Different Effects of Lard and Vegetable Blend Oil on Intestinal Microorganisms, Enzyme Activity and Blood Routine in Mice.
The intake of moderate oils and fats is necessary to maintain the body's energy balance, and the fatty acid composition of different oils and fats varies in their nutrition and function. The study aimed to investigate the effects of lard and vegetable blend oil on gut microbiota, intestinal enzyme activities, and blood routine. Kunming mice were assigned to the three groups: (1) Control group (CK) was gavage administration with distilled water, (2) Plant oil group (ZWY) was gavage administration with edible vegetable blend oil, (3) Lard group (DWY) was gavage administration with lard. After 42 days, microbiological, digestive enzymes, and blood routine were performed. Compared with the CK group, Escherichia coli, Lactobacilli, and Bifidobacteria were significantly decreased (p < 0.05), the activities of protease, cellulase, amylase, and xylanase were markedly reduced (p < 0.05), the hemoglobin was significantly increased (p < 0.05) in the ZWY group and DWY groups, and the hematocrit was increased in the ZWY group (p < 0.05), while other routine blood indices were increased (p > 0.05). Compared to the ZWY group, the activity of cellulase and amylase were significantly increased (p < 0.05), the intestinal microorganism and the routine blood indexes had no significant difference in the DWY group. Lard and vegetable blend oil diet affected the composition of the intestinal microorganisms, and the functions of digestive enzymes. Meanwhile, the levels of digestive enzymes may be correlated with the intestinal microbiota.


Information-theory-based snake adapted to multiregion objects with different noise models.
We propose a segmentation technique adapted to objects composed of several regions with gray-level fluctuations described by different probability laws. This approach is based on information theory techniques and leads to a multiregion polygonal snake driven by the minimization of a criterion without any parameters to be tuned by the user. We demonstrate the improvements obtained with this approach as well as its low computational cost. This approach is compatible with applications such as object recognition and object tracking with nonrigid deformation in images perturbed by different types of optical noise.


Digitally enabled flash glucose monitoring for inpatients with COVID-19: Feasibility and pilot implementation in a teaching NHS Hospital in the UK.
COVID-19 placed significant challenges on healthcare systems. People with diabetes are at high risk of severe COVID-19 with poor outcomes. We describe the first reported use of inpatient digital flash glucose monitoring devices in a UK NHS hospital to support management of people with diabetes hospitalized for COVID-19. Inpatients at University Hospitals Coventry & Warwickshire (UHCW) NHS Trust with COVID-19 and diabetes were considered for digitally enabled flash glucose monitoring during their hospitalization. Glucose monitoring data were analysed, and potential associations were explored between relevant parameters, including time in hypoglycaemia, hyperglycaemia, and in range, glycated haemoglobin (HbA1c), average glucose, body mass index (BMI), and length of stay. During this pilot, digital flash glucose monitoring devices were offered to 25 inpatients, of whom 20 (type 2/type 1: 19/1; mean age: 70.6 years; mean HbA1c: 68.2 mmol/mol; mean BMI: 28.2 kg/m2) accepted and used these (80% uptake). In total, over 2788 h of flash glucose monitoring were recorded for these inpatients with COVID-19 and diabetes. Length of stay was not associated with any of the studied variables (all p-values >0.05). Percentage of time in hyperglycaemia exhibited significant associations with both percentage of time in hypoglycaemia and percentage of time in range, as well as with HbA1c (all p-values <0.05). The average glucose was significantly associated with percentage of time in hypoglycaemia, percentage of time in range, and HbA1c (all p-values <0.05). We report the first pilot inpatient use of digital flash glucose monitors in an NHS hospital to support care of inpatients with diabetes and COVID-19. Overall, there are strong arguments for the inpatient use of these devices in the COVID-19 setting, and the findings of this pilot demonstrate feasibility of this digitally enabled approach and support wider use for inpatients with diabetes and COVID-19.


Influence of FK506, Cyclosporin A, Testosterone and Nimodipine on Motoneuron Survival Following Axotomy.
Injury to immature motoneurons results in extensive nerve cell death. Avulsion injury in adult animals has a similar effect. Rescuing injured neurons from degeneration and death is a prerequisite for succesful functional recovery. Here, we have explored the possible survival promoting effect of the immunosuppressant agents FK506 and cyclosporin A, the calcium channel blocker nimodipine as well testosterone on axotomized neonatal facial motoneurons. In addition, we examined the effect of cyclosporin A and Nimodipine, a calcium channel blocker, on survival of adult motoneurons following hypoglossal nerve avulsion. FK506 and cyclosporin A were administered intraperitoneally, testosterone intramuscularly and Nimodipine via the food. After the appropriate postoperative survival periods, the number of surviving facial or hypoglossal motoneurons respectively was calculated. FK506 and Cyclosporin A were found to enhance facial motoneuron survival following neonatal axotomy. Cyclosporin A and Nimodipine were found to promote motoneuron survival in adult rats after hypoglossal nerve avulsion. Nimodipine possibly also reduced motoneuron death in neonatal rats twenty-one days after facial nerve transsection, but failed to rescue motoneurons in neonatal rats during the first seven days after nerve injury. Treatment with testosterone was ineffective in preventing neonatal facial motoneurons from axotomy-induced death at seven days postaxotomy. The restults indicate that motoneuron degeneration can be counteracted to a large extent by immunosuppressant agents as well as by calcium channel blockers. Taken together with findings form previous studies, we conclude that motoneuron survival following axotomy can be promoted by a variety of endogenous and exogenous molecules acting on different cellular mechanisms.


Influence of age, sex, and production class on liver zinc concentration in calves.
Determination of zinc concentrations in the liver of calves and young stock is commonly requested by practitioners and nutritionists to assess whether they receive an appropriate amount of zinc in their diet. However, interpretation of liver zinc concentrations is currently based on information reported for adult cattle for which the health status was unknown and irrespective of production class, sex, and age. A retrospective study of necropsy reports was undertaken to assess the relationships between liver zinc concentrations and age, sex, and production class for calves that did not have a history compatible with zinc toxicosis or zinc deficiency. Results of a generalized least squares, polynomial regression analysis of 474 records found that zinc concentration was not affected by sex (P = 0.29) or production class (P = 0.50). Zinc concentration was significantly associated with linear (P < 0.00001) and nonlinear (quadratic, P = 0.0039) functions of age (r2 = 0.1503), where the concentration decreased from 93 mg/kg wet weight at 30 days of age to 57 mg/kg wet weight at 9 months of age, after which it began to increase. The age-specific 95% confidence limits of the mean concentration for a group of calves and the 95% prediction limits of a single concentration value for an individual animal estimated in this study suggest reconsideration of the recommended limits for liver zinc concentration in calves. As a consequence of the significant influence of age on liver zinc concentration of calves presumably not experiencing zinc toxicosis or deficiency, diagnosis of zinc imbalances based on liver zinc concentration needs to consider age as a diagnostic covariate.


International cohort study indicates no association between alpha-1 blockers and susceptibility to COVID-19 in benign prostatic hyperplasia patients.
Purpose: Alpha-1 blockers, often used to treat benign prostatic hyperplasia (BPH), have been hypothesized to prevent COVID-19 complications by minimising cytokine storm release. The proposed treatment based on this hypothesis currently lacks support from reliable real-world evidence, however. We leverage an international network of large-scale healthcare databases to generate comprehensive evidence in a transparent and reproducible manner. Methods: In this international cohort study, we deployed electronic health records from Spain (SIDIAP) and the United States (Department of Veterans Affairs, Columbia University Irving Medical Center, IQVIA OpenClaims, Optum DOD, Optum EHR). We assessed association between alpha-1 blocker use and risks of three COVID-19 outcomes-diagnosis, hospitalization, and hospitalization requiring intensive services-using a prevalent-user active-comparator design. We estimated hazard ratios using state-of-the-art techniques to minimize potential confounding, including large-scale propensity score matching/stratification and negative control calibration. We pooled database-specific estimates through random effects meta-analysis. Results: Our study overall included 2.6 and 0.46 million users of alpha-1 blockers and of alternative BPH medications. We observed no significant difference in their risks for any of the COVID-19 outcomes, with our meta-analytic HR estimates being 1.02 (95% CI: 0.92-1.13) for diagnosis, 1.00 (95% CI: 0.89-1.13) for hospitalization, and 1.15 (95% CI: 0.71-1.88) for hospitalization requiring intensive services. Conclusion: We found no evidence of the hypothesized reduction in risks of the COVID-19 outcomes from the prevalent-use of alpha-1 blockers-further research is needed to identify effective therapies for this novel disease.


