Fermentation temperature modulates phosphatidylethanolamine and phosphatidylinositol levels in the cell membrane of Saccharomyces cerevisiae.
During alcoholic fermentation, Saccharomyces cerevisiae is exposed to a host of environmental and physiological stresses. Extremes of fermentation temperature have previously been demonstrated to induce fermentation arrest under growth conditions that would otherwise result in complete sugar utilization at "normal" temperatures and nutrient levels. Fermentations were carried out at 15°C, 25°C, and 35°C in a defined high-sugar medium using three Saccharomyces cerevisiae strains with diverse fermentation characteristics. The lipid composition of these strains was analyzed at two fermentation stages, when ethanol levels were low early in stationary phase and in late stationary phase at high ethanol concentrations. Several lipids exhibited dramatic differences in membrane concentration in a temperature-dependent manner. Principal component analysis (PCA) was used as a tool to elucidate correlations between specific lipid species and fermentation temperature for each yeast strain. Fermentations carried out at 35°C exhibited very high concentrations of several phosphatidylinositol species, whereas at 15°C these yeast strains exhibited higher levels of phosphatidylethanolamine and phosphatidylcholine species with medium-chain fatty acids. Furthermore, membrane concentrations of ergosterol were highest in the yeast strain that experienced stuck fermentations at all three temperatures. Fluorescence anisotropy measurements of yeast cell membrane fluidity during fermentation were carried out using the lipophilic fluorophore diphenylhexatriene. These measurements demonstrate that the changes in the lipid composition of these yeast strains across the range of fermentation temperatures used in this study did not significantly affect cell membrane fluidity. However, the results from this study indicate that fermenting S. cerevisiae modulates its membrane lipid composition in a temperature-dependent manner.


Moving from maternal death review to surveillance and response: A paradigm shift.
In the era of the sustainable development goals, India is committed to reduce its maternal mortality ratio to less than 70 per one lakh live births by 2030. An important strategy that was adopted in the Reproductive and Child Health Programme in 2010 was maternal death review. Analysis of the progress so far has brought to light certain gaps which have prompted the paradigm shift toward Maternal Death Surveillance and Response (MDSR), which focuses on taking action on information obtained from every maternal death so as to prevent further maternal deaths. The new guidelines on MDSR were released by the Ministry of Health and Family Welfare in 2017.


Potential adverse effects of bronchodilators in the treatment of airways obstruction in older people: recommendations for prescribing.
Asthma and chronic obstructive pulmonary disease (COPD) are common disorders that are associated with increasing morbidity and mortality in older people. Bronchodilators are used widely in patients with these conditions, but even when used in inhaled form can have systemic as well as local effects. Older people experience more adverse drug effects because of pharmacodynamic and pharmacokinetic changes and particularly drug-drug and drug-disease interactions. Cardiovascular disease is common in older people and beta-adrenoceptor agonists (beta-agonists) have inotropic and chronotropic effects that can increase arrhythmias and cardiomyopathy. They can also worsen or induce myocardial ischaemia and cause electrolyte disturbances that contribute to arrhythmias. Tremor is a well known distressing adverse effect of beta-agonist administration. Long-term beta-agonist use can be associated with tolerance, poor disease control, sudden life-threatening exacerbations and asthma-related deaths. Functional beta2-adrenoceptors are present in osteoblasts, and chronic use of beta-agonists has been implicated in osteoporosis. Inhaled anticholinergics are usually well tolerated but may cause dry mouth, which can be troublesome in older people. Pupillary dilatation, blurred vision and acute glaucoma can occur from escape of droplets from loosely fitting nebulizer masks. Although ECG changes have not been seen in randomized controlled trials of long-acting inhaled anticholinergics, supraventricular tachycardias have been observed in a 5-year randomized controlled trial of ipratropium bromide. Paradoxical bronchoconstriction can occur with inhaled anticholinergics as well as with beta-agonists, but tolerance has not been reported with anticholinergics. Anticholinergic drugs also cause central effects, most notably impairment of cognitive function, and these effects have been noted with inhaled agents. Use of theophylline is limited by its adverse effects, which range from commonly occurring gastrointestinal symptoms to palpitations, arrhythmias and reports of myocardial infarction. Seizures have been reported, but are rare. Theophylline is metabolized primarily by the liver, and commonly interacts with other medications. Its concentration in plasma should be monitored closely, especially in older people. Although many clinical trials have been conducted on bronchodilators in obstructive airways disease, the results of these clinical trials need to be interpreted with caution as older people are often under-represented and subjects with co-morbidities actively excluded from these trials.


The method of bladder drainage in spinal cord injury patients may influence the histological changes in the mucosa of neuropathic bladder - a hypothesis.
In spinal cord injury (SCI) patients, no correlation was found between the number of bladder infections per year, the period since injury, the neurologic level of the spinal cord lesion and the histopathology of the urinary bladder mucosa. The use of chronic indwelling urethral and/or suprapubic catheters in SCI patients is often associated with inflammatory and proliferative pathological conditions in neuropathic bladder. We propose a hypothesis that the type of bladder drainage in SCI patients influences the histological changes in the mucosa of neuropathic bladder. This hypothesis implies that SCI patients with long-term indwelling urinary catheters develop certain histological changes in bladder mucosa, which are seen less frequently in SCI patients, who do not use long-term indwelling catheters. The latter group includes patients, who perform regular intermittent catheterisation and those, who wear a penile sheath and empty their bladders satisfactorily by reflex voiding. We hypothesise that the following histological lesions are seen more frequently in the neuropathic bladder of SCI patients with long-term indwelling catheters.(1) Papillary or polypoid cystitis; (2) widespread cystitis glandularis; (3) moderate to severe, acute and chronic inflammatory changes in bladder mucosa; (4) follicular cystitis; (5) squamous metaplasia; and (6) urothelial dysplasia. As per this hypothesis, it is postulated that the above pathological conditions are seen less often in SCI patients, who achieve complete, low-pressure emptying of the neuropathic bladder by regular intermittent catheterisation, and SCI patients with penile sheath drainage, who empty their bladders satisfactorily by reflex voiding. A large prospective study of bladder biopsies in SCI patients practising different methods of bladder drainage is required to validate this hypothesis that the histological changes in bladder mucosa are related to the method of bladder drainage in SCI patients. We propose a hypothesis that the method of bladder drainage in SCI patients influences histological changes in the bladder mucosa. If this hypothesis is validated, methods of bladder drainage such as intermittent catheterisation, which do not require the use of chronic indwelling catheters, should be recommended, in order to minimise adverse histological changes in the mucosa of neuropathic bladder of spinal cord injury patients.


Neuromuscular characterization of the urethra in continent women.
: The study's objective was to describe quantitative urethral function parameters in a racially diverse group of continent women. : After institutional review board approval, we recruited women without urinary incontinence from the community. To be considered continent, participants answered "never" to the first 6 questions on the stress subscale of the Medical, Epidemiologic, and Social Aspects of Aging urinary incontinence questionnaire. Participants all underwent quantitative concentric urethral electromyography (EMG) and urodynamic testing. : Thirty-one women with a mean (SD) age of 39 (14) years underwent EMG and urodynamic testing. The cohort was racially diverse with 13 (43%) white women, 13 (43%) African American women, and 4 (14%) Hispanic women. Body mass index (P = 0.12, 0.06), age (P = 0.40, 0.64), and vaginal parity (P = 0.53, 0.76) did not differ by race or ethnicity. We did not detect differences in any EMG parameter by race, ethnicity, or vaginally parity. A mean (range) of 30 (10-55) motor unit action potential (MUP) analyses was identified and analyzed in multiple MUP analysis, and 14 (8-21) were identified and analyzed in interference pattern (IP) analysis. On average, 37% (20%) (mean [SD]) MUPs were polyphasic.Age significantly correlated with several measures of urethral sphincter function. Increasing age was inversely correlated with IP turns (r = -0.57, P = 0.001), IP amplitude (r = -0.43, P = 0.02), IP turns-amplitude ratio (r = -0.54, P = 0.003), and maximum urethral closure pressures (r = -0.41, P = 0.04). Similarly, maximum urethral closure pressures correlated with IP amplitude (r = 0.38, P = 0.04). : These urethral neuromuscular function data on the largest cohort of continent women fully characterized with quantitative urethral EMG demonstrate significant neuropathic MUP changes with advancing age.


A population-based study of the associations of stroke occurrence with weather parameters in Siberia, Russia (1982-92).
Previous studies have established a seasonal variation in stroke occurrence, but none have assessed the influence of inclement weather conditions on stroke incidence in a general population of Russia. We performed a stroke population-based study in the Oktiabrsky District of Novosibirsk, Siberia, Russia. Included in the analysis were 1929 patients with their first occurrence of ischemic stroke (IS), 215 patients with their first occurrence of intracerebral hemorrhage (ICH) and 64 patients with their first occurrence of subarachnoid hemorrhage (SAH): all patients were aged between 25 and 74 years. The cumulative daily occurrence of total strokes and stroke subtypes was evaluated in relation to aggregated daily mean values of ambient temperature, relative humidity and air pressure by means of Poisson regression analysis to estimate the rate ratio (RR) with corresponding confidence interval (CI) and to identify the weather parameters of most importance. In a multivariate analysis, with adjustment for the effects of season, solar and geomagnetic activity, and age of the patients, low ambient temperature (RR 1.32; 95% CI 1.05-1.66) and mean value of air pressure (RR 0.986; 95% CI 0.972-0.999) were important predictors of IS occurrence, while mild ambient temperature (RR 1.52; 95% CI 1. 04-2.22) was an important predictor of ICH occurrence. No relationship between SAH occurrence and any one of the weather parameters studied was revealed. There was no interaction between any meteorological variables that was statistically significant. Inclement weather conditions are associated with the occurrence of IS and ICH in Siberia, Russia. Among the meteorological parameters studied, low ambient temperature and mean air pressure are the most important predictors of IS occurrence, whereas the occurrence of ICH is associated with mild ambient temperature. There is no association between any one of the weather parameters studied and the occurrence of SAH.


