Health-related quality of life in patients with substance use disorders enrolled to the residential treatment in Sri Lanka: a retrospective cross-sectional study.
Substance use disorder (SUD) is a serious public health concern that requires continuum care with effective treatment modalities such as residential rehabilitation. Improvement in health-related quality of life (HRQoL) is one of the determinants of treatment and rehabilitation effectiveness. Therefore, a retrospective cross-sectional study was carried out in seven residential rehabilitation centres in Sri Lanka to determine the HRQoL of the rehabilitees with SUD. The HRQoL of 464 individuals at their enrolment and during the rehabilitation period was assessed using EuroQol five-level five-dimensional questionnaire (EQ-5D-5L). Data were analysed using IBM SPSS version 26. The majority of the participants were Sinhala (n = 419, 90.3%) and Buddhist (n = 368, 79.3%) males (n = 461, 99.4%). Most were unmarried (n = 302, 65.1%), young adults (n = 385, 83.0%) who have pursued secondary or higher education (n = 276, 59.5%) and 87.3% were employed (n = 405). Most of the selected centres use biopsychosocial model (n = 4, 57.1%) as the rehabilitation approach while rest practice therapeutic community (n = 3, 42.9%). The average EQ-5D-5L index [range =( - 0.45)-1.00] of the rehabilitees at their enrolment was 0.52 ± 0.28 and the EQ-5D-5L Visual Analogue Scale (EQ-5D-5L VAS) score (range = 0-100%) was 47.17% ± 23.48%. The values were increased up to 0.83 ± 0.18 (EQ-5D-5L index) and 84.25% ± 16.79% (EQ-5D-5L VAS) during the rehabilitation period. Only 19.4% of the rehabilitees had a normal or upper normal HRQoL (≥ 0.75 EQ-5D-5L Index) at their enrolment and 72.2% of rehabilitees reported normal or upper normal HRQoL during the rehabilitation period. A significant improvement in the HRQoL of the participants was observed during the residential treatment in comparison to the enrolment, despite the differences in the rehabilitation programs.


Association of vascular injury with the proximal side branch and assessment of thrombosis rates in a new microarterial traction model.
The higher rate of anastomotic failure in avulsion injuries has been attributed mostly to the uncertainty in determining the uninjured vessel segment suitable for anastomosis and resection past a proximal branch that has been proposed to achieve good arterial flow. A graded, longitudinal, microarterial traction model in rats has been used to examine the histopathologic aspects of the extent of vascular injury and its association with the proximal side branch. Additionally, anastomoses were performed following traction, and thromboses rates were determined. Results indicated a more proximal vessel injury with increasing rates of traction and, although the vessel segment proximal to the side branch was spared, up to a certain degree of traction, the injury extended beyond this point with more aggressive traction force. Consistently increasing rates of thromboses, significantly higher than the control group, were demonstrated. This model may be of use in further studies on the efficacy of various antithrombotic agents.


Thermal conductivity and particle agglomeration in alumina nanofluids: experiment and theory.
In recent years many experimentalists have reported an anomalously enhanced thermal conductivity in liquid suspensions of nanoparticles. Despite the importance of this effect for heat transfer applications, no agreement has emerged about the mechanism of this phenomenon, or even about the experimentally observed magnitude of the enhancement. To address these issues, this paper presents a combined experimental and theoretical study of heat conduction and particle agglomeration in nanofluids. On the experimental side, nanofluids of alumina particles in water and ethylene glycol are characterized using thermal conductivity measurements, viscosity measurements, dynamic light scattering, and other techniques. The results show that the particles are agglomerated, with an agglomeration state that evolves in time. The data also show that the thermal conductivity enhancement is within the range predicted by effective medium theory. On the theoretical side, a model is developed for heat conduction through a fluid containing nanoparticles and agglomerates of various geometries. The calculations show that elongated and dendritic structures are more efficient in enhancing the thermal conductivity than compact spherical structures of the same volume fraction, and that surface (Kapitza) resistance is the major factor resulting in the lower than effective medium conductivities measured in our experiments. Together, these results imply that the geometry, agglomeration state, and surface resistance of nanoparticles are the main variables controlling thermal conductivity enhancement in nanofluids.


Regulated expression of human alpha- and beta-globin genes in transient heterokaryons.
We have examined the expression of human alpha- and beta-like globin genes in transient heterokaryons formed by fusion of human nonerythroid cells with terminally differentiating mouse erythroleukemia (MEL) cells or with a MEL cell variant (GM979) in which the endogenous mouse embryonic beta-globin genes are activated. In both the parental MEL cells and the heterokaryons, the alpha-globin genes were activated at least 12 h earlier than the embryonic, fetal, and adult beta-globin genes. These results suggest that kinetic differences in the activation of alpha- and beta-like globin genes are not simply the result of different rates of accumulation of erythroid-specific regulatory factors but may reflect differences in the mechanisms governing the transcriptional activation of these genes during erythroid cell differentiation. In mouse GM979 x human nonerythroid heterokaryons, the human embryonic beta-globin gene was activated, consistent with our previous demonstration that erythroid cells contain stage-specific trans-acting regulators of globin gene expression. Moreover, a dramatic increase in the ratio of human fetal to adult beta-globin transcription was observed compared with that seen in MEL-human nonerythroid hybrids. This ratio change may reflect competition between the fetal and adult beta-globin genes for productive interactions with erythroid cell-specific regulatory elements. Finally, we demonstrate that the behavior of naturally occurring mutations that lead to aberrant hemoglobin switching in humans also leads to aberrant expression in transient heterokaryons. Therefore, erythroid cells must contain trans-acting factors that interact with mutated regulatory elements to induce high-level expression of the human fetal globin genes.


[Accelerated blood clearance (ABC) phenomenon induced by administration of PEGylated liposome].
PEGylated liposomes (approximately 100 nm in diameter) lose their long-circulating characteristic upon repeated injection at certain intervals in the same animal (referred to as the "accelerated blood clearance (ABC) phenomenon"), as described by our group and by researchers in the Netherlands. Recently, it was demonstrated by our group that anti-PEG IgM, induced by the first dose of PEGylated liposomes, is responsible for the ABC phenomenon. The IgM produced in this manner then selectively bound to the surface of subsequently injected PEGylated liposomes, leading to substantial complement activation. It is generally believed that nanocarriers coated with a polymer, such as PEG, have no immunogenicity. However, unexpected immune responses occurred even in response to polymer-coated liposomes. This immunogenicity to PEGylated liposomes presents a serious concern in the development and clinical use of liposomal formulations. In this review, we demonstrate our recent observations regarding with the ABC phenomenon against liposomes.


Insertion-sequence-mediated mutations isolated during adaptation to growth and starvation in Lactococcus lactis.
We studied the activity of three multicopy insertion sequence (IS) elements in 12 populations of Lactococcus lactis IL1403 that evolved in the laboratory for 1000 generations under various environmental conditions (growth or starvation and shaken or stationary). Using RFLP analysis of single-clone representatives of each population, nine IS-mediated mutations were detected across all environmental conditions and all involving IS981. When it was assumed that these mutations were neutral, their frequency was higher under shaken than under stationary conditions, possibly due to oxygen stress. We characterized seven of the nine mutations at the molecular level and studied their population dynamics where possible. Two were simple insertions into new positions and the other five were recombinational deletions (of <1->10 kb) among existing and new copies of IS981; in all but one case these mutations disrupted gene functions. The best candidate beneficial mutations were two deletions of which similar versions were detected in two populations each. One of these two parallel deletions, affecting a gene involved in bacteriophage resistance, showed intermediate rearrangements and may also have resulted from increased local transposition rates.


Controlled ovarian hyperstimulation in breast cancer patients: Does oestrogen receptor status make a difference?
The presence of different breast cancer receptor status may impact ovarian stimulation outcomes. To study the association between oestrogen receptor (ER) status in breast cancer patients and fertility preservation outcomes in a major tertiary referral centre. Women who underwent fertility preservation following the diagnosis of breast cancer from 2008 to 2018 were included in the study. Patient age, ovarian stimulation parameters and laboratory outcomes were recorded and compared between the ER positive and negative groups. The primary outcome was total number of oocytes frozen. Secondary outcomes included total number of oocytes collected, mature oocytes, and embryos frozen. The women included in the study (n = 214) were analysed in the following groups based on their fertility preservation method: oocyte freezing (n = 131), embryo freezing (n = 70), and both embryo and oocyte freezing (n = 13). There was an increase in the mean (but not mature) number of oocytes frozen (12.4 and 9.2, P-value = 0.03) favouring the ER positive group, even though the women in this group were older (35.0 and 33.4, P-value of 0.03). There is no difference in the starting follicle-stimulating hormone dose, duration of stimulation, mature oocytes collected, and embryos frozen in both groups. Patients with ER positive breast cancer may have more positive ovarian stimulation outcomes.


Dietary magnesium, not calcium, prevents vascular calcification in a mouse model for pseudoxanthoma elasticum.
Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by ectopic calcification of connective tissue in skin, Bruch's membrane of the eye, and walls of blood vessels. PXE is caused by mutations in the ABCC6 gene, but the exact etiology is still unknown. While observations on patients suggest that high calcium intake worsens the clinical symptoms, the patient organization PXE International has published the dietary advice to increase calcium intake in combination with increased magnesium intake. To obtain more data on this controversial issue, we examined the effect of dietary calcium and magnesium in the Abcc6(-/-) mouse, a PXE mouse model which mimics the clinical features of PXE. Abcc6(-/-) mice were placed on specific diets for 3, 7, and 12 months. Disease severity was measured by quantifying calcification of blood vessels in the kidney. Raising the calcium content in the diet from 0.5% to 2% did not change disease severity. In contrast, simultaneous increase of both calcium (from 0.5% to 2.0%) and magnesium (from 0.05% to 0.2%) slowed down the calcification significantly. Our present findings that increase in dietary magnesium reduces vascular calcification in a mouse model for PXE should stimulate further studies to establish a dietary intervention for PXE.