The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway.
The KEAP1-NRF2 pathway is the principal protective response to oxidative and electrophilic stresses. Under homeostatic conditions, KEAP1 forms part of an E3 ubiquitin ligase, which tightly regulates the activity of the transcription factor NRF2 by targeting it for ubiquitination and proteasome-dependent degradation. In response to stress, an intricate molecular mechanism facilitated by sensor cysteines within KEAP1 allows NRF2 to escape ubiquitination, accumulate within the cell, and translocate to the nucleus, where it can promote its antioxidant transcription program. Recent advances have revealed that KEAP1 contains multiple stress sensors and inactivation modalities, which together allow diverse cellular inputs, from oxidative stress and cellular metabolites to dysregulated autophagy, to regulate NRF2 activity. This integration of the KEAP1-NRF2 system into multiple cellular signaling and metabolic pathways places NRF2 activation as a critical regulatory node in many disease phenotypes and suggests that the pharmaceutical modulation of NRF2's cytoprotective activity will be beneficial for human health in a broad range of noncommunicable diseases.


HPLC analysis of mesembrine-type alkaloids in Sceletium plant material used as an African traditional medicine.
Sceletium plant species have been reported to contain psychoactive alkaloids, specifically belonging to mesembrine-type alkaloids. Sceletium is presently marketed through health shops and on the internet as dried plant powder and as pharmaceutical dosage forms and purported to be useful in the treatment of psychological disorders. However, there are no validated analytical methods and reference standards of the relevant alkaloids are not commercially available for use in the analysis and quality control of Sceletium products and dosage forms. Hence, the objective of this research was to isolate and characterize appropriate analytical markers for use in the assay and as well as markers for fingerprinting by high performance liquid chromatography (HPLC). The separation of the relevant alkaloids was carried out on a C18 column and detected at a UV wavelength of 228 nm. The method was validated and used to assay the mesembrine-type alkaloids namely Δ(7)mesembrenone, mesembranol, mesembrenone, mesembrine and epimesembranol. The calibration curves were found to be linear over the entire concentration range of 400-60,000 ng/ml with correlation coefficients >0.99. The accuracies of the relevant alkaloids were found to be between 94.8 and 103.6% with an inter-day relative standard deviation (RSD) of less than 2.8%. The precision studies showed inter-day RSD's of less than 3%. The recoveries were all within the range of 95 and 105% (RSD <4.5%) and the limits of quantitation (LOQ) and detection (LOD) were found to be 100 and 200 ng/ml respectively using the respective S/N ratios of 3 and 10. Conclusions. An HPLC method for the quantitative analysis of Δ(7)mesembrenone, mesembranol, mesembrenone, mesembrine and epimesembranol in Sceletium plant material has been developed and validated. This assay method can be applied for the quality control of Sceletium plant material which is used as an African Traditional Medicine for the treatment of psychological disorders.


[The perception of professionals regarding planned home birth].
This is a qualitative study aimed to understand the perception of professionals regarding planned home birth. Eight professionals who took part in home births in Cascavel/PR were interviewed. The analysis revealed that home, as the care place, allows more prominence to women and family as a result of tranquility, peacefulness and autonomy. The environment is safe as long as some requirements are observed, such as low-risk pregnancy, appropriate assessment during labor, presence of the right equipment transdisciplinary network and predefined place for referrals. The professionals also emphasize that the family participation in the process is fundamental. It is concluded that home birth is an excellent strategy to change and improve obstetric care quality.


CYR61 triggers osteosarcoma metastatic spreading via an IGF1Rβ-dependent EMT-like process.
Osteosarcoma is the most prevalent primary bone malignancy in children and young adults. These tumors are highly metastatic, leading to poor outcome. We previously demonstrated that Cysteine-rich protein 61 (CYR61/CCN1) expression level is correlated to osteosarcoma aggressiveness in preclinical model and in patient tumor samples. The aim of the present study was to investigate the CYR61-induced intracellular mechanisms leading to the acquisition of an invasive phenotype by osteosarcoma cells. Modified murine and human osteosarcoma cell lines were evaluated for cell adhesion, aggregation (spheroid), motility (wound healing assay), phenotypic markers expression (RT-qPCR, western blot). Cell-derived xenograft FFPE samples and patients samples (TMA) were assessed by IHC. CYR61 levels controlled the expression of markers related to an Epithelial-mesenchymal transition (EMT)-like process, allowing tumor cells to migrate acquiring a competent morphology, and to be able to invade the surrounding stroma. This phenotypic shift indeed correlated with tumor grade and aggressiveness in patient samples and with the metastatic dissemination potential in cell-derived xenograft models. Unlike EGFR or PDGFR, IGF1Rβ levels correlated with CYR61 and N-cadherin levels, and with the aggressiveness of osteosarcoma and overall survival. The expression levels of IGF1Rβ/IGF1 axis were controlled by CYR61, and anti-IGF1 neutralizing antibody prevented the CYR61-induced phenotypic shift, aggregation, and motility abilities. Taken together, our study provides new evidence that CYR61 acts as a key inducing factor in the metastatic progression of osteosarcoma by playing a critical role in primary tumor dissemination, with a process associated with IGF1/IGFR stimulation. This suggests that CYR61 may represent a potential pivotal target for therapeutic management of metastases spreading in osteosarcoma, in correlation with IGF1/IGFR pathway.


Little evidence for an effect of smoking on multiple sclerosis risk: A Mendelian Randomization study.
The causes of multiple sclerosis (MS) remain unknown. Smoking has been associated with MS in observational studies and is often thought of as an environmental risk factor. We used two-sample Mendelian randomization (MR) to examine whether this association is causal using genetic variants identified in genome-wide association studies (GWASs) as associated with smoking. We assessed both smoking initiation and lifetime smoking behaviour (which captures smoking duration, heaviness, and cessation). There was very limited evidence for a meaningful effect of smoking on MS susceptibility as measured using summary statistics from the International Multiple Sclerosis Genetics Consortium (IMSGC) meta-analysis, including 14,802 cases and 26,703 controls. There was no clear evidence for an effect of smoking on the risk of developing MS (smoking initiation: odds ratio [OR] 1.03, 95% confidence interval [CI] 0.92-1.61; lifetime smoking: OR 1.10, 95% CI 0.87-1.40). These findings suggest that smoking does not have a detrimental consequence on MS susceptibility. Further work is needed to determine the causal effect of smoking on MS progression.


Clinical implications of plasma Epstein-Barr virus DNA in early-stage extranodal nasal-type NK/T-cell lymphoma patients receiving primary radiotherapy.
The clinical value of plasma Epstein-Barr virus (EBV) DNA has not been evaluated in patients with early-stage extranodal nasal-type NK/T-cell lymphoma (NKTCL) receiving primary radiotherapy. Fifty-eight patients with stage I disease and 11 with stage II disease were recruited. High pretreatment EBV-DNA concentrations were associated with B-symptoms, elevated lactate dehydrogenase levels, and a high International Prognostic Index score. EBV-DNA levels significantly decreased after treatment. The 3-year overall survival (OS) rate was 82.6% for all patients. Stage I or II patients with a pretreatment EBV-DNA level of ≤ 500 copies/mL had 3-year OS and progression-free survival (PFS) rates of 97.1% and 79.0%, respectively, compared with 66.3% (P = .002) and 52.2% (P = .045) in patients with EBV-DNA levels of > 500 copies/mL. The 3-year OS and PFS rates for patients with undetectable EBV-DNA after treatment was significantly higher than patients with detectable EBV-DNA (OS, 92.0% vs 69.8%, P = .031; PFS, 77.5% vs 50.7%, P = .028). Similar results were observed in stage I patients. EBV-DNA levels correlate with tumor load and a poorer prognosis in early-stage NKTCL. The circulating EBV-DNA level could serve both as a valuable biomarker of tumor load for the accurate classification of early-stage NKTCL and as a prognostic factor.


