTHrP production in NHFK cells and stimulated PTHrP production and mRNA levels in A253 cells. Colchicine also stimulated transcription of the PTHrP-luciferase reporter gene. Cytochalasin B stimulated PTHrP secretion and mRNA expression in A253 cells, but had no effect in NHFK cells. GTPgammaS had no effect on PTHrP secretion in either cell line. It was concluded that PTHrP secretion is dependent on the constitutive movement of secretory vesicles to the cytoplasmic membrane and regulation of PTHrP secretion and mRNA expression are altered in squamous carcinoma cells compared to normal human keratinocytes in vitro.


A review of neuraminidase inhibitor susceptibility in influenza strains.
Influenza human infections are considered as a persistent global public health issue. Whereas vaccination is important for prevention, given its limitations, antiviral therapy is at the forefront of treatment, while it also plays a significant role in prevention. Currently, two classes of drugs, adamantanes (M2 blockers) and neuraminidase inhibitors (NAIs), are available for treatment and chemoprophylaxis of influenza infections. Given the resistance patterns of circulating influenza strains, adamantanes are not currently recommended. The current review mainly focuses on the development of resistance to NAIs among A and B subtypes of influenza virus strains over the last 5 years. 'Permissive' drift mutations and reassortment of viral gene segments have resulted in NAI oseltamivir-resistant A/(H1N1) variants that rapidly became predominant worldwide in the period 2007-2009. However, the prevalence of antiviral resistance to NAI zanamivir remains relatively low. In addition, the recently developed NAIs, peramivir and laninamivir, while licensed in certain countries, are still under evaluation and only a few reports have described resistance to peramivir. Although in 2014, the majority of circulating human influenza viruses remains susceptible to all NAIs, the emergence of oseltamivir-resistant influenza variants that could retain viral transmissibility, highlights the necessity for enhanced epidemiological and microbiological surveillance and clinical assessment of antiviral resistance.


L-Citrulline: A novel hypothermic amino acid promoting thermotolerance in heat-exposed chickens.
With global warming becoming of increasing concern, poultry farms are experiencing a concomitant increase in heat stress. Chickens are very sensitive to high ambient temperature (HT), so the development of novel nutrients that will help deal with the challenge posed by heat stress is vital. We revealed that L-citrulline (L-Cit) can reduce body temperature in chickens. Orally administered L-Cit solution has been found to provide heat tolerance in chickens and to result in reduced food intake. Heat exposure and oral administration of L-Cit led to increased levels of plasma insulin, whereas heat stress led to a decline in plasma thyroxine. Dietary administration of L-Cit was also shown to be effective to reduce heat stress in broiler chickens. Moreover, L-Cit was found to be metabolized in the liver within 1 h of its administration, and in L-Cit-treated broiler chicks, the Cit-Arginine cycle and the Krebs cycle were found to be active. L-Cit has not yet been approved for inclusion in the poultry diet, so it is important to find alternative sources of L-Cit. Taken together, these findings suggest that L-Cit may serve as an important novel nutrient with the ability to produce heat tolerance in chickens under HT.


Light harvesting and energy transfer in multiporphyrin-modified CdSe nanoparticles.
Multiporphyrin-modified CdSe nanoparticles (CdSe-H2P) were prepared to elucidate the interaction between chromophores and luminescent semiconducting nanoparticles in the excited and ground states. The CdSe-H2P nanoparticles were obtained by place-exchange reactions of hexadecylamine-thiophenol-modified CdSe nanoparticles with porphyrin alkanethiols in toluene. The number of porphyrin molecules on the surface of a single CdSe nanoparticle increased with increasing reaction time to reach a saturated maximum of 21. The porphyrins as well as the core in CdSe-H2P can absorb UV/Vis radiation. Steady-state emission and emission-lifetime measurements reveal efficient energy transfer from the CdSe excited state to the porphyrins in the CdSe-H2P nanoparticles. The resulting porphyrin excited singlet state is not quenched by the CdSe core. These unique properties are in sharp contrast with those of multiporphyrin-modified metal and silica nanoparticles. Thus, semiconducting nanoparticle-multiporphyrin composites are highly promising as novel artificial photosynthetic materials.