Comparison of the acute-phase response in patients with ischemic stroke treated with high-dose heparin or aspirin.
Experimental studies have suggested that unfractionated heparin (UH) has antiinflammatory properties. It is unknown whether UH also has these properties in patients with acute ischemic stroke. Within 12-24 h of treatment onset we measured the acute-phase response as reflected by the erythrocyte sedimentation rate (ESR) and total number of leukocytes (x10(9)/l) in 706 consecutive patients with acute ischemic stroke treated with full-dose UH (n=450), or 300 mg/day aspirin (n=256). Clinical outcome (Mathew scale) at hospital discharge and the effect of factors such as treatment (UH and aspirin), and acute phase response were assessed using multivariate analyses adjusted for baseline confounders and incident complications. Separate models were created for patients with lacunar and nonlacunar stroke. Whereas there were not differences at baseline between the two treatment groups, total leukocyte counts (8. 0+/-4.1 vs. 8.6+/-3.2, P<0.01) and ESR (21.7+/-20.9 vs. 25.2+/-22.9, P<0.05) were statistically significantly lower in patients treated with UH. This effect of UH was more accentuated in patients with nonlacunar stroke. Overall, leukocytes (7.2+/-2.3 vs. 8.4+/-4.0, P<0. 01), and ESR (15.7+/-17.2 vs. 24.3+/-22.2, P=0.0001) were lower in patients with complete early recovery and this effect was restricted to patients with nonlacunar stroke. Whereas baseline impairment, symptomatic bleeding and stroke recurrence were independent negative outcome predictors, the use of UH was positively associated with early recovery in all patients. This study shows that full-dose UH reduces the acute-phase reaction that follows ischemic stroke more effectively than aspirin. The prognostic implications of such effect seem more notable in patients with nonlacunar stroke.


Vagus nerve stimulation…25 years later! What do we know about the effects on cognition?
VNS therapy was delivered to patients for the first time in 1988. After 25 years, insight in the antiepileptic and antidepressant mechanism of action of VNS has grown steadily. The effects on cognition and especially memory remain controversial. This review provides an elaborate overview of studies addressing cognition and describes potential underlying mechanisms for the reported effects. Short-term VNS has an effect on verbal memory recognition when administered at the correct timing and dosage. Chronic VNS resulted into a positive effect on the cognitive status in an Alzheimer population. Positive effect of chronic VNS in epilepsy or depression patients on global cognitive functioning are less convincing. Neither do the results reveal a negative effect which has major implications for chronic treatment of neurology patients. A cascade of neurochemical processes put in motion by changes in NE concentrations in reaction to stimulation of the vagal nerve may underlie the VNS-induced effects on cognition and memory. In Alzheimer pathology, NE may act as an anti-inflammatory agent on brainstem nuclei.


Effects of propranolol on response to exercise in hypertrophic obstructive cardiomyopathy.
The circulatory, respiratory, and metabolic responses to steady state submaximal exercise have been studied in four women and two men with hypertrophic obstructive cardiomyopathy, before treatment, after intravenous, and after three months of oral propranolol. The physical working capacity was significantly lower than in normal subjects, and the response to exercise was characterized by a tachycardia, low cardiac output and stroke volume, and high ventilation and blood lactate concentration. After propranolol there was a significant reduction in heart rate, but changes in most other measurements were slight and there was no improvement in effort tolerance though angina was relieved in the two patients in whom it was present. The possible causes of breathlessness and effort intolerance in hypertrophic obstructive cardiomyopathy are discussed in relation to known effects of propranolol. It is concluded that further trial of propranolol and other beta-adrenergic blocking agents is warranted.


Utility of admission cardiac troponin and "Ischemia Modified Albumin" measurements for rapid evaluation and rule out of suspected acute myocardial infarction in the emergency department.
To assess if the combination of cardiac troponin (cTn) and Ischemia Modified Albumin (IMA) can be used for early exclusion of acute myocardial infarction (AMI). Prospective consecutive admissions to the emergency department (ED) with undifferentiated chest pain were assessed clinically and by electrocardiography. A total of 539 patients (335 men, 204 women; median age 51.9 years) considered at low risk of AMI had blood drawn on admission. If the first sample was less than 12 hours from onset of chest pain, a second sample was drawn two hours later, at least six hours from onset of chest pain. Creatine kinase MB isoenzyme (CKMB) mass was measured on the first sample and CKMB mass and cTnT on the second sample. An aliquot from the first available sample was frozen and subsequently analysed for IMA. If cTnT had not been measured on the original sample cTnI was measured (n = 189). Complete data were available for 538/539 patients. IMA or cTn was elevated in the admission sample of all patients with a final diagnosis of AMI (n = 37) with IMA alone elevated in 2/37, cTn alone in 19/37, and both in 16/37. In 173/501 patients in whom AMI was excluded both tests were negative. In the non-AMI group 22 patients had elevation of both IMA and cTn in the initial sample, suggesting ischaemic disease. Admission measurement of cardiac troponin plus IMA can be used for early classification of patients presenting to the ED to assist in patient triage.


Extra-classical tuning predicts stimulus-dependent receptive fields in auditory neurons.
The receptive fields of many sensory neurons are sensitive to statistical differences among classes of complex stimuli. For example, excitatory spectral bandwidths of midbrain auditory neurons and the spatial extent of cortical visual neurons differ during the processing of natural stimuli compared to the processing of artificial stimuli. Experimentally characterizing neuronal nonlinearities that contribute to stimulus-dependent receptive fields is important for understanding how neurons respond to different stimulus classes in multiple sensory modalities. Here we show that in the zebra finch, many auditory midbrain neurons have extra-classical receptive fields, consisting of sideband excitation and sideband inhibition. We also show that the presence, degree, and asymmetry of stimulus-dependent receptive fields during the processing of complex sounds are predicted by the presence, valence, and asymmetry of extra-classical tuning. Neurons for which excitatory bandwidth expands during the processing of song have extra-classical excitation. Neurons for which frequency tuning is static and for which excitatory bandwidth contracts during the processing of song have extra-classical inhibition. Simulation experiments further demonstrate that stimulus-dependent receptive fields can arise from extra-classical tuning with a static spike threshold nonlinearity. These findings demonstrate that a common neuronal nonlinearity can account for the stimulus dependence of receptive fields estimated from the responses of auditory neurons to stimuli with natural and non-natural statistics.


Morbidity and mortality in patients managed with high compared with low blood pressure targets during on-pump cardiac surgery: a systematic review and meta-analysis of randomized controlled trials.
Many believe that blood pressure management during cardiac surgery is associated with postoperative outcomes. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the impact of high compared with low intraoperative blood pressure targets on postoperative morbidity and mortality in adults undergoing cardiac surgery on cardiopulmonary bypass (CPB). Our primary objective was to inform the design of a future large RCT. We searched MEDLINE, EMBASE, Web of Science, CINAHL, and CENTRAL for RCTs comparing high with low intraoperative blood pressure targets in adult patients undergoing any cardiac surgical procedure on CPB. We screened reference lists, grey literature, and conference proceedings. We included eight RCTs (N =1,116 participants); all examined the effect of blood pressure management only during the CPB. Trial definitions of high compared with low blood pressure varied and, in some, there was a discrepancy between the target and achieved mean arterial pressure. We observed no difference in delirium, cognitive decline, stroke, acute kidney injury, or mortality between high and low blood pressure targets (very-low to low quality evidence). Higher blood pressure targets may have increased the risk of requiring a blood transfusion (three trials; n = 456 participants; relative risk, 1.4; 95% confidence interval, 1.1 to 1.9; P = 0.01; moderate quality evidence) but this finding was based on a small number of trials. Individual trial definitions of high and low blood pressure targets varied, limiting inferences. The effect of high (compared with low) blood pressure targets on other morbidity and mortality after cardiac surgery remains unclear because of limitations with the body of existing evidence. Research to determine the optimal management of blood pressure during cardiac surgery is required. PROSPERO (CRD42020177376); registered: 5 July 2020.


Ursodeoxycholic acid does not affect the clinical outcome of SARS-CoV-2 infection: A retrospective study of propensity score-matched cohorts.
Ursodeoxycholic acid (UDCA) has been recently proposed as a modulator of angiotensin-converting enzyme 2 (ACE2) receptor expression, with potential effects on COVID-19. We retrospectively evaluated the clinical course and outcome of subjects taking UDCA admitted to the hospital for COVID-19 compared with matched infected subjects. Differences regarding the severity and outcome of the disease between treated and non-treated subjects were assessed. The Kaplan-Meier survival analysis and log-rank test were used to evaluate the effect of UDCA on all-cause intra-hospital mortality. Among 6444 subjects with confirmed COVID-19 admitted to the emergency department (ED) from 1 March 2020 to 31 December 2022, 109 subjects were taking UDCA. After matching 629 subjects were included in the study: 521 in the no UDCA group and 108 in the UDCA group. In our matched cohort, 144 subjects (22.9%) died, 118 (22.6%) in the no-UDCA group and 26 (24.1%) in the UDCA group. The Kaplan-Meier analysis showed no significant difference in survival between groups. In univariate regression analysis, the presence of pneumonia, National Early Warning Score (NEWS) score, and Charlson Comorbidity Index (CCI) were significant independent predictors of death. At multivariate Cox regression analysis, age, NEWS, pneumonia and CCI index were confirmed significant independent predictors of death. UDCA treatment was not a predictor of survival both in univariate and multivariate regressions. UDCA treatment does not appear to have significant effects on the outcome of COVID-19. Specially designed prospective studies are needed to evaluate efficacy in preventing infection and severe disease.