Subjective patients' opinion and evaluation of halitosis using halimeter and organoleptic scores.
The aim of the study was to evaluate the level of interest in fetor ex ore among respondents, patients of the Department of Conservative Dentistry in Warsaw. A questionnaire was completed by 295 patients, 202 females and 93 males aged 18-74 years (average 38.73 years). Each person was also examined for organoleptic score and volatile sulfur compounds (VSC) by Halimeter. Halitosis was diagnosed if the average level of VSC was > or =125 ppb and the organoleptic measurement using a 0-5 point scale was > or =2. Statistical analysis was performed using chi-square test. Incidence of halitosis was greatest in age ranges 25-34 years (29.68%) and 45-54 years (24.52%). Sixty-eight (43.87%) persons with diagnosed halitosis frequently reported having a problem with bad breath and only 5.81% persons with halitosis did not notice this problem (P < 0.001). Among 54 healthy persons three (5.56%) reported having a problem with halitosis (P < 0.001). A statistically significant correlation was found between clinical organoleptic diagnosis of halitosis and VSC level by halimeter. Subjective patients' opinion correlated well with objective evaluation of halitosis.


Frontoethmoidal encephaloceles, a study of their pathogenesis.
A prospective clinical study of 30 patients with frontoethmoidal encephaloceles was performed in order to find support for a proposed theory concerning its pathogenesis, based on a previously performed embryological study and relevant findings in the literature. According to this proposed theory the pathogenesis of frontoethmoidal encephaloceles is primarily based on a disturbance in separation of neural and surface ectoderm at the site of final closure of the rostral neuropore during the final phase of neurulation in the 4th week of gestation. An insufficient occurrence of apoptosis might cause this disturbance in separation. The nonseparation of neural and surface ectoderm will result secondarily in a midline mesodermal defect. This mesodermal defect is reflected in the median skull defect at the site of the foramen caecum. The outgrowth of the nasal septum with the concomitant forward displacement of epidermis (surface ectoderm) and attached brain tissue (neural ectoderm) may act as herniating force. The patient study consisted of a clinical investigation, radiological investigations (X skull and CT scans), and surgical treatment in order to obtain specimens which were examined histologically. Clinical findings supportive of the proposed hypothesis are (1) the consistency in the location of the internal skull defect, (2) the close relationship between epidermal structures and glial tissue in 15 out of 29 specimens, and (3) the presence of a normally developed nose in combination with interorbital hypertelorism in all patients. A discussion of these findings is presented with special reference to the embryological aspects.


Health information technology workforce needs of rural primary care practices.
This study assessed electronic health record (EHR) and health information technology (HIT) workforce resources needed by rural primary care practices, and their workforce-related barriers to implementing and using EHRs and HIT. Rural primary care practices (1,772) in 13 states (34.2% response) were surveyed in 2012 using mailed and Web-based questionnaires. EHRs or HIT were used by 70% of respondents. Among practices using or intending to use the technology, most did not plan to hire new employees to obtain EHR/HIT skills and even fewer planned to hire consultants or vendors to fill gaps. Many practices had staff with some basic/entry, intermediate and/or advanced-level skills, but nearly two-thirds (61.4%) needed more staff training. Affordable access to vendors/consultants who understand their needs and availability of community college and baccalaureate-level training were the workforce-related barriers cited by the highest percentages of respondents. Accessing the Web/Internet challenged nearly a quarter of practices in isolated rural areas, and nearly a fifth in small rural areas. Finding relevant vendors/consultants and qualified staff were greater barriers in small and isolated rural areas than in large rural areas. Rural primary care practices mainly will rely on existing staff for continued implementation and use of EHR/HIT systems. Infrastructure and workforce-related barriers remain and must be overcome before practices can fully manage patient populations and exchange patient information among care system partners. Efforts to monitor adoption of these skills and ongoing support for continuing education will likely benefit rural populations.


Rapid detection and simultaneous molecular profile characterization of Acanthamoeba infections.
Diagnosis of Acanthamoeba by microscopic examination, culture, and polymerase chain reactions (PCRs) has several limitations (sensitivity, specificity, lack of detection of several strains, cost of testing for discrimination among strains). We developed a new high-resolution melting real-time PCR (HRM) to detect and characterize Acanthamoeba infections. HRM performances were evaluated with strains from the American Type Culture Collection (ATCC) and with 20 corneal scrapings. The DNA extracted from specimens were amplified, detected, and characterized in 1 run using 2 original primers diluted in a solution containing an intercalating dye. Detection and molecular characterization of Acanthamoeba infections could be achieved in less than 2.5 h with a dramatic reduction in cost of reactants (postamplification procedures and radioactive or fluorescent-labeled molecular probes were unnecessary). HRM detection limits were 0.1 cyst/μL or less (including genotypes T5 and T11), and its sensitivity and specificity were higher than other molecular tests. For the tested strains from the ATCC, the HRM drafted 4 different profiles: Type I (genotypes T2 and T4), Type II (T5 and T7), Type III (T8), and Type IV (T1, T3, T6, T9, T11, T12, and T13).


Dissociation and reassembly of Escherichia coli outer membrane and of lipopolysaccharide, and their reassembly onto flagellar basal bodies.
Purified lipopolysaccharide vesicles dissociate when treated with ethylenediaminetetraacetic acid (EDTA) and then reassemble when dialyzed against Mg(2+). Purified outer, lipopolysaccharide membrane (L membrane) is partially dissociated by treatment with EDTA and fully dissociated upon further treatment with Triton X-100. Both the partially and fully dissociated L membrane can be reassembled by dialysis against Mg(2+). Reassembly of lipopolysaccharide or L membrane in the presence of intact flagella results in specific attachment of flagellar basal bodies to vesicles via the L and sometimes the M ring. Lipopolysaccharide and L membrane appear to be composed of substructures bound together by both Mg(2+) (divalent cation)-mediated and hydrophobic bonds.


Role of cholesterol in SNARE-mediated trafficking on intracellular membranes.
The cell surface delivery of extracellular matrix (ECM) and integrins is fundamental for cell migration in wound healing and during cancer cell metastasis. This process is not only driven by several soluble NSF attachment protein (SNAP) receptor (SNARE) proteins, which are key players in vesicle transport at the cell surface and intracellular compartments, but is also tightly modulated by cholesterol. Cholesterol-sensitive SNAREs at the cell surface are relatively well characterized, but it is less well understood how altered cholesterol levels in intracellular compartments impact on SNARE localization and function. Recent insights from structural biology, protein chemistry and cell microscopy have suggested that a subset of the SNAREs engaged in exocytic and retrograde pathways dynamically 'sense' cholesterol levels in the Golgi and endosomal membranes. Hence, the transport routes that modulate cellular cholesterol distribution appear to trigger not only a change in the location and functioning of SNAREs at the cell surface but also in endomembranes. In this Commentary, we will discuss how disrupted cholesterol transport through the Golgi and endosomal compartments ultimately controls SNARE-mediated delivery of ECM and integrins to the cell surface and, consequently, cell migration.


Diagnostic antigens for visceral leishmaniasis: clarification of nomenclatures.
Stimulated by the increasing recent use of 'K' or 'rK' nomenclature for antigens reported for visceral leishmaniasis (VL) diagnostic serology, we wished to give a chronological synopsis of their reporting and the potentially confusing terminology. The literature was examined for 'K' or 'rK' terminology for VL diagnostic antigens, with emphasis on the original publications in which terms were first used. A chronological account of the first use of these 'K' and 'rK' nomenclatures was compiled. Since the original use of this terminology in 1993 in the name rK39 for a Leishmania antigen fragment, we found nine subsequent instances where 'K' or 'rK' have been used to maintain consistency with this nomenclature. We also found instances where there were ambiguities regarding reported strain name, origin and GenBank accession numbers. We have documented here the uses in the literature of the 'K' or 'rK' prefix for VL diagnostic antigen nomenclature. We suggest that, to avoid confusion, the use of such nomenclature for future antigens should either provide the logical derivation of the term or indicate that the designation is entirely empirical.