Inverse analysis of light scattered at a small angle for characterization of a transparent dielectric fiber.
The objective of this paper is to discuss the possibility of noninvasive optical characterization of a transparent (glass) fiber by means of low-coherent light scattering. It will be shown that, by adjusting the temporal coherence of incident light, it is possible to select these specific orders of scattering, which are related to diffraction. Discussion will be devoted to the direct scattering and the inverse problem, where an inference about the diameter of a multilayered and transparent fiber is accomplished.


Short-term treadmill running in the rat: what kind of stressor is it?
The use of short-term (1-5 days) treadmill running is becoming increasingly common as a model to study physiological adaptations following the exercise. Although the beneficial effects of acute exercise seem clear, a paucity of data exist describing potential markers of stress in response to forced running. We subjected male and female Sprague-Dawley rats to 0, 1, 2, 5, or 10 days of treadmill running. Twenty-four to 32 h after the last bout of exercise animals were killed and examined for training-induced changes in several physiological variables. No effect of skeletal citrate synthase activity was observed in the male animals after any duration, and only at 10 days of running did females show a significant increase in citrate synthase. Myocardial heat shock protein 72 (HSP72) content was higher in male rats than female rats, and exercise led to increased HSP72 in both sexes, although the time course was different between males and females. Animals displayed several markers of systemic stress in response to the treadmill running, and this was done in a sex-dependent manner. Serum corticosterone was significantly elevated in both sexes 24 h after exercise in three of four exercise groups. Corticosterone-binding globulin was higher in females, and decreased after running in female rats. Body and spleen weights decreased in males (but not females) in response to the exercise training, and running did not alter adrenal gland weights in either sex. These data indicate that in response to short-term treadmill running both male and female rats show signs of systemic stress, but that the pattern of changes occurs in a sex-specific manner.


Decreased expression and aberrant methylation of RASSF5A correlates with malignant progression of gastric cardia adenocarcinoma.
Due to alternative splicing and differential promoter usage, RASSF5 exists in at least three isoforms, RASSF5A, RASSF5B, and RASSF5C. Expression and epigenetic inactivation of different transcripts of RASSF5 in gastric cardia adenocarcinoma (GCA) progression have not been evaluated. Quantitative real-time RT-PCR and immunohistochemistry (IHC) methods were used respectively to detect the role of RASSF5A, RASSF5B, and RASSF5C in 132 GCA cases and BS-MSP method was used to clarify the critical CpG sites of RASSF5A. Expression of RASSF5A and RASSF5C transcripts were easily detectable in all normal gastric cardia epithelial tissues; however, expression of RASSF5B was rare detected in normal gastric cardia epithelial tissues and tumor tissues. Both RASSF5A and RASSF5C expression were frequently downregulated in GCA tumor tissues and RASSF5A was more commonly down-regulated compared to RASSF5C. Abnormal reduction of RASSF5A was more commonly observed in advanced stage and poor differentiated tumors. The methylation frequency of CpG island 1 region of RASSF5A in GCA tumor tissues was significantly higher than that in corresponding normal tissues and was inversely correlated with RASSF5A expression. Aberrant promoter methylation of RASSF5C was not found in GCA. RASSF5A methylation and protein expression were independently associated with GCA patients' survival. These results indicate that down-regulation of RASSF5A and RASSF5C expression is a tumor-specific phenomenon and RASSF5A may be a more common target for inactivation in GCA. Inactivation of RASSF5A through CpG island 1 methylation may play an important role in GCA carcinogenesis and may serve as a prognostic biomarker for GCA.


FcγR requirements leading to successful immunotherapy.
Monoclonal antibody (mAb) immunotherapy is currently experiencing an unprecedented amount of success, delivering blockbuster sales for the pharmaceutical industry. Having experienced several false dawns and overcoming technical issues which limited progress, we are now entering a golden period where mAbs are becoming a mainstay of treatment regimes for diseases ranging from cancer to autoimmunity. In this review, we discuss how these mAbs are most likely working and focus in particular on the key receptors that they interact with to precipitate their therapeutic effects. Although their targets may vary, their engagement with Fcγ receptors (FcγRs) on numerous immune effector cells is almost universal, and here we review their roles in delivering successful immunotherapy.