Predictors of nontransport of older fallers who receive ambulance care.
To identify patient, clinical, and operational factors associated with nontransport of older people who have fallen and received ambulance care; and to develop a nontransport prediction tool that could be utilized during the dispatch process to rationalize allocation of emergency ambulance resources. The study was a planned subanalysis using data collected during a prospective observational cohort study of nonconsecutive emergency responses to older people aged 65 years or more who had fallen between October 1, 2010 and June 30, 2011. The data consisted of routinely collected ambulance dispatch and clinical records, combined with prospectively collected fall-specific information. Missing data were managed using multiple imputation. Multivariate logistic regression modeling was undertaken to identify predictors of nontransport. Results are described for original and imputated data sets, presented as odds ratios (OR) with 95%CI (confidence interval). Receiver operating curve (ROC) statistics were generated, with model discrimination determined by the area under the curve (AUC). There were 1,484 cases eligible for this subanalysis of which 419 (28.2%) were recorded as nontransport. Multivariate regression including dispatch and clinical variables identified a 6-item final model. Younger age group, nonurgent response priority, and presence of a personal alarm were predictors of nontransport, along with clinical variables, including normal vital signs, absence of injury, and unchanged functional status post-fall. The AUC was 0.88 (95% CI 0.86-0.90; p < 0.0001) (imputed data AUC 0.86 (95% CI 0.84-0.88)). Multivariate modeling of dispatch variables only identified a 3-item final model, which included response nonurgent response priority, younger age, and the presence of a personal alarm. The AUC was 0.68 (95% CI 0.64-0.71; p < 0.0001) (imputed data AUC 0.69 (95% CI 0.66-0.72)). In this population of confirmed older fallers attended to by paramedics, determination of the prehospital transport outcome is greatly influenced by on-scene findings resulting from paramedic assessment. The presence of new pain, abnormal physiology, and altered function post-fall were strongly associated with increased odds of transport. Conversely the presence of a personal alarm and allocation of a nonurgent dispatch priority increased the odds of nontransport. Accurate discrimination between older fallers who were and were not transported using dispatch data only was not possible.


Astragalus polysaccharide attenuates rat experimental colitis by inducing regulatory T cells in intestinal Peyer's patches.
To explore probable mechanism underlying the therapeutic effect of Astragalus polysaccharide (APS) against experimental colitis. Thirty-two Sprague-Dawley rats were randomly divided into four groups. Colitis was induced with 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The rats with colitis were treated with 400 mg/kg of APS for 7 d. The therapeutic effect was evaluated by colonic weight, weight index of the colon, colonic length, and macroscopic and histological scores. The levels of regulatory T (Treg) cells in Peyer's patches were measured by flow cytometry, and cytokines in colonic tissue homogenates were analyzed using enzyme-linked immunosorbent assay. The expression of related orphan receptor-γt (ROR-γt), IL-23 and STAT-5a was measured by Western blot. After 7-d treatment with APS, the weight index of the colon, colonic weight, macroscopical and histological scores were decreased, while the colonic length was increased compared with the model group. The expression of interleukin (IL)-2, IL-6, IL-17, IL-23 and ROR-γt in the colonic tissues was down-regulated, but Treg cells in Peyer's patches, TGF-β and STAT5a in the colonic tissues were up-regulated. APS effectively ameliorates TNBS-induced experimental colitis in rats, probably through restoring the number of Treg cells, and inhibiting IL-17 levels in Peyer's patches.


Expanding Phenotype of SYT1-Related Neurodevelopmental Disorder: Case Report and Literature Review.
Synaptotagmin 1 (SYT1), the predominant SYT isoform in the central nervous system, likely acts by promoting vesicle docking, deforming the plasma membrane via Ca2+-dependent membrane penetration. Here, we describe a 21-year-old woman harboring a novel variant in the SYT1 gene, who presents with a complex phenotype, featuring severe intellectual disability, absent speech, behavioral abnormalities, motor stereotypies, dystonic posturing of her hands, a hyperkinetic movement disorder in her childhood, infantile hypotonia, sialorrhea, mild dysmorphic features, epilepsy, peculiar EEG findings, and severe scoliosis. Based on our case and literature review on the 22 previously described patients, we can confirm a complex neurodevelopmental disorder in which, unlike other synaptopathies, epilepsy is present in a subset of cases (including our patient: 5/23, 22%), although characteristic EEG changes are far more common (10/23, 43.5%). Our patient's age allows us to provide long-term follow-up data and thus better delineate the SYT1-related clinical phenotype.


Orbital extraskeletal osteosarcoma following enucleation in a cat: a case report.
We present a unique case of a feline orbital extraskeletal osteosarcoma that developed 5 years post-enucleation. In 2002, an ophthalmologist enucleated the left eye of a 2-year-old neutered male DSH and submitted it to the Comparative Ocular Pathology Laboratory of Wisconsin (COPLOW). COPLOW diagnosed the left eye with feline diffuse iris melanoma. In June 2007, the cat presented to another veterinarian for moderate swelling of the enucleation site. Palpation suggested a firm mass along the lateral orbital rim and an exploratory orbitotomy revealed a cyst with a mass adhered to it and the ventrolateral orbital rim. The cyst and mass were excised by the veterinarian and submitted to COPLOW. COPLOW diagnosed the tissue as an orbital conjunctival inclusion cyst and an acquired orbital osteosarcoma. Following the enucleation, retained conjunctival epithelium became embedded in the connective tissue of the orbit and caused a cyst to develop. The cyst wall consisted of a myofibroblastic collagen-rich matrix and acted as a nidus of chronic irritation and tumor growth. This orbital osteosarcoma resembles feline vaccine-associated sarcomas (VAS), feline post-traumatic ocular sarcomas, and microchip-associated sarcomas in terms of it histopathology and its hypothesized pathogenesis related to exposure to antigenic material such as implanted epithelium, lens protein, vaccine components, and microchips as foreign bodies.


Breast cancer diagnosis under the age of forty years.
The authors report on a multicentric consecutive series of 382 cases of primary breast cancer detected before the age of 40 years. Physical examination (PE) was always performed, whereas other diagnostic tests were performed in selected cases, namely mammography (M) in 334, fine needle aspiration cytology (CYT) in 188 and thermography (TH) in 123 cases. Single tests showed a high rate of false-negative/benign cases (PE, 0.23; M, 0.26; CYT, 0.37 and TH, 0.50), especially when the T1 subgroup was considered (PE, 0.34; M, 0.38; CYT, 0.42 and TH, 0.78). The poor results recorded for TH make its current diagnostic use highly questionable. The policy of extensive biopsy of all "dubious" benign lesions on PE allowed for the detection of 41 of 382 cancers and reduced the PE false-negative/benign rate to 0.12 for the total or 0.15 for T1 cancers, although about 80 unnecessary biopsies for each cancer detected were performed in this way. The association of PE to one or more tests resulted in even lower false-negative rates (0.06 for the total, 0.10 for T1 cancers). The authors criticize the aggressive policy of extensive biopsy recommendation based only on a dubious report on PE alone and stress the opportunity of the routine association of M and CYT to PE, since this combination seems to achieve a higher breast cancer detection rate even in this age group.


Association Between Baseline Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers and Death Among Patients Tested for COVID-19.
Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) drugs may modify risk associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, we assessed whether baseline therapy with ACEIs or ARBs was associated with lower mortality, respiratory failure (noninvasive ventilation or intubation), and renal failure (new renal replacement therapy) in SARS-CoV-2-positive patients. This retrospective registry-based observational cohort study used data from a national database of emergency department patients tested for SARS-CoV-2. Symptomatic emergency department patients were accrued from January to October 2020, across 197 hospitals in the United States. Multivariable analysis using logistic regression evaluated end points among SARS-CoV-2-positive cases, focusing on ACEIs/ARBs and adjusting for covariates. Model performance was evaluated using the c statistic for discrimination and Cox plotting for calibration. A total of 13 859 (99.9%) patients had known mortality status, of whom 2045 (14.8%) died. Respiratory failure occurred in 2485/13 880 (17.9%) and renal failure in 548/13 813 (4.0%) patients with available data. ACEI/ARB status was associated with a 25% decrease in mortality odds (odds ratio [OR], 0.75; 95%CI, 0.59-0.94; P = .011; c = .82). ACEIs/ARBs were not significantly associated with respiratory failure (OR, 0.89; 95%CI, 0.78-1.06; P = .206) or renal failure (OR, 0.75; 95%CI, 0.55-1.04; P = .083). Adjusting for covariates, baseline ACEI/ARB was associated with 25% lower mortality in SARS-CoV-2-positive patients. The potential mechanism for ACEI/ARB mortality modification requires further exploration.


Testing hypotheses about the underlying deficit of apraxia of speech through computational neural modelling with the DIVA model.
Purpose: A recent behavioural experiment featuring a noise masking paradigm suggests that Apraxia of Speech (AOS) reflects a disruption of feedforward control, whereas feedback control is spared and plays a more prominent role in achieving and maintaining segmental contrasts. The present study set out to validate the interpretation of AOS as a possible feedforward impairment using computational neural modelling with the DIVA (Directions Into Velocities of Articulators) model.Method: In a series of computational simulations with the DIVA model featuring a noise-masking paradigm mimicking the behavioural experiment, we investigated the effect of a feedforward, feedback, feedforward + feedback, and an upper motor neuron dysarthria impairment on average vowel spacing and dispersion in the production of six/bVt/speech targets.Result: The simulation results indicate that the output of the model with the simulated feedforward deficit resembled the group findings for the human speakers with AOS best.Conclusion: These results provide support to the interpretation of the human observations, corroborating the notion that AOS can be conceptualised as a deficit in feedforward control.


The hepatotoxic action of allyl formate.
The hepatotoxic action of allyl formate on rat liver has been investigated. Biochemical changes can be detected in the liver cell many hours before the histological changes and it would appear that the toxin has a direct action on the liver parenchymal cell. The results suggest that allyl formate is not the toxic agent but that it is converted via allyl alcohol into acrolein. This reaction requires the presence of alcohol dehydrogenase. Histochemical studies have shown that this enzyme is localized in the periportal region of the liver lobule, and may explain why allyl formate solely produces a periportal necrosis. As glutathione and 1,4-dithiothreitol protect against the early biochemical changes produced by the poison, it is probable that acrolein alkylates proteins and nucleic acids.


[Production of extracellular higher fatty acids by yeasts grown on hexadecanoic acid].
Production of exocellular higher fatty acids by Candida yeasts was studied during their growth in a mineral medium with hexadecane. The qualitative and quantitative composition of exocellular higher fatty acids was investigated during cultivation of Candida lipolytica VCM Y 2378(695) under the conditions of different aeration (5 and 80% saturation of the medium with oxygen). Palmitic (C16:0), palmitooleic (C16:1), oleic (C18:1) and linoleic (C18:2) acids predominated among other higher fatty acids. The overall amount of fatty acids increased and the content of unsaturated fatty acids decreased when the yeast growth was limited with oxygen.