Simultaneous activation of complement and coagulation by MBL-associated serine protease 2.
The complement system is an important immune mechanism mediating both recognition and elimination of foreign bodies. The lectin pathway is one pathway of three by which the complement system is activated. The characteristic protease of this pathway is Mannan-binding lectin (MBL)-associated serine protease 2 (MASP2), which cleaves complement proteins C2 and C4. We present a novel and alternative role of MASP2 in the innate immune system. We have shown that MASP2 is capable of promoting fibrinogen turnover by cleavage of prothrombin, generating thrombin. By using a truncated active form of MASP2 as well as full-length MASP2 in complex with MBL, we have shown that the thrombin generated is active and can cleave both factor XIII and fibrinogen, forming cross-linked fibrin. To explore the biological significance of these findings we showed that fibrin was covalently bound on a bacterial surface to which MBL/MASP2 complexes were bound. These findings suggest that, as has been proposed for invertebrates, limited clotting may contribute to the innate immune response.


Loss of anti-contractile effect of perivascular adipose tissue in offspring of obese rats.
Maternal obesity pre-programmes offspring to develop obesity and associated cardiovascular disease. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect on the vasculature, which is reduced in hypertension and obesity. The objective of this study was to determine whether maternal obesity pre-programmes offspring to develop PVAT dysfunction in later life. Female Sprague-Dawley rats were fed a diet containing 10% (control) or 45% fat (high fat diet, HFD) for 12 weeks prior to mating and during pregnancy and lactation. Male offspring were killed at 12 or 24 weeks of age and tension in PVAT-intact or -denuded mesenteric artery segments was measured isometrically. Concentration-response curves were constructed to U46619 and norepinephrine. Only 24-week-old HFD offspring were hypertensive (P<0.0001), although the anti-contractile effect of PVAT was lost in vessels from HFD offspring of each age. Inhibition of nitric oxide (NO) synthase with 100 μM l-NMMA attenuated the anti-contractile effect of PVAT and increased contractility of PVAT-denuded arteries (P<0.05, P<0.0001). The increase in contraction was smaller in PVAT-intact than PVAT-denuded vessels from 12-week-old HFD offspring, suggesting decreased PVAT-derived NO and release of a contractile factor (P<0.07). An additional, NO-independent effect of PVAT was evident only in norepinephrine-contracted vessels. Activation of AMP-activated kinase (with 10 μM A769662) was anti-contractile in PVAT-denuded (P<0.0001) and -intact (P<0.01) vessels and was due solely to NO in controls; the AMPK effect was similar in HFD offspring vessels (P<0.001 and P<0.01, respectively) but was partially NO-independent. The diminished anti-contractile effects of PVAT in offspring of HFD dams are primarily due to release of a PVAT-derived contractile factor and reduced NO bioavailability.


Antagonistic selection on body size and sword length in a wild population of the swordtail fish, Xiphophorus multilineatus: Potential for intralocus tactical conflict.
Alternative reproductive tactics (ARTs) have provided valuable insights into how sexual selection and life history trade-offs can lead to variation within a sex. However, the possibility that tactics may constrain evolution through intralocus tactical conflict (IATC) is rarely considered. In addition, when IATC has been considered, the focus has often been on the genetic correlations between the ARTs, while evidence that the ARTs have different optima for associated traits and that at least one of the tactics is not at its optimum is often missing. Here, we investigate selection on three traits associated with the ARTs in the swordtail fish Xiphophorus multilineatus; body size, body shape, and the sexually selected trait for which these fishes were named, sword length (elongation of the caudal fin). All three traits are tactically dimorphic, with courter males being larger, deeper bodied and having longer swords, and the sneaker males being smaller, more fusiform and having shorter swords. Using measures of reproductive success in a wild population we calculated selection differentials, as well as linear and quadratic gradients. We demonstrated that the tactics have different optima and at least one of the tactics is not at its optimum for body size and sword length. Our results provide the first evidence of selection in the wild on the sword, an iconic trait for sexual selection. In addition, given the high probability that these traits are genetically correlated to some extent between the two tactics, our study suggests that IATC is constraining both body size and the sword from reaching their phenotypic optima. We discuss the importance of considering the role of IATC in the evolution of tactical dimorphism, how this conflict can be present despite tactical dimorphism, and how it is important to consider this conflict when explaining not only variation within a species but differences across species as well.


Rates of appropriate laxative prophylaxis for opioid-induced constipation in veterans with lung cancer: a retrospective cohort study.
Opioid-induced constipation (OIC) is the most common side effect in patient-prescribed opioids for cancer pain treatment. Current guidelines recommend routine prescription of a laxative for preventing OIC in all patients prescribed an opioid unless a contraindication exists. We determined patterns of prescription of laxative agents in patients with lung cancer initiating opioids. We performed a retrospective cohort study evaluating the prescription of laxatives for OIC to adult patients with incident lung cancer seen in the Veteran's Affairs (VA) system, between January 1, 2003, and December 31, 2016. Exposure to laxative agents was categorized as follows: none, docusate monotherapy, docusate plus another laxative, and other laxatives only. Prevalence of OIC prophylaxis was analyzed using descriptive statistics. Linear regression was performed to identify time trends in the prescription of OIC prophylaxis. Overall, 130,990 individuals were included in the analysis. Of these, 87% of patients received inadequate prophylaxis (75% no prophylaxis and 12% docusate alone), while 5% received OIC prophylaxis with the unnecessary addition of docusate to another laxative. Through the study period, laxative prescription significantly decreased, while all other categories of OIC prophylaxis were unchanged. We noted an inverse relationship with OIC prophylaxis and likelihood of a diagnosis of constipation at 3 and 6 months. In this study of veterans with lung cancer, almost 90% received inadequate or inappropriate OIC prophylaxis. Efforts to educate physicians and patients to promote appropriate OIC prophylaxis in combination with systems-level changes are warranted.


Multi-Omic blood analysis reveals differences in innate inflammatory sensitivity between species.
Vertebrates differ greatly in responses to pro-inflammatory agonists such as bacterial lipopolysaccharide (LPS), complicating use of animal models to study human sepsis or inflammatory disorders. We compared transcriptomes of resting and LPS-exposed blood from six LPS-sensitive species (rabbit, pig, sheep, cow, chimpanzee, human) and four LPS-resilient species (mice, rats, baboon, rhesus), as well as plasma proteomes and lipidomes. Unexpectedly, at baseline, sensitive species already had enhanced expression of LPS-responsive genes relative to resilient species. After LPS stimulation, maximally different genes in resilient species included genes that detoxify LPS, diminish bacterial growth, discriminate sepsis from SIRS, and play roles in autophagy and apoptosis. The findings reveal the molecular landscape of species differences in inflammation, and may inform better selection of species for pre-clinical models. Fundamental differences are present in blood of humans, mice and other species that differ in sensitivity to inflammation.


Characterization of Wellbeing and its Relationship with Exposure to Violence in Mexican and Chilean Early and Late Adolescents during the COVID-19 Pandemic.
The current COVID-19 (SARS-CoV-2) pandemic has generated negative psychological effects on the global population. In this context, one of the most vulnerable groups is adolescents, who have faced a range of challenging scenarios. The consequences of this pandemic for the wellbeing of adolescents need to be researched across countries. From this perspective, this study aims to characterize the wellbeing of adolescents from Mexico and Chile during the pandemic and delve into the relationship between victimization and the hedonic and eudaimonic types of wellbeing. Data from adolescent students (n = 3,275) were used, with the support of the Global Research Alliance. Descriptive and regression analyses were conducted and their results indicated that: 1) Late adolescents scored lower on flourishing, and males scored higher than females. There was also a higher prevalence of languishing in late adolescents from both countries, as well as high levels of languishing in non-binary adolescents, especially in Chile; 2) There was a high prevalence of poly-victimization, with the highest percentage reported by females and the late adolescent group in both countries; 3) Non-victims had a higher probability of being in the flourishing group than victims in both countries; 4) Poly-victimization especially had an effect on the eudaimonic wellbeing of early adolescents and on the hedonic and eudaimonic wellbeing of late adolescents in both countries. Implications related to the mental health policies for adolescence are discussed in terms of how to increase adolescent wellbeing.