Changes in cytokine profiles following treatment with food allergen-specific sublingual immunotherapy in dogs with adverse food reactions.
Food allergen-specific sublingual immunotherapy (FA-SLIT) is considered to be a novel, safe and effective approach in dogs with adverse food reactions (AFR). To investigate changes in key cytokines associated with FA-SLIT. Eleven dogs with confirmed AFR. Participants received either dose escalation of FA-SLIT or placebo over a six month period. Oral food challenge was performed at the beginning and end of the study, along with clinical examinations and collection of skin surface bacterial cytology and blood. Peripheral blood mononuclear cells were stimulated with the culprit food antigen. ELISA methods were used to quantify Interleukin (IL)-10, IFN-γ, IL-4 and IL-17A in the supernatant of stimulated cells. IL-10 and IFN-γ levels were significantly increased at the end of the study in the treatment group (T), compared with the placebo group (P), whereas no changes were found in IL-4 levels. IL-17A levels were decreased in both groups (but more profoundly in T). Bacterial scores on the skin were positively correlated with IL-17A and inversely correlated with IL-10 concentrations. Interleukins were not correlated with clinical scores. FA-SLIT may modulate the allergic response toward Th1 and Treg cell phenotypes, and induction of tolerance in dogs with AFR. Therefore, FA-SLIT may be a tool to desensitize dogs with AFR. However, more data on a larger number of cases and a broader panel of cytokines are needed to corroborate these findings, and to elucidate the mechanism of action for responses to FA-SLIT by dogs with AFR.


Variants of Papillary Thyroid Carcinoma: Multiple Faces of a Familiar Tumor.
Classically characterized by its papillary appearance, papillary thyroid carcinoma is the most common malignant neoplasm of the thyroid. Several variants of papillary carcinoma have been described considering size (microcarcinoma); nature of the tumor boundaries (encapsulated); architecture (follicular, macrofollicular, cribriform-morular, solid, micropapillary); cellular characteristics (tall cell, columnar, oncocytic, clear cell, hobnail); additional tumor components (papillary carcinoma with focal insular component, papillary carcinoma with spindle and giant cell carcinoma, papillary carcinoma with squamous cell carcinoma, papillary carcinoma with mucoepidermoid carcinoma); stromal features (papillary carcinoma with fasciitis like stroma); or a combination of the abovementioned characteristics (diffuse sclerosing, Warthin-like). Although most variants do not pose any diagnostic problems; some histological variants can be challenging to the pathologist and some are of clinical significance, because of prognostic implications or accompanying clinical conditions. It is not rare to find a papillary carcinoma showing characteristics of more than one variant. For example: an individual tumor can show hobnail features and present as a microcarcinoma; another case can show solid architecture and clear cytoplasm. In such cases, it is more important to comment on clinically relevant morphological characteristics of the tumor, rather than religiously trying to classify an individual tumor into a particular variant. In this review, pathologic and clinical features of papillary carcinoma variants are summarized.


Quantitative delineation of how breathing motions open ligand migration channels in myoglobin and its mutants.
Ligand migration and binding are central to the biological functions of many proteins such as myoglobin (Mb) and it is widely thought that protein breathing motions open up ligand channels dynamically. However, how a protein exerts its control over the opening and closing of these channels through its intrinsic dynamics is not fully understood. Specifically, a quantitative delineation of the breathing motions that are needed to open ligand channels is lacking. In this work, we present and apply a novel normal mode-based method to quantitatively delineate what and how breathing motions open ligand migration channels in Mb and its mutants. The motivation behind this work springs from the observation that normal mode motions are closely linked to the breathing motions that are thought to open ligand migration channels. In addition, the method provides a direct and detailed depiction of the motions of each and every residue that lines a channel and can identify key residues that play a dominating role in regulating the channel. The all-atom model and the full force-field employed in the method provide a realistic energetics on the work cost required to open a channel, and as a result, the method can be used to efficiently study the effects of mutations on ligand migration channels and on ligand entry rates. Our results on Mb and its mutants are in excellent agreement with MD simulation results and experimentally determined ligand entry rates.


Inhibition and Calendar Age Explain Variance in Game Performance of Youth Soccer Athletes.
The assessment of core executive functions (EFs; i.e., inhibition, working memory, cognitive flexibility) has often been presented as a diagnostic tool for evaluating cognitive functions in recent publications. For example, EFs are essential in soccer because players must quickly adapt, change strategies, and inhibit responses in rapidly changing game situations. Previous research has shown relations between (subjectively rated) game performance and the EFs of soccer players. Nevertheless, the previous studies' samples were heterogeneous in their performance level (experts vs. amateurs), and the ratings were rather unsystematic (no validated rating protocol). Therefore, the current study aimed to predict soccer players' game performance (i.e., systematically rated by coaches) with the help of EF performance. Therefore, we assessed the game performance (small-sided game, Game Performance Assessment Instrument [GPAI]) and EFs (inhibition: flanker task; working memory: 3-back task; cognitive flexibility: number-letter task) of 94 male soccer players (12-19 years old) from Germany's highest competitive level. Multiple regression model results indicate that inhibition (i.e., flanker effect) and calendar age explain ~18% of players' game performance variance. Results have to be interpreted with regard to the age-dependency of game performance and EFs. In conclusion, even though the results are based on a cross-sectional study, it appears that calendar age needs to be considered when assessing EFs.


ESGO/ESTRO/ESP guidelines for the management of patients with endometrial carcinoma.
A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.


Efficient fully 3D list-mode TOF PET image reconstruction using a factorized system matrix with an image domain resolution model.
A factorized system matrix utilizing an image domain resolution model is attractive in fully 3D time-of-flight PET image reconstruction using list-mode data. In this paper, we study a factored model based on sparse matrix factorization that is comprised primarily of a simplified geometrical projection matrix and an image blurring matrix. Beside the commonly-used Siddon's ray-tracer, we propose another more simplified geometrical projector based on the Bresenham's ray-tracer which further reduces the computational cost. We discuss in general how to obtain an image blurring matrix associated with a geometrical projector, and provide theoretical analysis that can be used to inspect the efficiency in model factorization. In simulation studies, we investigate the performance of the proposed sparse factorization model in terms of spatial resolution, noise properties and computational cost. The quantitative results reveal that the factorization model can be as efficient as a non-factored model, while its computational cost can be much lower. In addition we conduct Monte Carlo simulations to identify the conditions under which the image resolution model can become more efficient in terms of image contrast recovery. We verify our observations using the provided theoretical analysis. The result offers a general guide to achieve the optimal reconstruction performance based on a sparse factorization model with an image domain resolution model.


Guillain-Barre Syndrome in a Patient with Primary Extranodal Intestinal Non-Hodgkin's Lymphoma: Paraneoplastic, Drug Induced or Coincidental?
Neurological involvement is observed in 5%-25% of patients with lymphoma being either the first presentation of the disease or emerging during its course. However, Guillain-Barré syndrome is rarely reported. In this article, we present a case with intestinal lymphoma developing Guillain-Barré syndrome during the course of the disease. A 66-year-old male patient with primary extranodal intestinal lymphoma developed quadriparesis, sensory deficits and autonomic dysfunction while receiving chemotherapy. The findings of clinical, electrophysiological and laboratory examinations were consistent with Guillain-Barré syndrome. Guillain-Barré syndrome can potentially be fatal and mimic chemotherapy-induced neurotoxicity, especially in patients with lymphoma, and therefore, must be considered in the differential diagnosis.


[From knowledge of bacterial etiology to the treatment and prevention of the most prevalent infections in the community: odontological infections].
The prevalence of community odontological infections and their relevance to public health were reviewed. Knowledge of bacterial etiology (and the transmittability of these microbial agents) was used to study the disease (individual susceptibility to etiological agents) in order to review the effect of treatment on odontological pathogens and human microbials. The synergy between the primary care physician and the dentist is fundamental to the control of this endemic disease.


Phage HK022 Nun protein represses translation of phage lambda N (transcription termination/translation repression).
The N-terminal arginine-rich motif of phage HK022 Nun protein binds to NUT sequences in phage lambda nascent transcripts and induces transcription termination. Interactions between the Nun C terminus and RNA polymerase as well as the DNA template are required for termination. We have isolated Nun C-terminal point and deletion mutants that are unable to block transcription. The mutants bind NUT RNA and inhibit translation of the lambda N gene. Thus HK022 excludes lambda both by terminating transcription on the phage chromosome and by preventing translation of the essential lambda N gene. Like N autoregulation, translation repression by Nun requires host RNaseIII deficiency (rnc) or a mutation in the RNaseIII processing site (rIII) located between NUTL and the beginning of the N coding sequence. Our data support the idea that Nun bound at NUTL causes steric interference with ribosome attachment to the nearby N coding sequence. Two models, Nun acting alone or in complex with host proteins, are discussed.


[Cerebral circulation in the patients presenting with the early disorders of the sound perception function].
The present paper is focused on the study of the auditory function and cerebral circulation estimated based on the results of rheoencephalographc examination of 75 patients presenting with disordered sound perception and divided into two groups. Group 1 was comprised of the patients complaining of impaired hearing of the tones only within the extended frequency range (9-16 kHz), group 2 consisted of the patients suffering impaired hearing in the conventional frequency range (0.125-8 kHz). It was shown that the brainstem structures of the auditory analyzer in the patients of both groups remained unaffected whereas the cortical structures thereof in the patients of group 2 exhibited the signs of dysfunction. Cerebral circulation was disturbed in both groups, but its changes were especially well pronounced in the patients of group 2. These findings are of interest in the context of diagnostics and treatment of the patients presenting with early disorders of the sound perception function.