Effects of n-pentanol/biodiesel blend fuels on combustion and conventional and unconventional emission characteristics of diesel engine.
The use of n-pentanol/biodiesel as a diesel engine fuel is one of the important ways to reduce fossil fuel consumption and lower diesel engine emissions. The objective of this work was to investigate the mechanism of the effect of different n-pentanol blending ratios (0%, 10%, 20%, and 30%) on the combustion and emission performance of a common rail diesel engine. Tests were conducted on a four-cylinder supercharged intercooled diesel engine at 1540 r/min with brake mean effective pressures of 0.289, 0.578, and 0.867 MPa. The results showed that with the increase of the n-pentanol blending ratio, the ignition delay was prolonged, the combustion duration was shortened, and the heat release center was shifted forward. The combustion process at medium and high loads was improved. When the blending ratio of n-pentanol reached 20%, the blended fuel showed better combustion characteristics at all three loads, and the peak in-cylinder pressure of the blended fuel increased by 13.74%, 1.95%, and 5.26% at the three loads, respectively, compared with that of pure biodiesel. With the increase of the n-pentanol blending ratio, HC, CH2O, CH4, and CH3CHO emissions increased at all three loads. Soot emission was reduced by 25.86%, 19.71%, and 31.59% at three loads when the n-pentanol blending ratio was 30%. C2H4 emissions increased with the increase of n-pentanol blending ratio at the low-load condition and showed a decreasing tendency at the medium and high loads. At high load conditions, NOx emissions increased with increasing n-pentanol blending ratio, and CO emissions decreased with increasing n-pentanol blending ratio.


Evaluation of the levels of folate, vitamin B12, homocysteine and fluoride in the parents and the affected neonates with neural tube defect and their matched controls.
The aim of this study is to evaluate the folate, vitamin B12, fluoride and homocysteine levels in newborns with neural tube defect (NTD) and their parents. The study included 35 neonates with NTD and their parents, 31 neonates with congenital anomalies other than NTD formed control 1, 24 neonates with no anomalies, with the highest birth order and normal siblings formed control 2. These groups matched for socio-economic and nutritional status. Demographic, antenatal history, parental habits, folate (RBC, whole blood and serum), serum vitamin B12 and homocysteine levels were estimated using chemiluminescence technology. Chi-square test was used to assess association between factors and the outcome. One-way ANOVA was used to compare means in the three groups. To determine the risk factors for NTD, odds ratios (95% CI) was computed using bivariate and multivariate logistic regression analysis (STATA 9.0). No difference was found between NTD group and 'control 1' group. The fathers in NTD group had significantly lower folate and vitamin B12 and a higher homocysteine, in comparison to 'control 2' group (i.e. with normal babies). The babies with NTD had higher homocysteine while their mothers had significantly low folate levels in comparison to 'control 2' mothers. Low RBC folate, low serum vitamin B12 and high plasma homocysteine in both the parents had an association with NTD. Multivariate logistic regression revealed high homocysteine of father as the only independent significant risk factor [OR(95% CI):2.6(2.6, 226)] for NTD and also for other anomalies. NTD (and other congenital anomalies) may not only be due to nutritional deficiency in the mothers but also due to more intricate gene-nutrient interaction defects in the affected families, probably some abnormal folate-homocysteine metabolism. These defects seem to be affect the fathers more severely and in all likelihood, get transmitted to the babies from either or both the parents. The emergence of father's serum homocysteine levels as an independent risk factor for NTD and also other congenital anomalies calls for further studies to evaluate if this can be taken as a marker for congenital anomalies in the fetus during antenatal screening.


Metformin ameliorates the Phenotype Transition of Peritoneal Mesothelial Cells and Peritoneal Fibrosis via a modulation of Oxidative Stress.
Phenotype transition of peritoneum is an early mechanism of peritoneal fibrosis. Metformin, 5'-adenosine monophosphate-activated protein kinase (AMPK) activator, has recently received a new attention due to its preventive effect on organ fibrosis and cancer metastasis by inhibiting epithelial-to-mesenchymal transition (EMT). We investigated the effect of metformin on EMT of human peritoneal mesothelial cells (HPMC) and animal model of peritoneal dialysis (PD). TGF-β1-induced EMT in HPMC was ameliorated by metformin. Metformin alleviated NAPDH oxidase- and mitochondria-mediated ROS production with an increase in superoxide dismutase (SOD) activity and SOD2 expression. Metformin inhibited the activation of Smad2/3 and MAPK, GSK-3β phosphorylation, nuclear translocalization of β-catenin and Snail in HPMCs. Effect of metformin on TGF-β1-induced EMT was ameliorated by either AMPK inhibitor or AMPK gene silencing. Another AMPK agonist, 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide partially blocked TGF-β1-induced EMT. In animal model of PD, intraperitoneal metformin decreased the peritoneal thickness and EMT with an increase in ratio of reduced to oxidized glutathione and the expression of SOD whereas it decreased the expression of nitrotyrosine and 8-hydroxy-2'-deoxyguanosine. Therefore, a modulation of AMPK in peritoneum can be a novel tool to prevent peritoneal fibrosis by providing a favorable oxidant/anti-oxidant milieu in peritoneal cavity and ameliorating phenotype transition of peritoneal mesothelial cells.


Effects of Birthing Room Design on Maternal and Neonate Outcomes: A Systematic Review.
To summarize, categorize, and describe published research on how birthing room design influences maternal and neonate physical and emotional outcomes. The physical healthcare environment has significant effects on health and well-being. Research indicates that birthing environments can impact women during labor and birth. However, summaries of the effects of different environments around birth are scarce. We conducted a systematic review, searching 10 databases in 2016 and 2017 for published research from their inception dates, on how birthing room design influences maternal and neonate physical and emotional outcomes, using a protocol agreed a priori. The quality of selected studies was assessed, and data were extracted independently by pairs of authors and described in a narrative analysis. In total, 3,373 records were identified and screened by title and abstract; 2,063 were excluded and the full text of 278 assessed for analysis. Another 241 were excluded, leaving 15 articles presenting qualitative and quantitative data from six different countries on four continents. The results of the analysis reveal four prominent physical themes in birthing rooms that positively influence on maternal and neonate physical and emotional outcomes: (1) means of distraction, comfort, and relaxation; (2) raising the birthing room temperature; (3) features of familiarity; and (4) diminishing a technocratic environment. The evidence on how birthing environments affect outcomes of labor and birth is incomplete. There is a crucial need for more research in this field.


Effectiveness of Magnesium in Preventing Shivering in Surgical Patients: A Systematic Review and Meta-analysis.
Clinical trials regarding the antishivering effect of perioperative magnesium have produced inconsistent results. We conducted a systematic review and meta-analysis with Trial Sequential Analysis to evaluate the effect of perioperative magnesium on prevention of shivering. We searched PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, and 2 registry sites for randomized clinical trials that compared the administration of magnesium to a placebo or no treatment in patients undergoing surgeries. The primary outcome of this meta-analysis was the incidence of shivering. The incidence of shivering was combined as a risk ratio with 95% CI using a random-effect model. The effect of the route of administration was evaluated in a subgroup analysis, and Trial Sequential Analysis with a risk of type 1 error of 5% and power of 90% was performed. The quality of each included trial was evaluated, and the quality of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation approach. We also assessed adverse events. Sixty-four trials and 4303 patients (2300 and 2003 patients in magnesium and control groups, respectively) were included. The overall incidence of shivering was 9.9% in the magnesium group and 23.0% in the control group (risk ratio, 0.42; 95% CI, 0.33-0.52). Subgroup analysis revealed that the incidence of shivering was lower with IV (risk ratio, 0.29; 95% CI, 0.29-0.54; Grading of Recommendation Assessment, Development, and Evaluation, moderate), epidural (risk ratio, 0.24; 95% CI, 0.13-0.43; Grading of Recommendation Assessment, Development, and Evaluation, low), and intrathecal administration (risk ratio, 0.64; 95% CI, 0.43-0.96; Grading of Recommendation Assessment, Development, and Evaluation, moderate). Only trials with low risk of bias were included for Trial Sequential Analysis. The Z-cumulative curve for IV magnesium crossed the Trial Sequential Analysis monitoring boundary for benefit even though only 34.9% of the target sample size had been reached. The Z-cumulative curve for epidural or intrathecal administration did not cross the Trial Sequential Analysis monitoring boundary for benefit. No increase in adverse events was reported. Perioperative IV administration of magnesium effectively reduced shivering and Trial Sequential Analysis suggested that no more trials are required to confirm that IV magnesium effectively reduces shivering.


Induction of efficient energy dissipation in the isolated light-harvesting complex of Photosystem II in the absence of protein aggregation.
Under excess illumination, the Photosystem II light-harvesting antenna of higher plants has the ability to switch into an efficient photoprotective mode, allowing safe dissipation of excitation energy into heat. In this study, we show induction of the energy dissipation state, monitored by chlorophyll fluorescence quenching, in the isolated major light-harvesting complex (LHCII) incorporated into a solid gel system. Removal of detergent caused strong fluorescence quenching, which was totally reversible. Singlet-singlet annihilation and gel electrophoresis experiments suggested that the quenched complexes were in the trimeric not aggregated state. Both the formation and recovery of this quenching state were inhibited by a cross-linker, implying involvement of conformational changes. Absorption and CD measurements performed on the samples in the quenched state revealed specific alterations in the spectral bands assigned to the red forms of chlorophyll a, neoxanthin, and lutein 1 molecules. The majority of these alterations were similar to those observed during LHCII aggregation. This suggests that not the aggregation process as such but rather an intrinsic conformational transition in the complex is responsible for establishment of quenching. 77 K fluorescence measurements showed red-shifted chlorophyll a fluorescence in the 690-705 nm region, previously observed in aggregated LHCII. The fact that all spectral changes associated with the dissipative mode observed in the gel were different from those of the partially denatured complex strongly argues against the involvement of protein denaturation in the observed quenching. The implications of these findings for proposed mechanisms of energy dissipation in the Photosystem II antenna are discussed.