Secretory leukoprotease inhibitor in mucosal lymph node dendritic cells regulates the threshold for mucosal tolerance.
The notion that the mucosal immune system maintains a tolerogenic response to harmless Ags while continually being challenged with microbial products seems an enigma. The aim of this study was to unravel mechanisms that are involved in regulating the development of tolerance under constant microbial pressure. The tolerogenic response to Ags administered via the nasal mucosa is dependent on the organized lymphoid tissue of the cervical lymph nodes (LN). We show that cervical LN differentially express secretory leukoprotease inhibitor (SLPI) compared with peripheral LN. SLPI was expressed by dendritic cells (DCs) and because SLPI is known to suppress LPS responsiveness, it was hypothesized that its expression in mucosal DCs may be required to regulate cellular activation to microbial products. Indeed, compared with wild-type controls, bone marrow-derived DCs from SLPI(-/-) mice released more inflammatory cytokines and enhanced T cell proliferation after stimulation with low dose LPS. This increased sensitivity to LPS was accompanied by increased NF-kappaB p65 activation in SLPI(-/-) DCs. In vivo, nasal application of OVA with LPS to SLPI(-/-) mice resulted in enhanced DC activation in the cervical LN reflected by increased costimulatory molecule expression and release of inflammatory cytokines. This led to failure to maintain tolerance to nasal OVA application in the presence of low doses of LPS. We propose that expression of SLPI functions as a rheostat by controlling the level of bacterial stimuli that induce mucosal DC activation. As such, it regulates the quality of the ensuing Ag-specific immune response in the mucosa draining LN.


Studies on the development of infant foods from plant protein sources. Part I. Effect of germination of chickpea (Cicer arietinum) on the nutritive value and digestibility of proteins.
For the purpose of developing an infant food of improved dispersibility characteristics and high nutritive quality, different treatments and technologies were applied to chickpea (Cicer arietinum). Samples were germinated for two and four days at room temperature (25 - 27 degrees C). One portion of each germinated chickpea sample was boiled for 40 min and the other portion was autoclaved at 15 psi for 15 min. These processed samples were then compared with the corresponding value of raw germinated and ungerminated samples as well as with the ungerminated processed ones for the following characteristics: chemical composition, contents of antiphysiological factors, solubility of proteins, lysine availability, net protein ratio (NPR), and digestibility of proteins. Germination caused an increase in the protein content of the seeds. No appreciable changes were observed in the trypsin inhibitor and tannin contents during germination. Availability of lysine was found slightly lower in the germinated seeds. The solubility of the nitrogenous constituents was markedly increased during germination. Along with processing, germination had no beneficial effect in improving protein quality, although digestibility of the proteins was increased. Boiling was more advantageous in the case of germinated seeds than autoclaving, whereas the reverse was true in the case of ungerminated seeds.


Rice bran oil and human health.
The available data in humans suggest that rice bran oil (RBO) is an edible oil of preference for improving plasma lipid and lipoprotein profiles similar to more commonly used vegetable oils. The observation that blending RBO with safflower oil at a specific proportion magnifies the hypocholesterolemic efficacy is of particular interest with regard to utilization of this oil. The occurrence of peculiar components such as gamma-oryzanol and tocotrienols in RBO might be responsible for its hypocholesterolemic effect.


[Eyes test performance among unaffected mothers of patients with schizophrenia].
Theory of Mind (ToM) deficit is a widely accepted feature of schizophrenia. A number of studies have examined ToM deficits of first degree relatives of schizophrenic patients as genetic markers of schizophrenia. Examination of mentalization capacity among mothers of schizophrenia patients may improve our understanding of theory of mind impairments in schizophrenia. The aim of this study is to use Reading Mind in the Eyes test to examine theory of mind capacity among mothers of schizophrenic patients. Performance during the test "Reading the Mind in the Eyes" (Eyes Test) was compared between the mothers of schizophrenic patients (n=47) and mothers whose children have no psychotic mental illness (n=47). Test results were analyzed based on the categorization of test items as positive, negative, and neutral. Mothers of schizophrenic patients displayed poorer performance during the Eyes Test compare to mothers in the control group, particularly in the recognition of positive and neutral mental representations. There was no statistically significant difference in the recognition of negative mental representations between mothers of patients and the control groups. The results of this study indicate that mothers of schizophrenic patients differ in some theory of mind patterns. Theory of mind may be an important developmental or endophenotipic factor in the pathogenesis of schizophrenia and should be further evaluated using other biological markers.


[Social-work adaptation of patients with sluggish schizophrenia in the late stages of the course of the disease (according to the results of a clinico-epidemiologic study)].
The author presents the results of a clinico-epidemiological examination covering 156 patients with slowly progressive schizophrenia of long standing (over 10 years), who had fallen ill in adolescence. The parameters of the social and occupational adaptation of the patients with slowly progressive schizophrenia studied at the late stages of the disease included the educational level, qualification, the presence or absence of disability and the adaptation to the life in the family and to everyday household routine. The study has shown that patients with slowly progressive schizophrenia possess considerable potentialities with regard to social and occupational readaptation. This points to the need of developing the most effective social measures adequate for patients with slowly progressive schizophrenia (recommendations for the continuation of education in different training establishments, elaboration of the basic principles of familial psychotherapy).


Nucleic acid hybridization: from research tool to routine diagnostic method.
The nucleic acid hybridization reaction is extremely specific and thus a valuable tool for the identification of genes or organism of interest. The increasing use of nucleic acid hybridization in applied fields like diagnostic medicine has led to the development of more convenient hybridization assays than those originally used in basic research. In conventional nucleic acid hybridization methods immobilized nucleic acids are detected on a filter by a radiolabelled probe. Sandwich hybridization is a simple test format for the analysis of unpurified biological material, but has the disadvantage of a slow reaction rate. Solution hybridization methods are fast and easy to perform provided that a method to separate the formed hybrids from the reaction mixture is available. In non-isotopic detection the nucleic acid probe is modified with a chemical group, which is identified with a labelled detector molecule after hybridization. The low sensitivity of detection is the main problem in nucleic acid hybridization methods. Procedures to amplify the detectable signal or the amount of detectable nucleic acid sequences are potential solutions to this problem. The new hybridization methods have successfully been used for some applications, but still need to be combined into well performing tests to be applicable to any desired purpose.


Cell-derived vesicles for drug therapy and diagnostics: opportunities and challenges.
Extracellular vesicles are small lipid-based membrane-bound entities shed by cells under both physiological and pathological conditions. Their discovery as intercellular communicators through transfer of nucleic acid- and protein-based cargos between cells locally and at distance in a highly specific manner has created recent excitement. The information they transport and their composition may vary depending on the cell of origin as well as the eliciting stimulus. Such sensitive changes in vesicle characteristics hold significant promise for the improved diagnosis of pathological conditions, including infections and neoplastic lesions in a minimally invasive way. Similarly, these cell-derived vesicles exhibit promising characteristics that could enhance drug targeting efficiencies. Recent developments in the field have aimed at studying EVs as novel drug carriers due to their natural composition, biological function and selective cell interaction. In this review, we discuss new research avenues in diagnostics and drug therapy based on extracellular vesicles. We show how cell-derived vesicles can be harvested and engineered to meet application-specific design requirements. We finally discuss potential risks encountered when translating extracellular vesicle based approaches into (pre)clinical applications.


Ionic channels in mouse astrocytes in culture.
We observed Na, K, and Cl voltage-dependent currents in a patch-clamp study of mouse brain astrocytes. In whole-cell recordings, depolarizations activated inward currents that were identified as Na currents since they were blocked by TTX, although complete block required high concentrations (greater than 1 microM). The corresponding single-channel Na currents were observed in outside-out patches. The channels were opened by a depolarizing pulse applied from a holding potential identical to the resting potential (-70 to -80 mV). Therefore, they may be considered functional Na channels. After addition of veratridine and an alpha-scorpion toxin, the decay of Na currents in whole-cell recordings was slower than observed under control conditions. At the single-channel level, the channels appeared to open in bursts. Depolarization did not increase the duration of the bursts, but inside each burst, increased the time spent in the open state. The K currents observed in the whole-cell recording mode were separated into inactivating and noninactivating currents. The inactivating current resembled the A current in its kinetics, its insensitivity to tetraethylammonium, and its sensitivity to 4-aminopyridine. At the single-channel level, at least 3 classes of K channels were observed at steady depolarized potentials. They resembled the K channels found in chromaffin cells by Marty and Neher (1985). Large conductance channels (385 pS) activated around 0 mV were identified as Cl channels.