Renal function as a predictor of irinotecan-induced neutropenia.
Although approximately half of the administered dose of irinotecan is recovered in urine, scarce data are available on the association of renal function with irinotecan pharmacokinetics and toxicity. Here, these relationships are investigated in 187 patients treated with irinotecan in a three-weekly schedule. No significant effects on irinotecan pharmacokinetics were found in these patients. However, in 131 patients treated with the registered dose, categorized renal function was related to hematological toxicity. The incidence of grade 3-4 neutropenia decreased as function of creatinine clearance, particularly in nonsmoking patients (P < 0.01). Patients with slower creatinine clearance (35-66 ml/min) had a four-times higher risk of grade 3-4 neutropenia (58% vs. 14%; P < 0.001). This study suggests that pretreatment renal function values are associated with irinotecan-induced neutropenia. A confirmatory analysis is warranted to determine whether measures of renal function should be incorporated in future attempts toward individualized treatment with irinotecan.


Association between air pollution and lung function growth in southern California children: results from a second cohort.
A cohort of 1,678 Southern California children, enrolled as fourth graders in 1996, was followed for 4 years to determine whether the growth in lung function of the children was associated with their exposure to ambient air pollutants. These subjects comprised the second cohort of fourth grade children participating in the Children's Health Study. Significant deficits in lung function growth rate were associated with exposure to acid vapor, NO(2), particles with aerodynamic diameter less than 2.5 microm (PM(2.5)), and elemental carbon. For example, the average annual growth rates of maximal midexpiratory flow and forced expiratory volume in 1 second were reduced by approximately 11% (p = 0.005) and 5% (p = 0.03), respectively, across the observed range of acid exposure. Exposure to acid vapor was also associated with reductions in the ratio of maximal midexpiratory flow to forced vital capacity (p = 0.02), whereas exposure to ozone was correlated with reduced growth in peak flow rate (p = 0.006). Larger deficits in lung function growth rate were observed in children who reported spending more time outdoors. These findings provide important replication of our previous findings of an effect of air pollution on lung function growth that were based on the first fourth-grade cohort from the Children's Health Study (Am J Respir Crit Care Med 2000;162:1383-1390).


Garcinoic Acid Is a Natural and Selective Agonist of Pregnane X Receptor.
Pregnane X receptor (PXR) is a master xenobiotic-sensing transcription factor and a validated target for immune and inflammatory diseases. The identification of chemical probes to investigate the therapeutic relevance of the receptor is still highly desired. In fact, currently available PXR ligands are not highly selective and can exhibit toxicity and/or potential off-target effects. In this study, we have identified garcinoic acid as a selective and efficient PXR agonist. The properties of this natural molecule as a specific PXR agonist were demonstrated by the screening on a panel of nuclear receptors, the assessment of the physical and thermodynamic binding affinity, and the determination of the PXR-garcinoic acid complex crystal structure. Cytotoxicity, transcriptional, and functional properties were investigated in human liver cells, and compound activity and target engagement were confirmed in vivo in mouse liver and gut tissue. In conclusion, garcinoic acid is a selective natural agonist of PXR and a promising lead compound toward the development of new PXR-regulating modulators.


Coexistence of quiescent and active adult stem cells in mammals.
Adult stem cells are crucial for physiological tissue renewal and regeneration after injury. Prevailing models assume the existence of a single quiescent population of stem cells residing in a specialized niche of a given tissue. Emerging evidence indicates that both quiescent (out of cell cycle and in a lower metabolic state) and active (in cell cycle and not able to retain DNA labels) stem cell subpopulations may coexist in several tissues, in separate yet adjoining locations. Here, we summarize these findings and propose that quiescent and active stem cell populations have separate but cooperative functional roles.


Long-term follow-up of obstructive sleep apnea syndrome following surgery in children and adults.
Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent apneas during sleep, resulting in repetitive hypoxemia. The present study retrospectively analyzed subjective and objective assessments of the patients with OSAS in a relatively long-term follow-up. From February 1986 to August 1996, 53 patients received surgical treatment for OSAS and snoring. Thirty-seven (27 males and 10 females) out of 53 patients completed the questionnaire and postoperative sleep study was obtained in 6 patients. In 20 children (<15 years), snoring, sleep apnea, and daytime sleepiness completely disappeared in 12, 19, and 16, and improved in 8, 1, and 4, respectively. These findings confirm that tonsillectomy and/or adenoidectomy in children may be the first selection for treatment. In 17 adults, snoring, sleep apnea, and daytime sleepiness completely disappeared in 2, 5, and 8, improved in 11, 8, and 7, and was unchanged in 4, 4, and 1, respectively. The apnea index in adults was significantly decreased in both early and late postoperative periods. These results suggest that surgery is a satisfactory alternative for adult patients if performed accurate preoperative diagnosis of the localization of the airway collapse and careful long-term follow-up.


Wnt-induced transcriptional activation is exclusively mediated by TCF/LEF.
Active canonical Wnt signaling results in recruitment of β-catenin to DNA by TCF/LEF family members, leading to transcriptional activation of TCF target genes. However, additional transcription factors have been suggested to recruit β-catenin and tether it to DNA. Here, we describe the genome-wide pattern of β-catenin DNA binding in murine intestinal epithelium, Wnt-responsive colorectal cancer (CRC) cells and HEK293 embryonic kidney cells. We identify two classes of β-catenin binding sites. The first class represents the majority of the DNA-bound β-catenin and co-localizes with TCF4, the prominent TCF/LEF family member in these cells. The second class consists of β-catenin binding sites that co-localize with a minimal amount of TCF4. The latter consists of lower affinity β-catenin binding events, does not drive transcription and often does not contain a consensus TCF binding motif. Surprisingly, a dominant-negative form of TCF4 abrogates the β-catenin/DNA interaction of both classes of binding sites, implying that the second class comprises low affinity TCF-DNA complexes. Our results indicate that β-catenin is tethered to chromatin overwhelmingly through the TCF/LEF transcription factors in these three systems.


Solvent and Temperature Effects on Dynamics and Chiroptical Properties of Propeller Chirality and Toroidal Interaction of Hexaarylbenzenes.
Because of the unique interaction of radial aromatic blades, propeller-shaped hexaarylbenzenes (HABs) attract much research interest and find various practical applications. By introducing a small point-chiral group at the tip of aromatic blade(s), HAB becomes propeller-chiral to exhibit strong Cotton effects. Because of the dynamic nature of propeller chirality, the chiroptical properties of HAB critically responded to minute changes in the environment. Using a series of chiral HABs with one to six ( R)-1-methylpropyloxy substituent(s) introduced at the blade tip, we elucidated how the smallest chiral auxiliary at the HAB periphery progressively and cooperatively boosts the overall chiroptical properties and also how subtle changes in temperature and solvent structure affect the propeller dynamics and thus the chiroptical responses. The unique features of propeller-chiral HABs further enabled us to switch on/off their circularly polarized luminescence.


Dual-Wavelength Lasing in Quantum-Dot Plasmonic Lattice Lasers.
Arrays of metallic particles patterned on a substrate have emerged as a promising design for on-chip plasmonic lasers. In past examples of such devices, the periodic particles provided feedback at a single resonance wavelength, and organic dye molecules were used as the gain material. Here, we introduce a flexible template-based fabrication method that allows a broader design space for Ag particle-array lasers. Instead of dye molecules, we integrate colloidal quantum dots (QDs), which offer better photostability and wavelength tunability. Our fabrication approach also allows us to easily adjust the refractive index of the substrate and the QD-film thickness. Exploiting these capabilities, we demonstrate not only single-wavelength lasing but dual-wavelength lasing via two distinct strategies. First, by using particle arrays with rectangular lattice symmetries, we obtain feedback from two orthogonal directions. The two output wavelengths from this laser can be selected individually using a linear polarizer. Second, by adjusting the QD-film thickness, we use higher-order transverse waveguide modes in the QD film to obtain dual-wavelength lasing at normal and off-normal angles from a symmetric square array. We thus show that our approach offers various design possibilities to tune the laser output.


Brain tumor-related epilepsy management: A Society for Neuro-oncology (SNO) consensus review on current management.
Tumor-related epilepsy (TRE) is a frequent and major consequence of brain tumors. Management of TRE is required throughout the course of disease and a deep understanding of diagnosis and treatment is key to improving quality of life. Gross total resection is favored from both an oncologic and epilepsy perspective. Shared mechanisms of tumor growth and epilepsy exist, and emerging data will provide better targeted therapy options. Initial treatment with antiseizure medications (ASM) in conjunction with surgery and/or chemoradiotherapy is typical. The first choice of ASM is critical to optimize seizure control and tolerability considering the effects of the tumor itself. These agents carry a potential for drug-drug interactions and therefore knowledge of mechanisms of action and interactions is needed. A review of adverse effects is necessary to guide ASM adjustments and decision-making. This review highlights the essential aspects of diagnosis and treatment of TRE with ASMs, surgery, chemotherapy, and radiotherapy while indicating areas of uncertainty. Future studies should consider the use of a standardized method of seizure tracking and incorporating seizure outcomes as a primary endpoint of tumor treatment trials.


[Dental fluorosis in the Baikal region].
The incidence of dental fluorosis was evaluated in 9614 rural residents of the Baikal region. Subjects of both sexes of all age groups, living under different geographic conditions, were examined. The levels of dental fluorosis were determined, the relationship between the development of this condition and age and sex was evaluated, and the effect of breast feeding on its development was analyzed.