Total Mercury Released to the Environment by Human Activities.
We estimate that a cumulative total of 1540 (1060-2800) Gg (gigagrams, 109 grams or thousand tonnes) of mercury (Hg) have been released by human activities up to 2010, 73% of which was released after 1850. Of this liberated Hg, 470 Gg were emitted directly into the atmosphere, and 74% of the air emissions were elemental Hg. Cumulatively, about 1070 Gg were released to land and water bodies. Though annual releases of Hg have been relatively stable since 1880 at 8 ± 2 Gg, except for wartime, the distributions of those releases among source types, world regions, and environmental media have changed dramatically. Production of Hg accounts for 27% of cumulative Hg releases to the environment, followed by silver production (24%) and chemicals manufacturing (12%). North America (30%), Europe (27%), and Asia (16%) have experienced the largest releases. Biogeochemical modeling shows a 3.2-fold increase in the atmospheric burden relative to 1850 and a contemporary atmospheric reservoir of 4.57 Gg, both of which agree well with observational constraints. We find that approximately 40% (390 Gg) of the Hg discarded to land and water must be sequestered at contaminated sites to maintain consistency with recent declines in atmospheric Hg concentrations.


Prevalence and risk factors for primary glaucomas in adult urban and rural populations in the Andhra Pradesh Eye Disease Study.
To compare the prevalence of and risk factors for primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) in urban and rural populations in the Andhra Pradesh Eye Disease Study. A population-based, cross-sectional study using a stratified, random, cluster, and systematic sampling strategy. Between 1996 and 2000, participants from 94 clusters in 1 urban and 3 rural areas representative of the population were included. We performed a detailed eye examination, including applanation tonometry, gonioscopy, and dilated fundus evaluation after ruling out risk of angle closure. Humphrey threshold 24-2 visual fields were performed when indicated. Glaucoma was diagnosed and categorized using International Society of Geographical and Epidemiological Ophthalmology criteria. The prevalence and risk factors for POAG and PACG in subjects aged > or = 40 years were compared between the urban and rural cohorts. There were 3724 subjects > or = 40 years, with 934 in the urban and 2790 in the rural cohort. The prevalence of POAG was greater in the urban compared with the rural cohort (4% vs 1.6%; P<0.001). Age and intraocular pressure (IOP) were risk factors for POAG in both cohorts. Blindness owing to POAG was 11.1% in the rural and 2.7% in the urban cohort. The prevalence of PACG (1.8% vs 0.7%; P<0.01), primary angle closure (PAC) (0.8% vs 0.2%; P = 0.02) and primary angle closure suspect (PACS; 3.5% vs 1.5%; P<0.01) were significantly different between the urban and rural cohorts. Increasing age was a risk factor in the urban cohort. Intraocular pressure was a risk factor in both the populations. Blindness owing to PACG was equal (20%) in both the populations. Female gender was a risk factor in the rural cohort (P = 0.032). The prevalence of both POAG and PACG was greater in urban than in the rural population. Intraocular pressure was a significant risk factor for both POAG and PACG in both cohorts. Increasing age was a significant risk factor for POAG in both cohorts and for PACG in the urban cohort. Female gender was a risk factor for PACG in the rural cohort. There was more blindness owing to PACG than to POAG. The authors have no proprietary or commercial interest in any of the materials discussed in this article.


Portraits of care: medical research through portraiture.
The Portraits of Care study used portraiture to investigate ideas about care and care giving at the intersection of art and medicine. The study employed mixed methods involving both qualitative and quantitative research techniques. All aspects of the study were approved by the Institutional Review Board. The study included 26 patient and 20 caregiver subjects. Patient subjects were drawn from across the lifespan and included healthy and ill patients. Caregiver subjects included professional and familial caregivers. All subjects gave their informed consent for the study and the subsequent exhibition of artwork. The artist drew or painted 100 portraits during the 2-year study. A multi-disciplinary analysis team carried out the initial analysis of portraits and subject data. Findings from their qualitative analysis were used to develop a quantitative survey and qualitative journal tool that the public used to give feedback at the subsequent exhibition. Exhibition data confirmed the initial findings. Study results showed the introspection of subjects that revealed their sense of identity and psychological status. Patients appear as 'whole people', not fragmented by diagnosis. Caregivers' portraits reveal their commitment to care. There is also a sense of mutuality and fluidity in the background stories of subjects. Many patient subjects have been caregivers and, at times, caregivers are also patients. Public data emphasised the identity transformation of subjects, the centrality of the idea of mortality, the presence of hope despite adversity, and the importance of empathy and compassion in care.


Preoperative communication between anaesthetists and patients with obesity regarding perioperative risks and weight management: a structured narrative review.
Individuals with obesity frequently present for anaesthesia and surgery. Good communication during the preoperative consultation can optimise the provision of relevant health information and guide improvement of health status preoperatively. We planned a systematic literature review to assess existing guidelines and evidence of effectiveness for how anaesthetists should communicate with patients who have obesity in the preoperative period about perioperative risks and weight management. Database searches used keywords related to perioperative weight loss conversations. We found no papers that directly addressed our aim. The literature identified as most relevant was analysed in the form of a narrative review. The majority of suggestions for weight loss conversations came from primary care. Four primary themes potentially relevant to anaesthetists were identified: barriers to such conversations, communication tools, language and communication and specific recommendations. Identified barriers included lack of skills, training, poor remuneration, pessimism and time constraints for clinicians. Established discussion tools including the '5A's' approach (Assess, Advise, Agree, Assist, Arrange) and motivational interviewing may hold promise to improve preoperative conversations. The papers highlighted a need for empathetic language, including use of patient-specific language where possible. There are currently no published guidelines for how anaesthetists could most effectively discuss weight in the perioperative period with patients who have obesity. Much of the literature for obesity communication is based on the primary care setting. The perioperative period may represent an increased time of receptiveness for patients. Guidelines for discussions about weight management and associated perioperative risk are suggested.


Molecular Evolutionary Mechanisms of CYP6ER1vA-Type Variant Associated with Resistance to Neonicotinoid Insecticides in Field Populations of Nilaparvata lugens.
The evolution of insecticide resistance has threatened the control of Nilaparvata lugens. Research on mechanisms behind neonicotinoid resistance in N. lugens remains incomplete. This study examined P450-mediated resistance to neonicotinoids in a resistant N. lugens strain (XA-2017-3G). The overexpression of CYP6ER1 in the XA-2017-3G strain plays a role in neonicotinoid resistance, as confirmed by RNA interference. Phenotypic analyses of CYP6ER1-mediated resistance in strains, including laboratory-susceptible, field-collected, and imidacloprid-laboratory further-selected strains, revealed that the vA-type/vL-type genotype exhibited greater resistance to neonicotinoids compared to the vA-type/vA-type genotype. The mRNA expression levels of CYP6ER1vA-type were closely correlated with the levels of neonicotinoid resistance in N. lugens strains, in which CYP6ER1vA-type overexpression is in part attributed to increased copy numbers of CYP6ER1. CYP6ER1vA-type-mediated neonicotinoid resistance was further confirmed by a CYP6ER1vA-type transgenic Drosophila melanogaster line. Taken together, our findings strongly suggest that the overexpression of CYP6ER1vA-type, which can be partially attributed to copy number variations, plays a crucial role in N. lugens resistance to neonicotinoids.


Analgesic and psychoactive drugs in the chronic pain patient.
In contrast to the management of pain in patients with malignant disease, where manipulation of analgesic and psychoactive drugs may be necessary and effective, the elimination of drug use is a primary goal in programs for patients with chronic pain of benign rig in.; Drug use is often a significant component of pain behavior and, therefore, it is important to alter the use of drugs in freeing the patient of the chronic pain syndrome. Elimination of the unwanted side effects and medical complications of drug use may contribute significantly to the patient's physical and psychological well-being. Also, because many of these drugs are associated with physiological or psychological dependency, it also becomes important to identify and treat drug abuse and chemical dependency, which is a primary problem in a subgroup of chronic pain patients. This discussion will focus on the relationship of drug use to chronic pain behavior and methods of medication withdrawal. In addition, the problems of chemical dependency and its identification and management will be discussed.J Orthop Sports Phys Ther 1984;5(6):315-317.


Upregulation of S100A10 in metastasized breast cancer stem cells.
Metastatic progression remains the major cause of death in human breast cancer. Cancer cells with cancer stem cell (CSC) properties drive initiation and growth of metastases at distant sites. We have previously established the breast cancer patient-derived tumor xenograft (PDX) mouse model in which CSC marker CD44+ cancer cells formed spontaneous microscopic metastases in the liver. In this PDX mouse, the expression levels of S100A10 and its family proteins were much higher in the CD44+ cancer cells metastasized to the liver than those at the primary site. Knockdown of S100A10 in breast cancer cells suppressed and overexpression of S100A10 in breast cancer PDX cells enhanced their invasion abilities and 3D organoid formation capacities in vitro. Mechanistically, S100A10 regulated the matrix metalloproteinase activity and the expression levels of stem cell-related genes. Finally, constitutive knockdown of S100A10 significantly reduced their metastatic ability to the liver in vivo. These findings suggest that S100A10 functions as a metastasis promoter of breast CSCs by conferring both invasion ability and CSC properties in breast cancers.


[Drug induced linear IgA bullous dermatosis].
Linear IgA disease is an autoimmune subepidermal bullous disease in which linear IgA deposits are found at the basement membrane zone. It is classically idiopathic but a drug-induced variant seems to be individualized in which cutaneous lesions resolve spontaneously after cessation of responsible treatment. Among the commonly implicated drugs, vancomycin is the most frequently reported. One should not however ignore other precipitating events sometimes associated, particularly infectious diseases and non-lymphoid or lymphoproliferative malignancies. Authors present here clinical and histological features of this disease as well as drugs that have been implicated.


High-Throughput Magnetic Actuation Platform for Evaluating the Effect of Mechanical Force on 3D Tumor Microenvironment.
Accurately replicating and analyzing cellular responses to mechanical cues is vital for exploring metastatic disease progression. However, many of the existing in vitro platforms for applying mechanical stimulation seed cells on synthetic substrates. To better recapitulate physiological conditions, a novel actuating platform is developed with the ability to apply tensile strain on cells at various amplitudes and frequencies in a high-throughput multi-well culture plate using a physiologically-relevant substrate. Suspending fibrillar fibronectin across the body of the magnetic actuator provides a matrix representative of early metastasis for 3D cell culture that is not reliant on a synthetic substrate. This platform enables the culturing and analysis of various cell types in an environment that mimics the dynamic stretching of lung tissue during normal respiration. Metabolic activity, YAP activation, and morphology of breast cancer cells are analyzed within one week of cyclic stretching or static culture. Further, matrix degradation is significantly reduced in breast cancer cell lines with metastatic potential after actuation. These new findings demonstrate a clear suppressive cellular response due to cyclic stretching that has implications for a mechanical role in the dormancy and reactivation of disseminated breast cancer cells to macrometastases.