A geminivirus-related DNA mycovirus that confers hypovirulence to a plant pathogenic fungus.
Mycoviruses are viruses that infect fungi and have the potential to control fungal diseases of crops when associated with hypovirulence. Typically, mycoviruses have double-stranded (ds) or single-stranded (ss) RNA genomes. No mycoviruses with DNA genomes have previously been reported. Here, we describe a hypovirulence-associated circular ssDNA mycovirus from the plant pathogenic fungus Sclerotinia sclerotiorum. The genome of this ssDNA virus, named Sclerotinia sclerotiorum hypovirulence-associated DNA virus 1 (SsHADV-1), is 2166 nt, coding for a replication initiation protein (Rep) and a coat protein (CP). Although phylogenetic analysis of Rep showed that SsHADV-1 is related to geminiviruses, it is notably distinct from geminiviruses both in genome organization and particle morphology. Polyethylene glycol-mediated transfection of fungal protoplasts was successful with either purified SsHADV-1 particles or viral DNA isolated directly from infected mycelium. The discovery of an ssDNA mycovirus enhances the potential of exploring fungal viruses as valuable tools for molecular manipulation of fungi and for plant disease control and expands our knowledge of global virus ecology and evolution.


The role of the ubiquitin proteasome pathway in keratin intermediate filament protein degradation.
Lung injury, whether caused by hypoxic or mechanical stresses, elicits a variety of responses at the cellular level. Alveolar epithelial cells respond and adapt to such injurious stimuli by reorganizing the cellular cytoskeleton, mainly accomplished through modification of the intermediate filament (IF) network. The structural and mechanical integrity in epithelial cells is maintained through this adaptive reorganization response. Keratin, the predominant IF expressed in epithelial cells, displays highly dynamic properties in response to injury, sometimes in the form of degradation of the keratin IF network. Post-translational modification, such as phosphorylation, targets keratin proteins for degradation in these circumstances. As with other structural and regulatory proteins, turnover of keratin is regulated by the ubiquitin (Ub)-proteasome pathway. The degradation process begins with activation of Ub by the Ub-activating enzyme (E1), followed by the exchange of Ub to the Ub-conjugating enzyme (E2). E2 shuttles the Ub molecule to the substrate-specific Ub ligase (E3), which then delivers the Ub to the substrate protein, thereby targeting it for degradation. In some cases of injury and IF-related disease, aggresomes form in epithelial cells. The mechanisms that regulate aggresome formation are currently unknown, although proteasome overload may play a role. Therefore, a more complete understanding of keratin degradation--causes, mechanisms, and consequences--will allow for a greater understanding of epithelial cell biology and lung pathology alike.


Structure-activity relationship in cationic lipid mediated gene transfection.
Non-viral synthetic vectors for gene delivery represent a safer alternative to viral vectors. Their main drawback is the low transfection efficiency, especially in vivo. Among the non-viral vectors currently in use, the cationic liposomes composed of cationic lipids are the most common. This review discusses the physicochemical properties of cationic lipids, the formation, macrostructure and specific parameters of the corresponding formulated liposomes, and the effect of all these parameters on transfection efficiency. The optimisation of liposomal vectors requires both the understanding of the biological variables involved in the transfection process, and the effect of the structural elements of the cationic lipids on these biological variables. The biological barriers relevant for in vitro and in vivo transfection are identified, and solutions to overcome them based on rational design of the cationic lipids are discussed. The review focuses on the relationship between the structure of the cationic lipid and the transfection activity. The structure is analysed in a modular manner. The hydrophobic domain, the cationic head group, the backbone that acts as a scaffold for the other domains, the linkers between backbone, hydrophobic domain and cationic head group, the polyethyleneglycol chains and the targeting moiety are identified as distinct elements of the cationic lipids used in gene therapy. The main chemical functionalities used to built these domains, as well as overall molecular features such as architecture and geometry, are presented. Studies of structure-activity relationships of each cationic lipid domain, including the authors', and the trends identified by these studies, help furthering the understanding of the mechanism governing the formation and behaviour of cationic liposomes in gene delivery, and therefore the rational design of new improved cationic lipids vectors capable of achieving clinical significance.


An adaptive fuzzy-neural-network controller for ultrasonic motor drive using the LLCC resonant technique.
In this study an adaptive fuzzy-neural-network controller (AFNNC) is proposed to control a rotary traveling wave-type ultrasonic motor (USM) drive system. The USM is derived by a newly designed, high frequency, two-phase voltage source inverter using two inductances and two capacitances (LLCC) resonant technique. Then, because the dynamic characteristics of the USM are complicated and the motor parameters are time varying, an AFNNC is proposed to control the rotor position of the USM. In the proposed controller, the USM drive system is identified by a fuzzy-neural-network identifier (FNNI) to provide the sensitivity information of the drive system to an adaptive controller. The backpropagation algorithm is used to train the FNNI on line. Moreover, to guarantee the convergence of identification and tracking errors, analytical methods based on a discrete-type Lyapunov function are proposed to determine the varied learning rates of the FNNI and the optimal learning rate of the adaptive controller. In addition, the effectiveness of the adaptive fuzzy-neural-network (AFNN) controlled USM drive system is demonstrated by some experimental results.


Early diagnosis of chronic pancreatitis: understanding the factors associated with the development of chronic pancreatitis.
The prognosis of advanced chronic pancreatitis (CP) is poor with the mortality rate approximately two-fold higher than the general population according to a survey of the prognosis of CP. From this standpoint, the concept of early CP was propagated in Japan in 2009 to encourage the medical treatment for the earlier stages of CP. That is, picking up the patients suspicious for early CP and then providing medical treatment for them are very important not only for patients, but also for health care economics. In this review, we described some potential factors associated with the development of CP (alcohol, smoking, past history of acute pancreatitis, aging, gallstone, and gender) that are extremely important to discover patients with early-stage CP.


Factors Associated With Access to HIV Testing and Primary Care Among Migrants Living in Europe: Cross-Sectional Survey.
There is a heavy and disproportionate burden of human immunodeficiency virus (HIV) infection among migrant communities living in Europe. Despite this, the published evidence related to HIV testing, prevention, and treatment needs for migrants is sparse. The aim of this study was to identify the factors associated with access to primary care and HIV testing among migrant groups living in Europe. A Web-based survey (available in 14 languages) was open to all people aged 18 years and older, living outside their country of birth in the World Health Organization (WHO) European area. Community organizations in 9 countries promoted the survey to migrant groups, focusing on those at a higher risk of HIV (sub-Saharan Africans, Latin Americans, gay or bisexual men, and people who inject drugs). Multivariable analysis examined factors associated with access to primary care and previous history of an HIV test. In total, 559 women, 395 heterosexual men, and 674 gay or bisexual men were included in the analysis, and 68.1% (359/527) of women, 59.5% (220/371) of heterosexual men, and 89.6% (596/664) of gay or bisexual men had tested for HIV. Low perceived risk was the reason given for not testing by 62.3% (43/69) of gay or bisexual men and 83.3% (140/168) of women and heterosexual men who reported never having tested for HIV. Access to primary care was >60% in all groups. Access to primary care was strongly positively associated with living in Northern Europe compared with Southern Europe (women: adjusted odds ratio, aOR 34.56 [95% CI 11.58-101]; heterosexual men: aOR 6.93 [95% CI 2.49-19.35], and gay or bisexual men: aOR 2.53 [95% CI 1.23-5.19]), whereas those with temporary residency permits were less likely to have access to primary care (women: aOR 0.41 [95% CI 0.21-0.80] and heterosexual men: aOR 0.24 [95% CI 0.10-0.54] only). Women who had experience of forced sex (aOR 3.53 [95% CI 1.39-9.00]) or postmigration antenatal care (aOR 3.07 [95% CI 1.55-6.07]) were more likely to have tested for HIV as were heterosexual men who had access to primary care (aOR 3.13 [95% CI 1.58-6.13]) or reported "Good" health status (aOR 2.94 [95% CI 1.41-5.88]). Access to primary care is limited by structural determinants such as immigration and health care policy, which varies across Europe. For those migrants who can access primary care and other health services, missed opportunities for HIV testing remain a barrier to earlier testing and diagnosis for migrants in Europe. Clinicians should be aware of these potential structural barriers to HIV testing as well as low perception of HIV risk in migrant groups.