Assessing the anatomical variations of lingual foramen and its bony canals with CBCT taken from 102 patients in Isfahan.
Some studies have been performed on assessing the anatomical variations of lingual foramen and its bony canals, in many different countries but no study has been performed in Iran yet. The purpose of this study is to assess the anatomical variations of lingual foramen and its bony canals with cone-beam computed tomography (CBCT) imaging in Isfahan. This was a cross-sectional study in which CBCT images taken from 102 patients referred to the Radiology Department of Head and Neck in Esfahan (Iran) University between 2010 and 2011. The presence of the lingual foramen and its bony canals, the locations, sizes, and length were assessed. The distances between the terminal end of lingual canal at the buccal and lingual side from the inferior border of the mandible and alveolar crest were measured. We also evaluated the effect of patient age and gender on the dimensional measurements of the anatomical landmark mentioned above t test, analysis of variance (ANOVA), and pearson's correlation were used for statistical analysis and P value lower than 0.05 was considered significant. All of the CBCT images taken showed the presence of lingual foramen. Of all the participants, 52% of them had two foramens in their images. The mean diameters of the upper and lower lingual foramen were 1.12 and 0.9 mm, respectively. These anatomical landmarks in Isfahan population vary from previous studies. All of the images had at least one lingual foramen which demonstrates high prevalence of this anatomy among Isfehanian population. Therefore, it is recommended to use CBCT imaging for preoperative evaluation prior to installing dental implants.


Design and Benchmark Testing for Open Architecture Reconfigurable Mobile Spirometer and Exhaled Breath Monitor with GPS and Data Telemetry.
Portable and wearable medical instruments are poised to play an increasingly important role in health monitoring. Mobile spirometers are available commercially, and are used to monitor patients with advanced lung disease. However, these commercial monitors have a fixed product architecture determined by the manufacturer, and researchers cannot easily experiment with new configurations or add additional novel sensors over time. Spirometry combined with exhaled breath metabolite monitoring has the potential to transform healthcare and improve clinical management strategies. This research provides an updated design and benchmark testing for a flexible, portable, open access architecture to measure lung function, using common Arduino/Android microcontroller technologies. To demonstrate the feasibility and the proof-of-concept of this easily-adaptable platform technology, we had 43 subjects (healthy, and those with lung diseases) perform three spirometry maneuvers using our reconfigurable device and an office-based commercial spirometer. We found that our system compared favorably with the traditional spirometer, with high accuracy and agreement for forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), and gas measurements were feasible. This provides an adaptable/reconfigurable open access "personalized medicine" platform for researchers and patients, and new chemical sensors and other modular instrumentation can extend the flexibility of the device in the future.


Exploring the potential effect of polypharmacy on the hematologic profiles of clozapine patients.
Clozapine, an atypical antipsychotic with documented efficacy in the management of treatment-resistant schizophrenia, is associated with the risk of adverse hematological outcomes. Of particular concern are reductions in white blood cells (WBC) and absolute neutrophil counts (ANC). Individuals who display moderate leukopenia (3000/mm(3) > WBC ≥ 2000/mm) upon initiation of clozapine therapy are at increased risk of developing agranulocytosis, defined as an ANC less than 500/mm. Complications of agranulocytosis can be severe and include increased risk of infection and mortality. The primary objective of this study was to examine data on clozapine recipients who experienced adverse drug reactions (ADRs) related to decreases in WBC or ANC and ascertain whether other drugs and/or drug interactions had played a role. The analysis included multiple classes of medications. A retrospective chart review was performed of open and closed medical records of all inpatient recipients of clozapine at a state psychiatric center between January 1, 2004 and June 30, 2011. Laboratory records of patients prescribed clozapine were examined for abnormal WBC counts or ANC. A hematological ADR was considered to have occurred if there was a substantial drop in either WBC or ANC or mild or moderate leukopenia or granulocytopenia. Each episode was analyzed for medications that might have contributed to the ADR. Data were collected for all scheduled and STAT medications started at any point during the clozapine patient's hospitalization. The following seven medication groups, based on the Therapeutic Classification System of the American Hospital Formulary System (AHFS), were chosen for analysis because they were consistently used in the majority of the patient population: antihistamines, anti-infectives, autonomic agents, cardiovascular agents, antipsychotics, vitamins, and gastrointestinal agents. Pearson correlation coefficients were calculated to identify associations between the presence of hematological ADRs and medications administered concomitantly with clozapine. The following significant correlation coefficients were found between the use of a class of medications and the occurrence of a hematological ADR: antiinfective agents 0.409 (p < 0.01), gastrointestinal agents 0.329 (p < 0.01), and autonomic agents 0.309 (p < 0.01). In the subset of patients who were prescribed a proton-pump inhibitor or ranitidine concomitantly with clozapine, 24/26 (96%) experienced a hematological ADR. Autonomic agents, anti-infective agents, and proton pump inhibitors and other gastrointestinal agents were all associated with hematological ADRs when co-prescribed with clozapine. Medications from these classes should be initiated cautiously in patients being treated with clozapine to avoid precipitous drops in ANC or WBC that may increase the risk of agranulocytosis.


Structural basis for Pan3 binding to Pan2 and its function in mRNA recruitment and deadenylation.
The conserved eukaryotic Pan2-Pan3 deadenylation complex shortens cytoplasmic mRNA 3' polyA tails to regulate mRNA stability. Although the exonuclease activity resides in Pan2, efficient deadenylation requires Pan3. The mechanistic role of Pan3 is unclear. Here, we show that Pan3 binds RNA directly both through its pseudokinase/C-terminal domain and via an N-terminal zinc finger that binds polyA RNA specifically. In contrast, isolated Pan2 is unable to bind RNA. Pan3 binds to the region of Pan2 that links its N-terminal WD40 domain to the C-terminal part that contains the exonuclease, with a 2:1 stoichiometry. The crystal structure of the Pan2 linker region bound to a Pan3 homodimer shows how the unusual structural asymmetry of the Pan3 dimer is used to form an extensive high-affinity interaction. This binding allows Pan3 to supply Pan2 with substrate polyA RNA, facilitating efficient mRNA deadenylation by the intact Pan2-Pan3 complex.


Immune response to influenza vaccination in a large healthy elderly population.
Elderly individuals not only demonstrate a greater risk of morbidity and mortality from influenza than the young, but also have greater difficulty mounting a protective response to influenza vaccine. The mechanism of the decreased efficacy of influenza vaccination in the elderly is not well understood. The present study was designed to assess the interaction between cell-mediated and humoral immune responses to influenza vaccine in a large population (n = 233) of healthy elderly individuals (mean age = 80.7) living in six continuing care retirement communities (CCRCs). While influenza vaccination resulted in significant increases in the mean anti-influenza antibody titres and mean proliferative responses of peripheral blood mononuclear cells to purified subvirion trivalent influenza vaccine one month after vaccination, only 48.9% and 30.0% of subjects had intact humoral and cell-mediated immune responses, respectively. No association was observed between intact cell-mediated and humoral responses: 14.7% of subjects had an intact cell-mediated, but not humoral response, and 32.6% of subjects had an intact humoral, but not cell-mediated response. However, IFNgamma production was significantly correlated with both antibody and cell-mediated responses to influenza vaccination, a finding not previously reported in the elderly. These results indicate that there is considerable heterogeneity among immune responses of the elderly to influenza vaccination. This heterogeneity needs to be a major consideration in evaluation of new vaccine preparations.


MUC5B is the prominent mucin in human gallbladder and is also expressed in a subset of colonic goblet cells.
To elucidate the roles of human gallbladder mucin (HGBM), such as in gallstone formation and cytoprotection, it is essential to identify HGBM and study its expression. This was performed by metabolic labeling, Western blotting, immunohistochemistry, and RT-PCR. In a large number of individuals, antibodies against purified HGBM and against MUC5B detected a mucin precursor (approximately 470 kDa) in the gallbladder and colon, but not in the small intestine. In the gallbladder, Western blotting using specific anti-MUC5B antibodies showed that this mucin precursor represented an identical mucin, MUC5B. RT-PCR experiments demonstrated a similar tissue distribution pattern of MUC5B mRNA. Immunohistochemistry with anti-HGBM and anti-MUC5B showed staining in gallbladder epithelial cells and colonic goblet cells in the crypt base, but not in the small intestine; double labeling showed that HGBM was located in small granules within goblet cells, colocalizing to MUC2-containing goblet cells. Metabolic labeling demonstrated the secretion of mature MUC5B in the colon. Conclusively, MUC5B is identified as the prominent HGBM and is also expressed and secreted in the colon.


[(18)F]-fluorodeoxyglucose positron emission tomography and computed tomography in response evaluation of oncolytic adenovirus treatments of patients with advanced cancer.
Computed tomography (CT) is the most commonly used radiological response evaluation method in contemporary oncology. However, it may not be optimally suitable for assessment of oncolytic virus treatments because of paradoxical inflammatory tumor swellings, which result from virus treatments, particularly when viruses are armed with immunostimulatory molecules. Here we investigated the prognostic utility of CT and [(18)F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) in oncolytic virus treatments. We also investigated possible appearance of false-positive FDG signals in FDG-PET imaging of humans and hamsters treated with oncolytic adenoviruses. First, immunocompetent Syrian hamsters were treated with intratumoral adenovirus injections, tumor growth was followed up, and [(18)F]-FDG-uptake was quantitated with small animal PET/CT. Second, we describe a retrospective patient series, essentially 17 individual case reports, of advanced cancer patients treated with oncolytic adenoviruses in the context of an Advanced Therapy Access Program (ATAP) who underwent radiological response evaluation with both contrast-enhanced CT and FDG-PET. Third, we collected a retrospective case series of radiological response and survival data of 182 patients treated with oncolytic adenoviruses in ATAP to evaluate the prognostic reliability of CT and FDG-PET. Overall, responses in CT and FDG-PET correlated well with each other and were equally reliable as prognostic markers for long survival after oncolytic adenovirus treatment. Interestingly, we observed that new FDG-avid lymph nodes appearing in FDG-PET after virus treatments may represent inflammatory responses and therefore should not be interpreted as treatment failure in the absence of other signs or verification of disease progression. We also observed indications that FDG-PET might be more sensitive in detection of responses than tumor size.