ESUMS: a mobile system for continuous home monitoring of rehabilitation patients.
The pressure on the healthcare services is building up for several reasons. The ageing population trend, the increase in life-style related disease prevalence, as well as the increased treatment capabilities with associated general expectation all add pressure. The use of ambient healthcare technologies can alleviate the situation by enabling time and cost-efficient monitoring and follow-up of patients discharged from hospital care. We report on an ambulatory system developed for monitoring of physical rehabilitation patients. The system consists of a wearable multisensor monitoring device; a mobile phone with client application aggregating the data collected; a service-oriented-architecture based server solution; and a PC application facilitating patient follow-up by their health professional carers. The system has been tested and verified for accuracy in controlled environment trials on healthy volunteers, and also been usability tested by 5 congestive heart failure patients and their nurses. This investigation indicated that patients were able to use the system, and that nurses got an improved basis for patient follow-up.


Late follow-up of the randomized radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) trial for advanced head and neck cancer.
The radiation and concomitant high-dose intra-arterial or intravenous cisplatin (RADPLAT) phase III trial compared intra-arterial (IA) to intravenous (IV) cisplatin-based chemoradiation for head and neck cancer. Long-term efficacy and toxicity are reported after a median follow-up of 7.5 years. Patients with inoperable squamous cell carcinoma (SCC) of the oropharynx, oral cavity, or hypopharynx, were randomized between radiotherapy (RT) + IA cisplatin 150 mg/m(2) , followed by systemic rescue or RT + I.V. cisplatin 100 mg/m(2) . RT consisted of 46 Gy to the affected and elective areas, followed by a boost of 24 Gy. Among 237 patients, 57 recurred locally, 35 regionally, and 80 locoregionally. There were 32 second primary tumors, 65 distant metastases, and 154 deaths. Locoregional control and overall survival were not different between the treatment arms. Late dysphagia was worse in the I.V. arm (log-rank p = .014). IA cisplatin did not improve tumor control compared to I.V. administered cisplatin, despite the higher dose in IA delivery of the drug. © 2015 Wiley Periodicals, Inc. Head Neck 38: E488-E493, 2016.


Adaptation of soil biological nitrification to heavy metals.
The adaptive response of soil biological nitrification to Zn and Pb was assessed using an in situ method we have developed. The method is based on reinoculating a sterilized metal contaminated soil with the same soil that is either uncontaminated or has been incubated with metal. This approach excludes the potentially confounding effects of metal aging reactions in soils. We found added Zn concentrations which gave rise to a decrease in nitrification to 50% that of the uncontaminated soil (i.e. EC50) of 210 mg/kg for communities not previously exposed to Zn and 850 mg/kg for communities exposed to Zn for 17 months, indicating that significant adaptation of the community to Zn had occurred. Similarly, this protocol was able to demonstrate adaptation of soil biological nitrification to Pb, with EC50 values of 1960 and 3150 mg/kg for the unexposed and exposed treatments, respectively. Exposure of unadapted and adapted microbial communities to a combination of Zn and Cd showed that the presence of Cd did not lead to greater toxicity in either community. Adapted communities were not more sensitive to decreases in soil pH than unadapted communities. Prior exposure to Zn was found to confer significantly greater tolerance of the community to Pb. Prior exposure to Pb similarly conferred significantly greater tolerance of the community to Zn. Implications of the adaptive capacity of soil microbes to the development of critical threshold values for heavy metals in soil based on ecotoxicity assessments are discussed.


The natural history of intracranial venous angiomas.
Cerebral venous angiomas are congenital anomalies of the intracranial venous drainage. Many believe that they are associated with a high risk of hemorrhage and neurological dysfunction, but newer neurodiagnostic imaging techniques are showing not only that they are more common than previously known but also that many have no associated symptoms. In this retrospective study, the natural history of venous angiomas was examined in 100 patients (48 males and 52 females) with radiographically identifiable lesions treated over a 14-year period. Information on the natural history of the lesion was obtained from clinical records and follow-up data. Imaging studies included angiography, computerized tomography, and magnetic resonance imaging. Angioma locations were classified as frontal (42 cases), parietal (24 cases), occipital (4 cases), temporal (2 cases), basal or ventricular (11 cases), cerebellar (14 cases), or brain stem (3 cases); 47 lesions were on the left side. Headache as a presenting symptom was common (36 patients) and often led to other radiographic studies, but this appeared to be related to the vascular lesion in only four patients. Other possibly related complications were hemorrhage in one patient, seizures in five, and transient focal deficits in eight. Fifteen patients had no neurological signs or symptoms. The mean patient age at last contact was 45.3 years (range 3 to 94 years). All patients have been managed without surgery. It is concluded that significant complications secondary to venous angiomas are infrequent and that surgical resection of these lesions and of surrounding brain is rarely indicated.


Content validity for dementia of three generic preference based health related quality of life instruments.
A semi-structured interview was conducted with dementia patients and their caregivers in order to explore which aspects of quality of life were perceived as relevant and important. These aspects of quality of life were compared with the content of three generic utility-based quality of life instruments: European Quality of Life Instrument, Health Utilities Index, and Quality of Well-Being (QWB) Scale. Twenty patients with mild dementia and 20 caregiver volunteers provided narrative data derived from interviews that were analyzed using a modified Grounded Theory method of analysis. Essential attributes of dementia quality of life identified by the respondents were missing in the three utility-based quality of life instruments selected for the study. Patients provided a wider range of attributes than the instruments including some attributes not described by caregivers. Of the three utility-based measures, the QWB scale included the largest number of quality of life attributes but still missed many. Compared to the respondent generated attributes all three utility-based quality of life instruments have important shortcomings in content validity.


End-to-side nerve repair in the upper extremity of rat.
The end-to-side nerve-repair technique, i.e., when the distal end of an injured nerve is attached end-to-side to an intact nerve trunk in an attempt to attract nerve fibers by collateral sprouting, has been used clinically. The technique has, however, been questioned. The aim of the present study was to investigate end-to-side repair in the upper extremity of rats with emphasis on functional recovery, source, type, and extent of regenerating fibers. End-to-side repair was used in the upper limb, and the radial or both median/ulnar nerves were attached end-to-side to the musculocutaneous nerve. Pawprints and tetanic muscle force were used to evaluate functional recovery during a 6-month recovery period, and double retrograde labeling was used to detect the source of the regenerated nerve fibers. The pawprints showed that, in end-to-side repair of either one or two recipient nerves, there was a recovery of toe spreading to 60-72% of the preoperative value (lowest value around 47%). Electrical stimulation of the end-to-side attached radial or median/ulnar nerves 6 months after repair resulted in contraction of muscles in the forearm innervated by these nerves (median tetanic muscle force up to 70% of the contralateral side). Retrograde labeling showed that both myelinated (morphometry) sensory and motor axons were recruited to the end-to-side attached nerve and that these axons emerged from the motor and sensory neuronal pool of the brachial plexus. Double retrograde labeling indicated that collateral sprouting was one mechanism by which regeneration occurred. We also found that two recipient nerves could be supported from a single donor nerve. Our results suggest that end-to-side repair may be one alternative to reconstruct a brachial plexus injury when no proximal nerve end is available.


Differential Corticospinal Excitability and Cortical Functional Connectivity Modulation by Spinal Cord Transcutaneous Stimulation-based Motor Training versus Motor Training alone in Able-bodied and SCI participants: A Multiple Case Study.
Spinal cord transcutaneous stimulation (scTS) has shown its potential for boosting motor, sensory, and autonomic function recovery after a spinal cord injury. Despite the demonstrated benefits, little is known about the exact neuromodulatory mechanisms triggered by scTS and the cortex involvement in the beneficial effects observed. Here, we examine the effects of scTS-based motor training and motor training alone on sensorimotor cortical functional connectivity and corticospinal excitability in able-bodied and SCI participants.Clinical Relevance- The results show preliminary evidence of differential cortical involvement and modulation by scTS-based motor training in uninjured and spinal-cord injured individuals. A better understanding of scTS mechanisms of action could help optimize the intervention design and potentiate its benefits.


Is bureaucracy being busted in research ethics and governance for health services research in the UK? Experiences and perspectives reported by stakeholders through an online survey.
It has long been noted that the chain from identification of need (research gap) to impact in the real world is both long and tortuous. This study aimed to contribute evidence about research ethics and governance arrangements and processes in the UK with a focus on: what works well; problems; impacts on delivery; and potential improvements. Online questionnaire widely distributed 20th May 2021, with request to forward to other interested parties. The survey closed on 18th June 2021. Questionnaire included closed and open questions related to demographics, role, study objectives. Responses were received from 252 respondents, 68% based in universities 25% in the NHS. Research methods used by respondents included interviews/focus groups (64%); surveys/questionnaires (63%); and experimental/quasi experimental (57%). Respondents reported that participants in the research they conducted most commonly included: patients (91%); NHS staff (64%) and public (50%). Aspects of research ethics and governance reported to work well were: online centralised systems; confidence in rigorous, respected systems; and helpful staff. Problems with workload, frustration and delays were reported, related to overly bureaucratic, unclear, repetitive, inflexible and inconsistent processes. Disproportionality of requirements for low-risk studies was raised across all areas, with systems reported to be risk averse, defensive and taking little account of the risks associated with delaying or deterring research. Some requirements were reported to have unintended effects on inclusion and diversity, particularly impacting Patient and Public Involvement (PPI) and engagement processes. Existing processes and requirements were reported to cause stress and demoralisation, particularly as many researchers are employed on fixed term contracts. High negative impacts on research delivery were reported, in terms of timescales for completing studies, discouraging research particularly for clinicians and students, quality of outputs and costs. Suggested improvements related to system level changes / overall approach and specific refinements to existing processes. Consultation with those involved in Health Services Research in the UK revealed a picture of overwhelming and increasing bureaucracy, delays, costs and demoralisation related to gaining the approvals necessary to conduct research in the NHS. Suggestions for improvement across all three areas focused on reducing duplication and unnecessary paperwork/form filling and reaching a better balance between risks of harm through research and harms which occur because research to inform practice is delayed or deterred.