Fever screening during the influenza (H1N1-2009) pandemic at Narita International Airport, Japan.
Entry screening tends to start with a search for febrile international passengers, and infrared thermoscanners have been employed for fever screening in Japan. We aimed to retrospectively assess the feasibility of detecting influenza cases based on fever screening as a sole measure. Two datasets were collected at Narita International Airport during the 2009 pandemic. The first contained confirmed influenza cases (n = 16) whose diagnosis took place at the airport during the early stages of the pandemic, and the second contained a selected and suspected fraction of passengers (self-reported or detected by an infrared thermoscanner; n = 1,049) screened from September 2009 to January 2010. The sensitivity of fever (38.0 °C) for detecting H1N1-2009 was estimated, and the diagnostic performances of the infrared thermoscanners in detecting hyperthermia at cut-off levels of 37.5 °C, 38.0 °C and 38.5 °C were also estimated. The sensitivity of fever for detecting H1N1-2009 cases upon arrival was estimated to be 22.2% (95% confidence interval: 0, 55.6) among nine confirmed H1N1-2009 cases, and 55.6% of the H1N1-2009 cases were under antipyretic medications upon arrival. The sensitivity and specificity of the infrared thermoscanners in detecting hyperthermia ranged from 50.8-70.4% and 63.6-81.7%, respectively. The positive predictive value appeared to be as low as 37.3-68.0%. The sensitivity of entry screening is a product of the sensitivity of fever for detecting influenza cases and the sensitivity of the infrared thermoscanners in detecting fever. Given the additional presence of confounding factors and unrestricted medications among passengers, reliance on fever alone is unlikely to be feasible as an entry screening measure.


The role of iron in the pathogenesis of porphyria cutanea tarda. II. Inhibition of uroporphyrinogen decarboxylase.
Porphria cutanea tarda is characterized biochemically by excessive hepatic synthesis and urinary excretion of uroporphyrin I and 7-carboxylporphyrins. This pattern of excretion suggest an impaired ability to decarboxylate uroporphyrinogen to the paired ability to decarboxylate uroporphyringen to the 4-carboxyl porphyrinogen, coproporphyrinogen, a reaction catalyzed by the enzyme uroporphyringen decarboxylase. Because clinical evidence has implicated iron in the pathogenesis of porphyria cutanea tarda, these experiments were designed to study the effect of iron on uroporphyrinogen decarboxylase in procine crude liver extracts. Mitochondria-free crude liver extracts were preincubated with ferrous ion and aliquots were assayed for uroporphyrinogen decarboxylase activity. Uroporphyrinogens I and III, the substrates for the decarboxylase assay, were prepared enzymatically from (3H)porphobilinogen. The products of the decarboxylase reaction were identified and quantitated by three methods: (a) extraction into 1.5 N HCl and spectrophotometric quantitation; (b) adsorption onto talc, esterification, paper chromatographic identification, and quantitation by liquid scintillation counting; and (c) adsorption onto talc, esterification, thin-layer chromatographic identification on silica gel, and quantitation by liquid scintillation counting. The thin-layer scinllation method proved most sensitive as it was the only method which accurately identified and quantitated the 7-carboxyl porphyrin reaction product. Uroporphyrinogens I and III were decarboxylated at the same rate by porcine hepatic uroporphyrinogen decarboxylase, and the addition of iron induced marked inhibition of the decarboxylase activity. Ortholpehanthroline blocked the inhibitory effect of iron. The inhibition of uroporphyrinogen decarboxylase by ferrous ion, coupled with its previously reported inhibitory effect on uroporphyrinogen III cosynthetase, provides a possible biochemical explanation for the pattern of urinary porphyrin excretion observed in patients with porphyria cutanea tarda and the clinical association with disordered iron metabolism.


Anesthesia for patients with a history of malignant hyperthermia.
Malignant hyperthermia-susceptible patients have an increased risk during anaesthesia. The aim of this review is to present current knowledge about pathophysiology and triggers of malignant hyperthermia as well as concepts for safe anaesthesiological management of these patients. Trigger substances and mechanisms have been well defined to date. Anaesthesia can be safely performed with i.v. anaesthetics, nitrous oxide, nondepolarizing muscle relaxants, local anaesthetics as well as xenon. Attention must be directed to the preparation of the anaesthetic machine because modern workstations need longer cleansing times than their predecessors. Alternatively, activated charcoal might be beneficial for elimination of volatile anaesthetics. Day case surgery can be performed in malignant hyperthermia-susceptible patients, if all safety aspects are regarded. Whether there is an association between malignant hyperthermia susceptibility and other disorders is still a matter of debate. The incidence of malignant hyperthermia is low, but the prevalence can be estimated as up to 1: 3000. Because malignant hyperthermia is potentially lethal, it is relevant to establish management concepts for perioperative care in susceptible patients. This includes preoperative genetic and in-vitro contracture testing, preparation of the anaesthetic workstation, use of nontriggering anaesthetics, adequate monitoring, availability of sufficient quantities of dantrolene and appropriate postoperative care. Taking these items into account, anaesthesia can be safely performed in susceptible patients.


Low-Grade Dysplastic Nodules Revealed as the Tipping Point during Multistep Hepatocarcinogenesis by Dynamic Network Biomarkers.
Hepatocellular carcinoma (HCC) is a complex disease with a multi-step carcinogenic process from preneoplastic lesions, including cirrhosis, low-grade dysplastic nodules (LGDNs), and high-grade dysplastic nodules (HGDNs) to HCC. There is only an elemental understanding of its molecular pathogenesis, for which a key problem is to identify when and how the critical transition happens during the HCC initiation period at a molecular level. In this work, for the first time, we revealed that LGDNs is the tipping point (i.e., pre-HCC state rather than HCC state) of hepatocarcinogenesis based on a series of gene expression profiles by a new mathematical model termed dynamic network biomarkers (DNB)-a group of dominant genes or molecules for the transition. Different from the conventional biomarkers based on the differential expressions of the observed genes (or molecules) for diagnosing a disease state, the DNB model exploits collective fluctuations and correlations of the observed genes, thereby predicting the imminent disease state or diagnosing the critical state. Our results show that DNB composed of 59 genes signals the tipping point of HCC (i.e., LGDNs). On the other hand, there are a large number of differentially expressed genes between cirrhosis and HGDNs, which highlighted the stark differences or drastic changes before and after the tipping point or LGDNs, implying the 59 DNB members serving as the early-warning signals of the upcoming drastic deterioration for HCC. We further identified the biological pathways responsible for this transition, such as the type I interferon signaling pathway, Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway, transforming growth factor (TGF)-β signaling pathway, retinoic acid-inducible gene I (RIG-I)-like receptor signaling pathway, cell adhesion molecules, and cell cycle. In particular, pathways related to immune system reactions and cell adhesion were downregulated, and pathways related to cell growth and death were upregulated. Furthermore, DNB was validated as an effective predictor of prognosis for HCV-induced HCC patients by survival analysis on independent data, suggesting a potential clinical application of DNB. This work provides biological insights into the dynamic regulations of the critical transitions during multistep hepatocarcinogenesis.


Acupuncture for pain relief during childbirth.
There are few studies on acupuncture in childbirth despite the generally established analgesic effect of acupuncture treatment. The analgesic effect of acupuncture during childbirth was assessed by comparing the need for other pain treatments (epidural analgesia using bupivacaine, pudendal nerve block, intramuscular meperidine, nitrous oxide/oxygen, intracutaneous sterile water injections) in 90 women given acupuncture (acupuncture group) with that in 90 women not given acupuncture (control group). 52 women (58%) in the acupuncture group and 13 (14%) in the control group managed their deliveries without further pain treatment (p < 0.001). The groups were similar with respect to age, pariety, duration of delivery, use of oxytocine and incidence of Caesarean section. Acupuncture treatment was found to have no major side effects, and 85 women (94%) given acupuncture reported that they would reconsider acupuncture in future deliveries. Acupuncture reduces the need for other methods of analgesia in childbirth.