Screening for Inhibitors of Main Protease in SARS-CoV-2: In Silico and In Vitro Approach Avoiding Peptidyl Secondary Amides.
In addition to vaccines, antiviral drugs are essential for suppressing COVID-19. Although several inhibitor candidates were reported for SARS-CoV-2 main protease, most are highly polar peptidomimetics with poor oral bioavailability and cell membrane permeability. Here, we conducted structure-based virtual screening and in vitro assays to obtain hit compounds belonging to a new chemical space, excluding peptidyl secondary amides. In total, 180 compounds were subjected to the primary assay at 20 μM, and nine compounds with inhibition rates of >5% were obtained. The IC50 of six compounds was determined in dose-response experiments, with the values on the order of 10-4 M. Although nitro groups were enriched in the substructure of the hit compounds, they did not significantly contribute to the binding interaction in the predicted docking poses. Physicochemical properties prediction showed good oral absorption. These new scaffolds are promising candidates for future optimization.


The monoaminergic footprint of depression and psychosis in dementia with Lewy bodies compared to Alzheimer's disease.
Depression and psychosis are two of the most severe neuropsychiatric symptoms (NPS) in dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). Both NPS have negative effects on cognitive performance and life expectancy. The current study aimed to investigate and compare monoaminergic etiologies between both neurodegenerative conditions, given the lack of an efficient pharmacological treatment until present. Eleven behaviorally relevant brain regions of the left frozen hemisphere of 10 neuropathologically confirmed AD patients with/without depression (AD + D/-D; 5 were psychotic within AD + D), 10 confirmed DLB patients, all of whom were depressed (DLB + D; 5 psychotic patients), and, finally, 10 confirmed control subjects were regionally dissected. All patients were retrospectively assessed before death using the Behavioral Pathology in Alzheimer's Disease Rating Scale (Behave-AD) and Cornell Scale for Depression in Dementia amongst others. The concentrations of dopamine (DA), serotonin (5-HT), (nor)adrenaline and respective metabolites, i.e. 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 5-hydroxy-3-indoleacetic acid (5-HIAA), and, 3-methoxy-4-hydroxyphenylglycol (MHPG), were determined using reversed-phase high-performance liquid chromatography with electrochemical detection. DLB subjects had the overall lowest monoamine and metabolite concentrations regarding 33 out of 41 significant monoaminergic group alterations. Moreover, MHPG levels were significantly decreased in almost 8 out of 11 brain regions of DLB- compared to AD patients. We also observed the lowest 5-HT and 5-HIAA levels, and 5-HIAA/5-HT turnover ratios in DLB + D compared to AD + D subjects. Additionally, a 4- and 7-fold increase of DOPAC/DA and HVA/DA turnover ratios, and, a 10-fold decrease of thalamic DA levels in DLB + D compared to AD + D patients and control subjects was noticed. Regarding psychosis, hippocampal DA levels in the overall DLB group significantly correlated with Behave-AD AB scores. In the total AD group, DA levels and HVA/DA ratios in the amygdala significantly correlated with Behave-AD AB scores instead. Monoaminergic neurotransmitter alterations contribute differently to the pathophysiology of depression and psychosis in DLB as opposed to AD, with a severely decreased serotonergic neurotransmission as the main monoaminergic etiology of depression in DLB. Similarly, psychosis in DLB might, in part, be etiologically explained by dopaminergic alterations in the hippocampus, whereas in AD, the amygdala might be involved.


Adaptive fuzzy control of unstable nonlinear systems.
This paper addresses the structure and an associated on-line learning algorithm of a feedforward multilayer connectionist network for realizing the basic elements and functions of a traditional fuzzy logic controller. The proposed Fuzzy Adaptive Learning Control Network (FALCON) can be contrasted with the traditional fuzzy logic control systems in their network structure and learning ability. An on-line structure/parameter learning algorithm, called FALCON-ART, is proposed for constructing the FALCON dynamically. The FALCON-ART can partition the input/output space in a flexible way based on the distribution of the training data. Hence it can avoid the problem of combinatorial growing of partitioned grids in some complex systems. It combines the backpropagation learning scheme for parameter learning and the fuzzy ART algorithm for structure learning. More notably, the FALCON-ART can on-line partition the input/output spaces, tune membership functions, and find proper fuzzy logic rules dynamically without any a priori knowledge or even any initial information on these. The proposed learning scheme has been successfully used to control two unstable nonlinear systems. They are the seesaw system and the inverted wedge system.


Diabetes prevalence rates among First Nations adults on Saskatchewan reserves in 1990: comparison by tribal grouping, geography and with non-First Nations people.
To determine age-specific, sex-specific and total prevalence rates of diabetes mellitus among Saskatchewan First Nations adults and to compare these rates by tribal grouping, geography and with non-First Nations people. A point prevalence study of all Saskatchewan reserves in 1990. Age-adjusted rates of diabetes mellitus were higher (risk ratio 1.8) among First Nations adults (9.7%) than among non-First Nations adults (6.1%). These racial differences were greater between women (12.1 vs 6.6%) than men (7.2 vs 5.6%). First Nations diabetes rates were highest among individuals with Saulteaux and Sioux ancestry, and among those living on southern reserves. The prevalence of diabetes mellitus among Saskatchewan First Nations people has increased from 0% to almost 10% within the adult population since 1934 and has more than doubled from 1980 to 1990. This epidemic manifests itself to a greater extent among women and certain tribal groups, possibly due to differences in exposure to non-traditional lifestyles.


Inhibition of in vitro tumor cell invasion by Arg-Gly-Asp-containing synthetic peptides.
The interaction of cells with extracellular matrix components such as fibronectin, vitronectin, and type I collagen has been shown to be mediated through a family of cell-surface receptors that specifically recognize an arginine-glycine-aspartic acid (RGD) amino acid sequence within each protein. Synthetic peptides containing the RGD sequence can inhibit these receptor-ligand interactions. Here, we use novel RGD-containing synthetic peptides with different inhibition properties to investigate the role of the various RGD receptors in tumor cell invasion. The RGD-containing peptides used include peptides that inhibit the attachment of cells to fibronectin and vitronectin, a peptide that inhibits attachment to fibronectin but not to vitronectin, a cyclic peptide with the opposite specificity, and a peptide, GRGDTP, that inhibits attachment to type I collagen in addition to inhibiting attachment to fibronectin and vitronectin. The penetration of two human melanoma cell lines and a glioblastoma cell line through the human amniotic basement membrane and its underlying stroma was inhibited by all of the RGD-containing peptides except for the one that inhibits only the vitronectin attachment. Various control peptides lacking RGD showed essentially no inhibition. This inhibitory effect on cell invasion was dose-dependent and nontoxic. A hexapeptide, GRGDTP, that inhibits the attachment of cells to type I collagen in addition to inhibiting fibronectin- and vitronectin-mediated attachment was more inhibitory than those RGD peptides that inhibit only fibronectin and vitronectin attachment. Analysis of the location of these cells that were prevented from invading indicated that they attached to the amniotic basement membrane but did not proceed further into the tissue. These results suggest that interactions between RGD-containing extracellular matrix adhesion proteins and cells are necessary for cell invasion through tissues and that fibronectin and type I collagen are important for this process.


[Radiation diagnosis of Langerhans cell histiocytosis (LCH) of lung].
The authors studied the pattern of X-ray changes detectable in the lungs of 41 patients with LCH. The results of classical X-ray study were supplemented by the data of computed tomography, ultrasonography, and 99mTc and 67Ga citrate radioisotopic studies. The diagnostic values of these techniques were compared. X-ray syndromes of changes in the lung in LCH were found to be interstitial, interstitial and granulomatous, tumorous (focal). The authors emphasize the multisystematic character of a lesion, the phasic nature and progression of the disease into fibrosis.


Soluble CD5 and CD6: Lymphocytic Class I Scavenger Receptors as Immunotherapeutic Agents.
CD5 and CD6 are closely related signal-transducing class I scavenger receptors mainly expressed on lymphocytes. Both receptors are involved in the modulation of the activation and differentiation cell processes triggered by clonotypic antigen-specific receptors present on T and B cells (TCR and BCR, respectively). To serve such a relevant immunomodulatory function, the extracellular region of CD5 and CD6 interacts with soluble and/or cell-bound endogenous counterreceptors but also microbial-associated molecular patterns (MAMPs). Evidence from genetically-modified mouse models indicates that the absence or blockade of CD5- and CD6-mediated signals results in dysregulated immune responses, which may be deleterious or advantageous in some pathological conditions, such as infection, cancer or autoimmunity. Bench to bedside translation from transgenic data is constrained by ethical concerns which can be overcome by exogenous administration of soluble proteins acting as decoy receptors and leading to transient "functional knockdown". This review gathers information currently available on the therapeutic efficacy of soluble CD5 and CD6 receptor infusion in different experimental models of disease. The existing proof-of-concept warrants the interest of soluble CD5 and CD6 as safe and efficient immunotherapeutic agents in diverse and relevant pathological conditions.


Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline.
Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results:1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.


Special adhesion of natural honeycomb walls and their application.
In this paper, we investigated the wettability and adhesive behavior of the natural honeycomb wall for water and honey droplets. The cell walls have hydrophobic and highly adhesive properties for both water and honey in air. This highly adhesive cell wall was used as a "mechanical hand" to transfer micro-droplets. These findings will help us to comprehensively understand the surface properties of honeycomb walls, and will provide a novel strategy for achieving functional biomimetics based on honeycombs.