Studies of endogenous inhibitors of microsomal glutathione S-transferase.
Glutathione S-transferase is present in rat liver microsomal fraction, but its activity is low relative to the transferase activity present in the soluble fraction of the hepatocyte. We have found, however, that the activity of microsomal glutathione S-transferase is increased 5-fold after treatment with small unilamellar vesicles made from phosphatidylcholine. The increase in activity is due to the removal of an inhibitor of the enzyme from the microsomal membrane. The inhibitor is present in the organic layer of a washed Folch extract of the microsomal fraction. When this fraction of the microsomal extract is reconstituted in the form of small unilamellar vesicles, it inhibits microsomal glutathione S-transferase that had been activated by prior treatment with small unilamellar vesicles of pure phosphatidylcholine, but does not affect the activity of unactivated microsomal glutathione S-transferase. The inhibitor did not seem to be formed during the isolation of the microsomal fraction, and hence may be a physiological regulator of microsomal glutathione S-transferase. In this regard, both free fatty acid (palmitate) and lysophosphatidylcholine were shown to inhibit the enzyme reversibly. The results indicate that the activity of microsomal glutathione S-transferase is far greater than appreciated until now, and that this form of the enzyme may be an important factor in the hepatic metabolism of toxic electrophiles.


Papillary carcinoma.
In addition to a description of the basic criteria for the diagnosis of papillary carcinoma, a review of discussions by all workshop participants on the illustrative cases is presented. Areas of consensus included the following: classification of mixed papillary and follicular carcinomas as papillary, regardless of follicular dominance; recognition of three morphological variants--follicular, encapsulated, and diffuse sclerosing; nonspecificity of individual histological criteria, with the necessity to utilize a combination of characteristic features as guidelines for establishing a diagnosis; citing of nuclear features as probably the most important diagnostic criteria, ie, increased N/C ratio, irregularity in outline, and paleness of staining (ground glass appearance); grading of tumors on the basis of either cytological or architectural characteristics remains of unproven prognostic value. (Gross extent of tumor at the first operation remains the most valuable single prognostic criterion.); defining small carcinomas by size rather than using the imprecise term "occult" with its variable definitions including some clinically evident tumors; classifying as undifferentiated those carcinomas presenting a mixed papillary and anaplastic appearance at the time of the first operation, and retaining the papillary designation for papillary cancers which later undergo dedifferentiation; and recognition that thyroglobulin is a constant and keratin an inconstant tumor cell marker, with the latter not specific for distinguishing papillary carcinomas from follicular carcinomas or from hyperplastic adenomas.


Semantics and ambiguity of stochastic RNA family models.
Stochastic models, such as hidden Markov models or stochastic context-free grammars (SCFGs) can fail to return the correct, maximum likelihood solution in the case of semantic ambiguity. This problem arises when the algorithm implementing the model inspects the same solution in different guises. It is a difficult problem in the sense that proving semantic nonambiguity has been shown to be algorithmically undecidable, while compensating for it (by coalescing scores of equivalent solutions) has been shown to be NP-hard. For stochastic context-free grammars modeling RNA secondary structure, it has been shown that the distortion of results can be quite severe. Much less is known about the case when stochastic context-free grammars model the matching of a query sequence to an implicit consensus structure for an RNA family. We find that three different, meaningful semantics can be associated with the matching of a query against the model--a structural, an alignment, and a trace semantics. Rfam models correctly implement the alignment semantics, and are ambiguous with respect to the other two semantics, which are more abstract. We show how provably correct models can be generated for the trace semantics. For approaches, where such a proof is not possible, we present an automated pipeline to check post factum for ambiguity of the generated models. We propose that both the structure and the trace semantics are worth-while concepts for further study, possibly better suited to capture remotely related family members.


EMAS clinical guide: selective estrogen receptor modulators for postmenopausal osteoporosis.
Osteoporosis and the resulting fractures are major public health issues as the world population is ageing. Various therapies such as bisphosphonates, strontium ranelate and more recently denosumab are available. This clinical guide provides the evidence for the clinical use of selective estrogen modulators (SERMs) in the management of osteoporosis in postmenopausal women.


Genome wide analysis of transcript levels after perturbation of the EGFR pathway in the Drosophila ovary.
Defects in the epidermal growth factor receptor (EGFR) pathway can lead to aggressive tumor formation. Activation of this pathway during normal development produces multiple outcomes at the cellular level, leading to cellular differentiation and cell cycle activation. To elucidate the downstream events induced by this pathway, we used genome-wide cDNA microarray technology to identify potential EGFR targets in Drosophila oogenesis. We focused on genes for which the transcriptional responses due to EGFR pathway activation and inactivation were in opposite directions, as this is expected for genes that are directly regulated by the pathway in this tissue type. We perturbed the EGFR pathway in epithelial follicle cells using seven different genetic backgrounds. To activate the pathway, we overexpressed an activated form of the EGFR (UAS-caEGFR), and an activated form of the signal transducer Raf (UAS-caRaf); we also over- or ectopically expressed the downstream homeobox transcription factor Mirror (UAS-mirr) and the ligand-activating serine protease Rhomboid (UAS-rho). To reduce pathway activity we used loss-of-function mutations in the ligand (gurken) and receptor (torpedo). From microarrays containing 6,255 genes, we found 454 genes that responded in an opposite manner in gain-of-function and loss-of-function conditions among which are many Wingless signaling pathway components. Further analysis of two such components, sugarless and pangolin, revealed a function for these genes in late follicle cell patterning. Of interest, components of other signaling pathways were also enriched in the EGFR target group, suggesting that one reason for the pleiotropic effects seen with EGFR activity in cancer progression and development may be its ability to regulate many other signaling pathways.


In vitro enzyme activation and folded stability of Pseudomonas aeruginosa exotoxin A and its C-terminal peptide.
Pseudomonas aeruginosa exotoxin A(ETA) and its C-terminal, enzymatically active fragment (PE40, 375 residues) were studied by high-performance size-exclusion chromatography, steady-state and stopped-flow fluorescence spectroscopy, and circular dichroism spectroscopy. Both proteins have been overexpressed and purified by high-performance liquid chromatography. The effect of various activation conditions (pH, urea, and DTT) on enzymatic activity was studied. Upon enzymatic activation, structural changes induced within both proteins' structures were monitored, and these changes were correlated with concomitant alterations in the catalytic activity of the proteins. The pH optimum of enzymatic activity for both ETA and PE40 was between 7.0 and 8.0, decreasing to nearly zero at acidic (pH 5.0) and basic (pH 11-12) values. Analysis of the pH titration data revealed the presence of two distinct pKa values which implicate a His residue(s) (likely His-440 and -426) and a Tyr or Lys residue (possibly Tyr-481). The identity and possible role of an active site Lys residue is not known. Additionally, a significant increase in the Stokes radii of both proteins was detected when the pH was lowered from 8.0 to 6.0. The enzymatic activity of PE40 was not affected by urea or DTT, and its Stokes radius decreased monotonically with increasing urea concentration in the presence of DTT. In contrast, the enzymatic activity of ETA peaked when the protein was preincubated with 4.0 M urea, and this coincided with a large transition (increase) in the protein's Stokes radius between 3 and 5 M urea. Furthermore, loss of helical secondary structure of both PE40 and ETA commenced at approximately 2 M urea and progressively diminished at higher denaturant concentrations. The unfolding of both proteins in urea (and DTT) was reversible, and the free energies of unfolding were determined by both circular dichroism and fluorescence spectroscopy and were found to be 13.7 +/- 2.9 and 9.8 +/- 3.4 kJ/mol, respectively, for ETA and were 17.8 +/- 6.8 and 7.5 +/- 3.6 kJ/mol, respectively, for PE40. The refolding rate of PE40 was relatively rapid [t 1/2(1) = 27 s, t 1/2(2) = 624 s], which was in stark contrast to the refolding rate of ETA (t 1/2 = several hours). The relative refolding rates of PE40 and ETA help to explain the mechanism of in vitro enzyme activation and assay.


CDKN2A was a cuproptosis-related gene in regulating chemotherapy resistance by the MAGE-A family in breast cancer: based on artificial intelligence (AI)-constructed pan-cancer risk model.
Before the discovery of cuproptosis, copper-loaded nanoparticle is a wildly applied strategy for enhancing the tumor-cell-killing effect of chemotherapy. Although copper(ii)-related researches are wide, details of cuproptosis-related bioprocess in pan-cancer are not clear yet now, especially for prognosis and drug sensitivity prediction yet now. In this study, VOSviewer is used for the literature review, and R4.2.0 is used for data analysis. Public data are collected from TCGA and GEO, local breast cancer cohort is collected to verify the expression level of CDKN2A. 7036 published articles exhibited a time-dependent linear relationship (R=0.9781, p<0.0001), and breast cancer (33.4%) is the most researched topic. Cuproptosis-related-genes (CRGs)-based unsupervised clustering divides pan-cancer subgroups into four groups (CRG subgroup) with differences in prognosis and tumor immunity. 44 tumor-driver-genes (TDGs)-based prediction model of drug sensitivity and prognosis is constructed by artificial intelligence (AI). Based on TDGs and clinical features, a nomogram is (C- index: 0.7, p= 6.958e- 12) constructed to predict the prognosis of breast cancer. Importance analysis identifies CDKN2A has a pivotal role in AI modeling, whose higher expression indicates worse prognosis in breast cancer. Furthermore, inhibition of CDKN2A down-regulates decreases Snail1, Twist1, Zeb1, vimentin and MMP9, while E-cadherin is increased. Besides, inhibition of CDKN2A also decreases the expression of MEGEA4, phosphorylated STAT3, PD-L1, and caspase3, while cleaved-caspase3 is increased. Finally, we find down-regulation of CDKN2A or MAGEA inhibits cell migration and wound healing, respectively. AI identified CRG subgroups in pan-cancer based on CRGs-related TDGs, and 44-gene-based AI modeling is a novel tool to identify chemotherapy sensitivity in breast cancer, in which CDKN2A/MAGEA4 pathway played the most important role.


Vessel wall signal enhancement on 3-T MRI in acute stroke patients after stent retriever thrombectomy.
OBJECTIVE In vivo and in vitro studies have demonstrated histological evidence of iatrogenic endothelial injury after stent retriever thrombectomy. However, noncontrast vessel wall (VW)-MRI is insufficient to demonstrate vessel injury. Authors of this study prospectively evaluated iatrogenic endothelial damage after stent retriever thrombectomy in humans by utilizing high-resolution contrast-enhanced VW-MRI. Characterization of VW-MRI changes in vessels subject to mechanical injury from thrombectomy may allow better understanding of the biological effects of this intervention. METHODS The authors prospectively recruited 11 patients for this study. The treatment group included 6 postthrombectomy patients and the control group included 5 subjects undergoing MRI for nonvascular indications. All subjects were evaluated on a Signa HD× 3.0-T MRI scanner with an 8-channel head coil. Both pre- and postcontrast T1-weighted Cube VW images as well as MR angiograms were acquired. Sequences obtained for evaluation of the brain parenchyma included diffusion-weighted, gradient echo, and T2-FLAIR imaging. Two independent neuroradiologists, who were blinded to the treatment status of each patient, determined the presence of VW enhancement. Patient age, National Institutes of Health Stroke Scale score on presentation, location of occlusion, stroke etiology, type of device used, number of device deployments, Thrombolysis in Cerebral Infarction (TICI) reperfusion score, stroke volume, and 90-day modified Rankin Scale score were also noted. RESULTS Postcontrast T1-weighted VW enhancement was detected in the M2 segment in 100% of the thrombectomy patients, in the M1 segment in 83%, and in the internal carotid artery in 50%. One patient also demonstrated A1 segment enhancement, which was attributable to thrombectomy treatment of that vessel segment during the same procedure. None of the control patients demonstrated VW enhancement of their intracranial vasculature on T1-weighted images. CONCLUSIONS The study findings suggest that VW injury incurred during stent retriever thrombectomy can be reliably detected utilizing contrast-enhanced 3-T VW-MRI. The results further demonstrate that endothelial injury is associated with oversizing of stent retrievers relative to the treated vessel. Further studies are needed to evaluate the clinical significance of endothelial injury and to characterize the differential effects of various devices.


Axillary lymphadenopathy at the time of COVID-19 vaccination: ten recommendations from the European Society of Breast Imaging (EUSOBI).
Unilateral axillary lymphadenopathy is a frequent mild side effect of COVID-19 vaccination. European Society of Breast Imaging (EUSOBI) proposes ten recommendations to standardise its management and reduce unnecessary additional imaging and invasive procedures: (1) in patients with previous history of breast cancer, vaccination should be performed in the contralateral arm or in the thigh; (2) collect vaccination data for all patients referred to breast imaging services, including patients undergoing breast cancer staging and follow-up imaging examinations; (3) perform breast imaging examinations preferentially before vaccination or at least 12 weeks after the last vaccine dose; (4) in patients with newly diagnosed breast cancer, apply standard imaging protocols regardless of vaccination status; (5) in any case of symptomatic or imaging-detected axillary lymphadenopathy before vaccination or at least 12 weeks after, examine with appropriate imaging the contralateral axilla and both breasts to exclude malignancy; (6) in case of axillary lymphadenopathy contralateral to the vaccination side, perform standard work-up; (7) in patients without breast cancer history and no suspicious breast imaging findings, lymphadenopathy only ipsilateral to the vaccination side within 12 weeks after vaccination can be considered benign or probably-benign, depending on clinical context; (8) in patients without breast cancer history, post-vaccination lymphadenopathy coupled with suspicious breast finding requires standard work-up, including biopsy when appropriate; (9) in patients with breast cancer history, interpret and manage post-vaccination lymphadenopathy considering the timeframe from vaccination and overall nodal metastatic risk; (10) complex or unclear cases should be managed by the multidisciplinary team.


Arginine vasotocin: site and mode of action in the reptilian kidney.
Recent morphological, physiological, and molecular studies that shed light on the functional significance of the neurohypophysial peptide arginine vasotocin (AVT) in the reptilian kidney are reviewed. Several structural features of the reptilian nephron are highlighted, including the presence of an incipient juxta-glomerular apparatus, aglomerular nephrons, and the thin, very short intermediate segment (IS) joining proximal and distal convoluted tubules. Although the V(2)-like AVT receptor and its gene have yet to be sequenced in any reptile, AVT receptors have been located in both the IS and the branched collecting duct system in the agamid lizard Ctenophorus ornatus. These findings suggest that AVT may have a dual effect in the reptilian kidney, first diluting the urinary fluid in the thin-intermediate segment, prior to its entering the collecting duct system, and then facilitating water reabsorption along an osmotic gradient as the urine passes through the final segments of the nephron. The IS may thus prove to be the evolutionary homologue of the thin-ascending limb of the loop of Henle in the mammalian kidney.


Inhibitory effect of epigallocatechin-gallate on brain tumor cell lines in vitro.
We investigated the effect of epigallocatechin-gallate (EGCG), the main constituent of green tea polyphenols, on human glioblastoma cell lines U-373 MG and U-87 MG, rat glioma cell line C6, and rat nonfunctioning pituitary adenoma cell line MtT/E. Cell viability was determined by assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and the extent of apoptosis was studied by flow cytometric analysis. Apoptosis was also characterized by morphology using fluorescent microscopy. The role of insulin-like growth factor-I (IGF-I) was studied by assay with MTT, immunohistochemistry, and immunoradiometric assay. After 72-h exposure, a statistically significant loss of viability (P = < 0.0001) was observed at concentrations of 12.5, 25, 50, and 100 microg/ml in U-373 MG cells and U-87 MG cells. EGCG at concentrations of 50 microg/ml and higher significantly reduced the viability of C6 cells. EGCG inhibited viability of MtT/E cells only at a concentration of 100 microg/ml. Quantitative study by flow cytometry demonstrated that lower doses of EGCG (12.5, 25, 50 microg/ml) induced apoptosis in U-373 MG, U-87 MG, and C6 cells; however, only the highest dose (100 microg/ml) induced apoptosis in MtT/E cells. Compared with other cell lines, MtT/E cells showed stronger IGF-I immunoreactivity. Neutralization of IGF-I with an antihuman IGF-I antibody reduced viability of the cell lines. It can be concluded that EGCG has an inhibitory effect on malignant brain tumors, and IGF-I may be involved in the effects of EGCG.


Osteoid osteoma of the cuboid bone: a rare cause of foot pain.
Osteoid osteoma, a common bone lesion of benign nature, is more rarely seen in feet. It most commonly involves the talus yet rarely the cuboid. The atypical symptoms of foot involvement may delay the diagnosis. Differential diagnosis most commonly includes ankle sprain, monoarticular arthritis, anterior impingement syndrome, tarsal spur, osteomyelitis, stress fracture, eosinophilic granuloma. The delay in diagnosis and treatment of osteoid osteoma in the foot may be a cause of chronic foot pain. In this study, we present a 17-year-old boy with osteoid osteoma in his right cuboid bone. The patient was undiagnosed during the first year of his symptoms. After surgical removal of the tumor, his complaints were resolved. The pathological examination confirmed the diagnosis of osteoid osteoma. Osteoid osteoma is an unusual bone tumor of the foot. It should be included in the differential diagnosis of patients exhibiting foot pain. In speculative cases with no obvious radiographic findings, further imaging studies, such as CT, should be considered.


Recurrent aphthous stomatitis.
Etiology and Epidemiology: The Greek term aphthai was initially used in relation to disorders of the mouth and is credited to Hippocrates (460-370 BC). Today, recurrent aphthous ulceration, or recurrent aphthous stomatitis (RAS), is recognized as the most common oral mucosal disease known to human beings. Considerable research attention has been devoted to elucidating the causes of RAS; local and systemic conditions, and genetic, immunologic, and infectious microbial factors all have been identified as potential etiopathogenic agents (Table 1). However, to date, no principal etiology has been discovered. Epidemiologic studies indicate that the prevalence of RAS is between 2% and 50% in the general population; most estimates fall between 5% and 25%. In selected groups, such as medical and dental students, it has been observed with a frequency as high as 50% to 60%. The peak age of onset for RAS is between 10 and 19 years. After childhood and adolescence, it may continue throughout the entire human lifespan without geographic or age-, sex-, or race-related preference.


Near-infrared autofluorescence imaging to detect parathyroid glands in thyroid surgery.
Objective To identify and save parathyroid glands during thyroidectomy by displaying their autofluorescence. Methods Autofluorescence imaging was carried out during thyroidectomy with and without central lymph node dissection. After visual recognition by the surgeon, the parathyroid glands and the surrounding tissue were exposed to near-infrared light with a wavelength of 690-770 nm using a modified Karl Storz near infrared/indocyanine green endoscopic system. Parathyroid tissue was expected to show near infrared autofluorescence at 820 nm, captured in the blue channel of the camera. Results We investigated 41 parathyroid glands from 20 patients; 37 glands were identified correctly based on near-infrared autofluorescence. Neither lymph nodes nor thyroid revealed substantial autofluorescence and nor did adipose tissue. Conclusions Parathyroid tissue is characterised by showing autofluorescence in the near-infrared spectrum. This effect can be used to identify and preserve parathyroid glands during thyroidectomy.


Lasers and laser-like devices: part two.
Part two of this review series evaluates the use of lasers and laser-like devices in dermatology based on published evidence and the collective experience of the senior authors. Dermatologists can laser-treat a wide range of dermatoses, including vascular, pigmentary, textural, benign proliferative and premalignant conditions. Some of these conditions include vascular malformation, haemangioma, facial telangiectases, café-au-lait macules, naevi of Ota, lentigines, acne scarring, rhytides, rhinophyma and miscellaneous skin lesions. Photodynamic therapy with lasers and intense pulsed light is addressed, with particular reference to actinic keratosis and actinic cheilitis. A treatment algorithm for acne scarring based on scar morphology and severity is comprehensively outlined. Following from part one, the various devices are matched to the corresponding dermatological conditions with representative pictorial case vignettes illustrating likely clinical outcomes as well as limitations and potential complications of the various laser and light therapies.