Determination of High-affinity Antibody-antigen Binding Kinetics Using Four Biosensor Platforms.
Label-free optical biosensors are powerful tools in drug discovery for the characterization of biomolecular interactions. In this study, we describe the use of four routinely used biosensor platforms in our laboratory to evaluate the binding affinity and kinetics of ten high-affinity monoclonal antibodies (mAbs) against human proprotein convertase subtilisin kexin type 9 (PCSK9). While both Biacore T100 and ProteOn XPR36 are derived from the well-established Surface Plasmon Resonance (SPR) technology, the former has four flow cells connected by serial flow configuration, whereas the latter presents 36 reaction spots in parallel through an improvised 6 x 6 crisscross microfluidic channel configuration. The IBIS MX96 also operates based on the SPR sensor technology, with an additional imaging feature that provides detection in spatial orientation. This detection technique coupled with the Continuous Flow Microspotter (CFM) expands the throughput significantly by enabling multiplex array printing and detection of 96 reaction sports simultaneously. In contrast, the Octet RED384 is based on the BioLayer Interferometry (BLI) optical principle, with fiber-optic probes acting as the biosensor to detect interference pattern changes upon binding interactions at the tip surface. Unlike the SPR-based platforms, the BLI system does not rely on continuous flow fluidics; instead, the sensor tips collect readings while they are immersed in analyte solutions of a 384-well microplate during orbital agitation. Each of these biosensor platforms has its own advantages and disadvantages. To provide a direct comparison of these instruments' ability to provide quality kinetic data, the described protocols illustrate experiments that use the same assay format and the same high-quality reagents to characterize antibody-antigen kinetics that fit the simple 1:1 molecular interaction model.


High-speed tilt mirror for image stabilization.
A magnetostrictively driven tilt-mirror mount for image stabilization of NASA's Marshall Space Flight Center's Experimental Vector Magnetograph has been designed, built, and tested. A simple improvement in the mounting technique of the actuator resulted in a factor of 3 increase in the lowest resonant frequency of the device. The tilt-mirror device was built, and the lowest structural resonant frequency was experimentally found to be 603 Hz.


In vitro antifungal properties of mouthrinses containing antimicrobial agents.
The purpose of this study was to investigate the in vitro antifungal properties of seven commercial mouthrinses containing antimicrobial agents. These included cetylpyridinium chloride (CPC), chlorhexidine digluconate (CHX), hexetidine (HEX), sanguinarine (SNG), and triclosan (TRN). The minimum fungicidal concentration (MFC) against six species of yeasts was determined by a broth macrodilution method. The kill-time of mouthrinses at half the concentration of the commercial formulations was also determined. MFCs were achieved with each mouthrinse, except the SNG-containing mouthrinse, against all the organisms being tested. However, the CPC-containing mouthrinse appeared more active than the other products (P < 0.001). There were no significant differences in MFC values among CHX mouthrinse products, once adjusted for initial concentration differences (P = 0.1). Kill-times of mouthrinses containing either CHX or CPC were less than or equal to 180 seconds with all the species of yeasts, and no significant differences were found among these products (P = 0.18). On the other hand, mouthrinses containing either TRN or HEX did not show a lethal effect on Candida albicans, Candida parapsilosis, or Candida guilliermondii. No kill-times were achieved with the SNG-containing mouthrinse. These results suggest that mouthrinses containing antimicrobial agents might represent an appropriate alternative to conventional antifungal drugs in the management of oral candidiasis. However, the effectiveness of antimicrobial mouthrinses as antifungal agents needs to be evaluated in further clinical trials.


A dynamic exchange of TCF3 and TCF4 transcription factors controls MYC expression in colorectal cancer cells.
Deregulated Wnt/β-catenin signaling promotes colorectal cancer (CRC) by activating expression of the c-MYC proto-oncogene (MYC). In the nucleus, the β-catenin transcriptional co-activator binds T-cell factor (TCF) transcription factors, and together TCF/β-catenin complexes activate MYC expression through Wnt responsive DNA regulatory elements (WREs). The MYC 3' WRE maps 1.4-kb downstream from the MYC transcription stop site and binds TCF4/β-catenin transcription complexes to activate MYC. However, the underlying mechanisms for how this element operates are not fully understood. Here, we report that the TCF family member, TCF3, plays an important role in regulating MYC expression in CRCs. We demonstrate that TCF3 binds the MYC 3' WRE to repress MYC. When TCF3 is depleted using shRNAs, the MYC 3' WRE is more available to bind TCF4/β-catenin complexes. Stimulating downstream Wnt/β-catenin signaling by inhibiting GSK3β causes an exchange of TCF3 with TCF4/β-catenin complexes to activate MYC. Finally, this transcription factor switch at the MYC 3' WRE controls MYC expression as quiescent cells re-enter the cell cycle and progress to S phase. These results indicate that a dynamic interplay of TCF transcription factors governs MYC gene expression in CRCs.


[Assessing the loss of health as a result of road accidents].
The analysis of the loss of health due to road accidents provides the basis for important practical conclusions concerning groups and periods of the maximum risk and measures to reduce road traumatism. As a rule, these programs are based on the assessments made by the staff of the State Inspection of Road Traffic Safety. However their effectiveness is determined not by specialists but rather by participants of the road traffic. The opinion of persons injured acquires special significance.


Cine MRI assessment of motility in the unprepared small bowel in the fasting and fed state: Beyond the breath-hold.
The symptoms of functional bowel disorders are common in postprandial but investigations are generally undertaken in the fasted state using invasive procedures. MRI provides a noninvasive tool to study the gastrointestinal tract in an unperturbed, fed state. The aim of this study was to develop a technique to assess small bowel motility from cine MRI data in the unprepared bowel in fasting and fed states. Fifteen healthy volunteers underwent a baseline MRI scan after which they consumed a 400 g soup. Subjects then underwent a postprandial scan followed by further scans at regular intervals. Small bowel motility was assessed using single-slice bTFE cine MRI. An optimized processing technique was used to generate motility data based on power spectrum analysis of voxel-signal changes with time. Interobserver variability (n = 15) and intra-observer (n = 6) variability were assessed. Changes in the motility index were compared between fasted and immediate postprandial state. Excellent agreement between observers was seen across the range of motility measurements acquired, with intraclass correlation coefficient (ICC) of 0.979 (P < 0.0001) and Bland-Altman limits of agreement 95% CI: -28.9 to 45.9 au. Intra-observer variability was low with ICC of 0.992 and 0.960 (2 observers, P < 0.0001). Changes from the fasted to immediately postprandial state showed an average increase of 122.4% ± 98.7% (n = 15). This optimized technique showed excellent inter and intra observer agreement. It was sensitive to changes in motility induced feeding. This technique will be useful to study contractile activity and regional patterns along the gastrointestinal tract under physiological conditions.


The CellBox-2 Mission to the International Space Station: Thyroid Cancer Cells in Space.
A spaceflight to the International Space Station (ISS) is a dream of many researchers. We had the chance to investigate the effect of real microgravity (CellBox-2 Space mission) on the transcriptome and proteome of FTC-133 human follicular thyroid cancer cells (TCC). The cells had been sent to the ISS by a Falcon 9 rocket of SpaceX CRS-13 from Cape Canaveral (United States) and cultured in six automated hardware units on the ISS before they were fixed and returned to Earth. Multicellular spheroids (MCS) were detectable in all spaceflight hardware units. The VCL, PXN, ITGB1, RELA, ERK1 and ERK2 mRNA levels were significantly downregulated after 5 days in space in adherently growing cells (AD) and MCS compared with ground controls (1g), whereas the MIK67 and SRC mRNA levels were both suppressed in MCS. By contrast, the ICAM1, COL1A1 and IL6 mRNA levels were significantly upregulated in AD cells compared with 1g and MCS. The protein secretion measured by multianalyte profiling technology and enzyme-linked immunosorbent assay (AngiogenesisMAP®, extracellular matrix proteins) was not significantly altered, with the exception of elevated angiopoietin 2. TCC in space formed MCS, and the response to microgravity was mainly anti-proliferative. We identified ERK/RELA as a major microgravity regulatory pathway.


Neurofilament protein abnormalities in PC12 cells: comparison with neurofilament proteins of normal cultured rat sympathetic neurons.
The studies described here characterize abnormalities in the expression of neurofilament (NF) proteins in a clonal rat pheochromocytoma (PC12) cell line as compared with normal NF proteins in cultured rat sympathetic neurons (RSNs). Cytoskeletal extracts from PC12 cells grown in the presence (PC12+ cells) or absence (PC12- cells) of nerve growth factor (NGF) and from RSNs grown in the presence of NGF were analyzed in nitrocellulose replicas of one- and two-dimensional polyacrylamide gels by the immunoblot method using monoclonal antibodies and antiserum to individual NF subunits. RSNs failed to express the high molecular weight NF subunit (NF200) for the first 10 days in culture although both lower molecular weight NF subunits (NF68 and NF150) were expressed by these cells. At later times in culture, all three NF subunits were present in immunoblots of RSNs. The immunoblot profile of NF proteins in PC12- cells was identical to that of RSNs grown in culture for up to 10 days. Growth of PC12 cells in NGF for up to 3 weeks did not alter this immunoblot profile except that no immunoband corresponding in NF200 was seen and the immunobands corresponding to NF68 and NF150 became more prominent. These data suggest that abnormalities in NF protein expression in PC12 cells are due to a paucity of NF200 or to the presence of immunochemically altered NF200. PC12 cells are an attractive model system for probing abnormal NF metabolism.


Chain reaction pulsed HF laser: a simple model.
With economical, yet accurate, predictions of pulsed H(2) + F(2) laser performance as a goal, a rate equation model is formulated that includes only the dominant kinetic mechanisms in the active medium. Effects of model assumptions are examined, and predictions of pulse characteristics are compared with results from a more comprehensive model presented in an earlier study. Computing costs for the present model are less than 1% of those for the comprehensive model; moreover, the present model yields laser pulse characteristics that are consistent with experiment and in excellent agreement with the more comprehensive model. In order to illustrate the model's capability, the effects of initial gas mixture composition and cavity threshold on laser performance are studied over the regime of practical interest. Some possible extensions and applications of the model are also discussed.


[Acute Guillain-Barré-like polyradiculoneuritis revealing acute systemic lupus erythematosus: two case studies and review of the literature].
The involvement of the peripheral nervous system in systemic lupus erythematosus (SLE) is rare and is dominated by distal symmetric axonal polyneuropathy and multiple mononeuropathy. It usually occurs in late course of the disease. Acute polyradiculoneuropathy of Guillain-Barré syndrome type is very rare and can frequently constitute the first symptom of systemic lupus. We report two cases of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) complicated by respiratory failure due to systemic lupus. In the first case, the pure motor AIDP was the first manifestation of the SLE. The outcome under prednisone treatment was dramatically good with regression of clinical deficit and normalisation of nerve conduction within one month and 12 months of treatment respectively. In the second case the AIDP occurred only one week after diagnosis of SLE and corticotherapy. It was a demyelinating sensory-motor neuropathy. Clinical improvement was obtained after two cures of intravenous gammaglobulin (IVIg). The normalisation of nerve conduction was obtained within 8 months. AIDP is a very rare complication of SLE, but it should be searched as an aetiology of Guillain-Barré syndrome associated to systemic clinical symptoms or to blood inflammation. Corticotherapy could be sufficient, but in some cases the addition of IVIg or plasmapheresis might be necessary.


Resolution enhancement for topography measurement of high-dynamic-range surfaces via image fusion.
In this paper, we introduce a method and algorithm for resolution enhancement of low-resolution surface topography data by fusing them with corresponding high-resolution intensity images. This fusion is achieved by linking the three-dimensional topographical map to its intensity image via an intrinsic image-based shape-from-shading algorithm. Through computational simulation and physical experiments, the proposed method's effectiveness and repeatability have been evaluated, and the computational cost has been shown to be less than other state-of-the-art algorithms. This proposed method can be easily integrated with high-speed in-line measurements of high-dynamic-range surfaces.


Biotransformation of 2,4,6-trinitrotoluene by Diaphorobacter sp. strain DS2.
Diaphorobacter strain DS2 degrades 3-nitrotoluene and 2-nitrotoluene via ring oxidation with 3-nitrotoluene dioxygenase (3NTDO). In the current study, we hypothesized that 3NTDO might also be involved in the degradation of 2,4,6-trinitrotoluene (TNT), a major nitroaromatic explosive contaminant in soil and groundwater. Strain DS2 transforms TNT as a sole carbon and nitrogen source when grown on it. Ammonium chloride and succinate in the medium accelerated the TNT degradation rate. A resting cell experiment suggested that TNT does not compete with 3NT degradation (no negative impact of TNT on the reaction velocity for 3NT). Enzyme assay with 3NTDO did not exhibit TNT transformation activity. The above results confirmed that 3NTDO of DS2 is not responsible for TNT degradation. In the resting cell experiment, within 10 h, 4ADNT completely degraded. The degradation of 2ADNT was 97% at the same time. We hypothesized that 3NTDO involve in this reaction. Based on the DS2 genome, we proposed that the N-ethylmaleimide reductases (nemA) were involved in the initial reduction of the nitro group and aromatic ring of TNT. Our findings suggest that strain DS2 could be helpful for the removal of TNT from contaminated sites with or without any additional carbon and nitrogen source and with minimal accumulation of undesirable intermediates.


Relationship of child-feeding practices to overweight in low-income Mexican-American preschool-aged children.
The purpose of this research was to examine the relationship of child-feeding practices and other factors to overweight in low-income Mexican-American preschool-aged children. Cross-sectional survey with anthropometric measurements of mothers and target children. Trained bilingual staff interviewed the parents to collect data on child-feeding strategies, food patterns, child's health history, parental acculturation level, food insecurity, and other household characteristics. Subjects and setting Complete data were available from 204 low-income Mexican-American parents residing in California with at least one child aged 3 to 5 years. Outcomes measured Risk of overweight was defined as body mass index (BMI) (measured as weight [in kilograms]/height [in meters](2)) >/=85th percentile and overweight was defined as BMI >/=95th percentile. The Student t test, chi(2) test, and logistic regression were used. Three variables were positively related to risk of overweight: birth weight (odds ratio [OR], 2.31; 95% confidence interval [CI], 1.11 to 4.82), mother's BMI >/=30 (OR, 2.05; 95% CI, 1.11 to 3.79), and juice intake (OR, 2.33; 95% CI, 1.09 to 4.98). Being enrolled in the Special Supplemental Nutrition Program for Women, Infants, and Children was negatively related to risk of overweight (OR, 0.40; 95% CI, 0.21 to 0.75). Additional variables related to overweight were monthly income >$1,500 (OR, 2.33; 95% CI, 1.00 to 5.42) and child takes food from the refrigerator between meals (OR, 0.32; 95% CI, 0.13 to 0.76). The results of this study suggest that biological and socioeconomic factors are more associated with overweight in Mexican-American preschool-aged children than most of the self-reported child-feeding strategies.


Development of a total dissolved solids (TDS) chronic effects benchmark for a northern Canadian lake.
Laboratory chronic toxicity tests with plankton, benthos, and fish early life stages were conducted with total dissolved solids (TDS) at an ionic composition specific to Snap Lake (Northwest Territories, Canada), which receives treated effluent from the Snap Lake Diamond Mine. Snap Lake TDS composition has remained consistent from 2007 to 2014 and is expected to remain unchanged through the life of the mine: Cl (45%-47%), Ca (20%-21%), Na (10%-11%), sulfate (9%); carbonate (5%-7%), nitrate (4%), Mg (2%-3%), and minor contributions from K and fluoride. The TDS concentrations that resulted in negligible effects (i.e., 10% or 20% effect concentrations) to taxa representative of resident biota ranged from greater than 1100 to greater than 2200 mg/L, with the exception of a 21% effect concentration of 990 mg/L for 1 of 2 early life stage fish dry fertilization tests (wet fertilization results were >1480 mg/L). A conservative, site-specific, chronic effects benchmark for Snap Lake TDS of 1000 mg/L was derived, below the lowest negligible effect concentration for the most sensitive resident taxon tested, the cladoceran, Daphnia magna (>1100 mg/L). Cladocerans typically only constitute a few percent of the zooplankton community and biomass in Snap Lake; other plankton effect concentrations ranged from greater than 1330 to greater than 1510 mg/L. Chironomids, representative of the lake benthos, were not affected by greater than 1380 mg/L TDS. Early life stage tests with 3 fish species resulted in 10% to 20% effect concentrations ranging from greater than 1410 to greater than 2200 mg/L. The testing undertaken is generally applicable to northern freshwaters, and the concept can readily be adapted to other freshwaters either for TDS where ionic composition does not change or for major ionic components, where TDS composition does change.


Falls in hospital patients with acquired communication disability secondary to stroke: A systematic review and meta-analysis.
Falls are a common safety incident in people with stroke. Studies report that between 14% and 65% of people with stroke fall at least once during their hospital admission. Risk factors for falls in people with stroke have been reported to include neglect, balance and dependence for activities of daily living. Communication disability has been identified as a risk factor for patient safety incidents in hospital that has not been closely examined as a potential risk factor for falls in people with stroke. To determine the association between communication disability secondary to stroke and falls in people with stroke in hospital. Systematic searches of five electronic databases were conducted in June 2019 using the key concepts of 'falls' and 'stroke' (PROSPERO CRD 42019137199). Included studies provided comparative data of falls in patients with stroke with and without communication disability. The methodological quality of the studies was examined using the Quality Assessment Tool for Studies with Diverse Designs (QATSDD). Both a narrative synthesis and a meta-analysis were completed. A total of 15 studies met the criteria for inclusion and 11 were included in a meta-analysis. Three studies found people with communication disability had an increased rate of falls in hospital. However, a meta-analysis showed no significant association between a non-specific classification of communication disability and an increased risk of falls. There was some indication from individual studies that higher risk of falls may be associated with severe communication disability, but there were insufficient data reported on the severity of the communication disability to draw robust conclusions. The results of this systematic review suggest that a generic classification of communication disability following stroke is not a risk factor for falls. However, further research that is inclusive of this population and considers severity of communication disability more specifically is required. What this paper adds What is already known on the subject The association between communication disability following stroke and falls in hospital is unclear. The literature reports mixed results regarding the impact of a communication disability following stroke on falls risk or rates of falls during hospital admission. What this paper adds to existing knowledge This review is the first to bring together this diverse literature to examine the association between communication disability following stroke and falls in hospital. The results suggest that a generic classification of communication disability following stroke is not a risk factor for falls. What are the potential or actual clinical implications of this work? There is a possibility that moderate to severe communication disability may be related to falls in patients in hospital. Further research is indicated to be more inclusive of people with communication disability, including those with severe communication disability.


Evidence of jak2 val617phe positive essential thrombocythemia with splanchnic thrombosis during estroprogestinic treatment.
The discovery of the Janus kinase 2 Val617Phe mutation has brought new insights into the development of myeloproliferative disorders; however, the pathogenesis of essential thrombocythemia and its related thrombotic complications has not been completely understood. Although the Janus kinase 2 Val617Phe mutation confirms the initially suspected clonal character of the disease, factors influencing clonal transformation and expansion in the bone marrow have not been fully detected. Furthermore, patients affected by essential thrombocythemia who are carriers of the Janus kinase 2 Val617Phe mutation show a higher incidence of venous thromboembolism both before, and at the time of diagnosis, compared with noncarriers, and recent evidence of splanchnic and cerebral vein thrombosis in carriers of the Janus kinase 2 Val617Phe mutation has been reported. The intake of oral contraceptives is a strong and independent risk factor for venous thromboembolism. In addition, in-vitro tests showed both an altered primary haemostatic plug formation and enhanced platelet aggregation in patients taking such drugs. Little is known, though, about the influence of steroid hormones on both megakaryopoiesis and platelet function in patients with the Janus kinase 2 Val617Phe mutation. Herewith, we report the case of a 30-year-old woman who took a third generation oral contraceptive for 5 months and developed an essential thrombocythemia with spleno-portal axis and superior mesenteric vein thrombosis. She was found to carry the kinase gene Janus kinase 2 mutation.