The histone deacetylase inhibitor trichostatin A suppresses murine innate allergic inflammation by blocking group 2 innate lymphoid cell (ILC2) activation.
Group 2 innate lymphoid cells (ILC2) are an important source of the type 2 cytokines interleukin (IL)-5 and IL-13 that are critical to the allergic airway phenotype. Previous studies reported that histone deacetylase (HDAC) inhibition by trichostatin A (TSA) downregulated adaptive allergic immune responses; however, the effect of HDAC inhibition on the early innate allergic immune response is unknown. Therefore, we investigated the effect of TSA on innate airway inflammation mediated by ILC2 activation. BALB/c mice were challenged intranasally with Alternaria extract, exogenous recombinant mouse IL-33 (rmIL-33) or the respective vehicles for four consecutive days following TSA or vehicle treatment. Bronchoalveolar lavage (BAL) fluids and lungs were harvested 24 h after the last challenge. We found that TSA treatment significantly decreased the number of ILC2 expressing IL-5 and IL-13 in the lungs challenged with Alternaria extract or rmIL-33 compared with vehicle treatment (p<0.05). TSA treatment significantly decreased protein expression of IL-5, IL-13, CCL11 and CCL24 in the lung homogenates from Alternaria extract-challenged mice or rmIL-33-challenged mice compared with vehicle treatment (p<0.05). Further, TSA treatment significantly decreased the number of perivascular eosinophils and mucus production in the large airways that are critical components of the asthma phenotype (p<0.05). TSA did not change early IL-33 release in the BAL fluids; however, TSA decreased lung IL-33 expression from epithelial cells 24 h after last Alternaria extract challenge compared with vehicle treatment (p<0.05). These results reveal that TSA reduces allergen-induced ILC2 activation and the early innate immune responses to an inhaled protease-containing aeroallergen.


Congestive cardiomyopathy induced in ducklings fed graded amounts of furazolidone.
Newly hatched male White Pekin ducklings (n = 119) were allotted to 7 groups of 17 each and fed furazolidone (FZ) at dose levels of 0, 100, 250, 500, 750, 1,000, and 1,250 mg/kg of feed for 4 weeks. The frequency and severity of clinical signs of FZ toxicosis, including growth retardation, ascites, and mortality, were dose related. At necropsy, the affected ducklings had ascites, hydropericardium, and biventricular dilatation. The frequencies of cardiomyopathy, ascites, and mortality, respectively, for the several dose levels of drug were as follows: 0, 100, and 250 mg of FZ/kg of feed--0%, 0%, 0%; for the 500 mg/kg level--35%, 12%, 0%; for the 750 mg/kg level--100%, 53%, 18%; for the 1,000 mg/level--79%, 57%, 57%; and for the 1,250 mg/kg level--33%, 20%, 73%. Ducklings with FZ-induced congestive cardiomyopathy had decreased left ventricular free wall and ventricular septal thickness, increased left ventricular chamber diameter, increased left ventricular dilatation score, decreased absolute heart weight, and increased relative heart weight. Cardiac histopathologic changes were minimal; some ducklings had myocytolysis. Liver and lungs were congested. Furazolidone-induced cardiomyopathy in ducklings offers a model for studies of congestive cardiomyopathy in a species that is free from the hereditary cardiomyopathy ("round heart disease") seen in turkeys.


Hypertrophy without increased isometric strength after weight training.
Eight men (20-23 years) weight trained 3 days.week-1 for 19 weeks. Training sessions consisted of six sets of a leg press exercise (simultaneous hip and knee extension and ankle plantar flexion) on a weight machine, the last three sets with the heaviest weight that could be used for 7-20 repetitions. In comparison to a control group (n = 6) only the trained group increased (P less than 0.01) weight lifting performance (heaviest weight lifted for one repetition, 29%), and left and right knee extensor cross-sectional area (CAT scanning and computerized planimetry, 11%, P less than 0.05). In contrast, training caused no increase in maximal voluntary isometric knee extension strength, electrically evoked knee extensor peak twitch torque, and knee extensor motor unit activation (interpolated twitch method). These data indicate that a moderate but significant amount of hypertrophy induced by weight training does not necessarily increase performance in an isometric strength task different from the training task but involving the same muscle group. The failure of evoked twitch torque to increase despite hypertrophy may further indicate that moderate hypertrophy in the early stage of strength training may not necessarily cause an increase in intrinsic muscle force generating capacity.


Spindle cell lipoma of the oral cavity. Report of a rare intramuscular case with fine needle aspiration findings.
Spindle cell lipoma (SCL) is a benign neoplasm characterized by a mixture of mature fat, bland spindle cells and wiry collagen in a variably myxoid background. Oral SCLs are rare, and only four cases of intramuscular SCL exist in the literature. We report the first case of intramuscular SCL of the oral cavity with fine needle aspiration (FNA) findings. A 61-year-old woman presented with a 3-cm mass in the right gingivobuccal sulcus. Papanicolaoustained FNA smears were hypocellular and contained loose collections of spindle cells in a myxoid background, numerous mast cells, rare capillary fragments and portions of skeletal muscle. The spindle cells had mild nuclear enlargement, focal nuclear irregularities, rare intranuclear inclusions and occasional small nucleoli. No lipoblasts or mitoses were identified. There was intermingling of the spindle cells with the skeletal muscle fragments. Intraoral SCL is a rare lesion but should be considered in the differential for a benign spindle cell neoplasm in the oral cavity. Clues to diagnosis on cytology include mature fat, bland spindle cells, a myxoid background and mast cells.


ADP-induced platelet shape change: an investigation of the signalling pathways involved and their dependence on the method of platelet preparation.
Shape change is an important early event in platelet activation. In this study we show that the Ca2+ chelator BAPTA and the Rho-kinase inhibitor Y-27632 inhibit ADP-induced myosin light chain (MLC) phosphorylation and platelet shape change through distinct pathways and with distinct kinetics. Ca2+ is largely responsible for the initial onset of shape change, whilst Rho-kinase plays a major role in the maintenance of the response. The relative contribution of these two pathways to each stage of the response was dependent on the method of platelet preparation, but in all cases shape change was shown to be downstream of the P2Y1 receptor. Similar observations were made in murine platelets. The shape change response was modulated via changes in cAMP levels, possibly via the P2TAC receptor, but not by tyrosine phosphorylation. We conclude that ADP-induced shape change occurs via the P2Y1 receptor, which can be differentially coupled to Rho-kinase and Ca2+-linked pathways dependent on the method of platelet preparation.


Chemokines as adjuvants for immunotherapy: implications for immune activation with CCL3.
Immunotherapy embodies any approach that manipulates the immune system for therapeutic benefit. In this regard, various clinical trials have employed direct vaccination with patient-specific dendritic cells or adoptive T cell therapy to target highly aggressive tumors. Both modalities have demonstrated great specificity, an advantage that is unmatched by other treatment strategies. However, their full potential has yet to be realized. Areas covered: In this review, we provide an overview of chemokines in pathogen and anti-tumor immune responses and discuss further improving immunotherapies by arming particular chemokine axes. Expert commentary: The chemokine macrophage inflammatory protein-1 alpha (MIP-1α, CCL3) has emerged as a potent activator of both innate and adaptive responses. Specifically, CCL3 plays a critical role in recruiting distinct immune phenotypes to intratumoral sites, is a pivotal player in regulating lymph node homing of dendritic cell subsets, and induces antigen-specific T cell responses. The recent breadth of literature outlines the various interactions of CCL3 with these cellular subsets, which have now served as a basis for immunotherapeutic translation.


Crusted (Norwegian) scabies. Occurrence in a child undergoing a bone marrow transplant.
A case of crusted (Norwegian) scabies is reported in a child who was a recipient of a bone marrow transplant. The infestation is presumed to have predated the bone marrow transplant and continued asymptomatically during chemotherapy and total body x-irradiation in preparation for transplant. The child was asymptomatic until 23 days after transplantation, when bone marrow engraftment was attained. The altered host-parasite relationship is emphasized by the observation that the onset of symptomatic pruritus coincided with successful engraftment.


A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility.
Multiple morphological abnormalities of the sperm flagellum (MMAF) is a severe form of male infertility defined by the presence of a mosaic of anomalies, including short, bent, curled, thick, or absent flagella, resulting from a severe disorganization of the axoneme and of the peri-axonemal structures. Mutations in DNAH1, CFAP43, and CFAP44, three genes encoding axoneme-related proteins, have been described to account for approximately 30% of the MMAF cases reported so far. Here, we searched for pathological copy-number variants in whole-exome sequencing data from a cohort of 78 MMAF-affected subjects to identify additional genes associated with MMAF. In 7 of 78 affected individuals, we identified a homozygous deletion that removes the two penultimate exons of WDR66 (also named CFAP251), a gene coding for an axonemal protein preferentially localized in the testis and described to localize to the calmodulin- and spoke-associated complex at the base of radial spoke 3. Sequence analysis of the breakpoint region revealed in all deleted subjects the presence of a single chimeric SVA (SINE-VNTR-Alu) at the breakpoint site, suggesting that the initial deletion event was potentially mediated by an SVA insertion-recombination mechanism. Study of Trypanosoma WDR66's ortholog (TbWDR66) highlighted high sequence and structural analogy with the human protein and confirmed axonemal localization of the protein. Reproduction of the human deletion in TbWDR66 impaired flagellar movement, thus confirming WDR66 as a gene associated with the MMAF phenotype and highlighting the importance of the WDR66 C-terminal region.


Hippocampal pathology reflects memory deficit and brain imaging measurements in Alzheimer's disease: clinicopathologic correlations using three sets of pathologic diagnostic criteria.
Neurofibrillary tangles (NFT), neuritic plaques and amyloid load were quantified in sections of the hippocampus at the level of the lateral geniculate body in 41 consecutive cases fulfilling pathological criteria for diagnosis of Alzheimer's disease (AD) and coming to autopsy after longitudinal study during life. A strong correlation was found between NFT density in the hippocampus and cognitive impairment scores obtained shortly before death, particularly with scores of memory impairment. Weaker and less consistent correlations were found for hippocampal neuritic plaques and amyloid load with cognitive/memory deficits. No significant correlations were found between hippocampal pathology and either age of onset or disease duration. All three measures of hippocampal pathology were inversely correlated with the minimum medial temporal lobe (MTL) width, a measure of the MTL atrophy made from temporal-lobe-oriented X-ray computed tomography scans performed during life; the strongest correlation being between atrophy of the MTL and NFT density in the hippocampus.