Adenosine receptors and behavioral actions of methylxanthines.
Central stimulant actions of 10 methylxanthines in mice correlate with affinities for adenosine receptors labeled with N6-[3H]cyclohexyladenosine. Affinities of methylxanthines for adenosine receptors are consonant with central levels attained at behaviorally effective doses. The much higher concentrations of methylxanthines required to influence benzodiazepine receptor binding do not correlate with behavioral potency. N6-(L-Phenylisopropyl)adenosine (L-PIA), a metabolically stable analog of adenosine with high affinity for adenosine receptors, is an extremely potent behavioral depressant, reducing locomotor activity of mice at doses as little as 0.05 mumol/kg. The D isomer, which has much less affinity for adenosine receptors, is much less active as a central depressant. Theophylline stimulates locomotor activity and reverses depressant effects of L-PIA. Caffeine or 1,7-dimethylxanthine, when administered alone, elicits biphasic effects, with locomotor depression at lower doses and stimulation at higher doses. When administered with L-PIA, even low doses of caffeine produce marked stimulation. 3-Isobutyl-1-methylxanthine given alone elicits only behavioral depression. However, like theophylline and caffeine, isobutylmethylxanthine reverses the L-PIA-evoked depression, converting it into pronounced locomotor stimulation. The data strongly suggest that the behavioral stimulant effects of methylxanthines involve a blockade of central adenosine receptors.


Capillary gingival hemangioma in a cat.
A 12-year-old spayed female American short-haired cat presented with a palatal gingival mass located between the right maxillary third incisor and the canine teeth. The mass was dark red and had a narrow attachment to the gingival margin of the canine tooth. The mass was completely removed by marginal excision and the histopathological diagnosis was a capillary hemangioma. The mass did not relapse until 1 year later; however, the tooth was extracted because of cervical resorption of the right maxillary canine immediately adjacent to the mass resection site. This report presents a rare case of the gingival hemangioma in a cat and the possibility of a causal relationship between the occurrence of external cervical tooth resorption and hemangioma resection.


Cyclin and DNA distributed cell cycle model for GS-NS0 cells.
Mammalian cell cultures are intrinsically heterogeneous at different scales (molecular to bioreactor). The cell cycle is at the centre of capturing heterogeneity since it plays a critical role in the growth, death, and productivity of mammalian cell cultures. Current cell cycle models use biological variables (mass/volume/age) that are non-mechanistic, and difficult to experimentally determine, to describe cell cycle transition and capture culture heterogeneity. To address this problem, cyclins-key molecules that regulate cell cycle transition-have been utilized. Herein, a novel integrated experimental-modelling platform is presented whereby experimental quantification of key cell cycle metrics (cell cycle timings, cell cycle fractions, and cyclin expression determined by flow cytometry) is used to develop a cyclin and DNA distributed model for the industrially relevant cell line, GS-NS0. Cyclins/DNA synthesis rates were linked to stimulatory/inhibitory factors in the culture medium, which ultimately affect cell growth. Cell antibody productivity was characterized using cell cycle-specific production rates. The solution method delivered fast computational time that renders the model's use suitable for model-based applications. Model structure was studied by global sensitivity analysis (GSA), which identified parameters with a significant effect on the model output, followed by re-estimation of its significant parameters from a control set of batch experiments. A good model fit to the experimental data, both at the cell cycle and viable cell density levels, was observed. The cell population heterogeneity of disturbed (after cell arrest) and undisturbed cell growth was captured proving the versatility of the modelling approach. Cell cycle models able to capture population heterogeneity facilitate in depth understanding of these complex systems and enable systematic formulation of culture strategies to improve growth and productivity. It is envisaged that this modelling approach will pave the model-based development of industrial cell lines and clinical studies.


Adoption of a Short-Term (4-Week) Vegan Diet as Part of 'Veganuary' Significantly Reduces Saturated Fatty Acid (SFA), Cholesterol, B12, and Iodine Intake in Omnivorous Individuals-An Observational Study.
Global veganism campaigns like 'Veganuary' have gained popularity. We conducted an observational study to assess the impact of a 4-week vegan diet during 'Veganuary' on nutrient intake, status, knowledge, and motivations for veganism. Data were collected before and after 'Veganuary', using Food Frequency Questionnaires (FFQs) to estimate dietary intake. Micronutrient knowledge and motivation were assessed through questionnaires. A total of 154 UK adults aged 18-60 years (2019: n81; 2020: n73) participated. Groups were vegetarians and omnivores committed to a 4-week vegan diet during 'Veganuary'. Control groups were vegans and omnivores who did not transition. Short-term vegan diets significantly decreased intake of iodine, B12, cholesterol, and saturated fatty acids (SFAs) in omnivores. Micronutrient knowledge was low, and motivation for veganism varied. Short-term vegan diets reduce macro- and micronutrient intake in omnivores. Veganuary participants could benefit from nutritional guidance or supplementation. Attention is required for UK micronutrient intake and knowledge. Motivations for vegan pledges may influence diets, warranting further research.


Polyneuropathy in occult hypothyroidism.
A patient who developed symptoms and signs of a polyneuropathy was found to have hypothyroidism, though this diagnosis was not clinically suspected. Treatment with thyroxine resulted in resolution of his symptoms and restored his nerve conduction studies to normal.


A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using 18F-FDG PET of the Brain.
Purpose To develop and validate a deep learning algorithm that predicts the final diagnosis of Alzheimer disease (AD), mild cognitive impairment, or neither at fluorine 18 (18F) fluorodeoxyglucose (FDG) PET of the brain and compare its performance to that of radiologic readers. Materials and Methods Prospective 18F-FDG PET brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2109 imaging studies from 2005 to 2017, 1002 patients) and retrospective independent test set (40 imaging studies from 2006 to 2016, 40 patients) were collected. Final clinical diagnosis at follow-up was recorded. Convolutional neural network of InceptionV3 architecture was trained on 90% of ADNI data set and tested on the remaining 10%, as well as the independent test set, with performance compared to radiologic readers. Model was analyzed with sensitivity, specificity, receiver operating characteristic (ROC), saliency map, and t-distributed stochastic neighbor embedding. Results The algorithm achieved area under the ROC curve of 0.98 (95% confidence interval: 0.94, 1.00) when evaluated on predicting the final clinical diagnosis of AD in the independent test set (82% specificity at 100% sensitivity), an average of 75.8 months prior to the final diagnosis, which in ROC space outperformed reader performance (57% [four of seven] sensitivity, 91% [30 of 33] specificity; P < .05). Saliency map demonstrated attention to known areas of interest but with focus on the entire brain. Conclusion By using fluorine 18 fluorodeoxyglucose PET of the brain, a deep learning algorithm developed for early prediction of Alzheimer disease achieved 82% specificity at 100% sensitivity, an average of 75.8 months prior to the final diagnosis. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Larvie in this issue.


Association of miRNA-145 expression in vascular smooth muscle cells with vascular damages in patients with lupus nephritis.
miRNAs have been found to contribute to the regulation of multiple cellular processes, including cell apoptosis, differentiation and proliferation. The patients with lupus nephritis (LN) exhibit thickened renal vascular membrane and highly proliferative vascular smooth muscle cells (VSMCs). Of various miRNAs discovered, miR-145 is essential to mediate the proliferation of VSMCs and the formation of atherosclerotic plaques. In this study, we studied the pathological and vascular damage of renal LN, and the correlation between miR-145 expression in VSMCs and the vascular damages. Serum, urine, and renal biopsies were obtained from 41 patients with active LN. The serum and urinary VEGF levels were examined to confirm the renal damage of each patient. Biopsies were stained to observe the glomerular segmental lesions, sclerosis, and to evaluate the vascular damages. The expression of miR-145 was also examined to determine the correlation between its expression and the vascular damages. The expression of miR-145 was mainly detected in the renal VSMCs and the epithelial cells of glomerular proximal convoluted tubule. Nevertheless, the expression of miR-145 reduced as the tunicae media vasorum ratios increased, indicating the development of LN inhibits the expression of miR-145. Furthermore, our studies revealed no significant correlation among renal interstitial vascular damage, glomerular damage and severity classification of LN. Therefore, we suggest the damage of renal interstitial vascular should be considered as one of the factors to evaluate the severity of the LN.


Analysis of visual search patterns with EMD metric in normalized anatomical space.
Eye movements provide important insight into the cognitive processes underlying the visual search tasks. For image understanding, although the visual search patterns of different observers while studying the same scene bear some common characteristics, the idiosyncrasy associated with individual observers provides both research opportunities and challenges. The aim of this paper is to study the spatial characteristics of visual search, together with the intrinsic visual features of the fixation points for comparing different visual search strategies. An analysis framework based on earth mover's distance (EMD) in normalized anatomical space is proposed, and the results are demonstrated with high resolution computed tomography (HRCT) images of the lungs. The study shows that through the effective use of both spatial and feature space representation, it is possible to untangle what appear to be uncorrelated fixation distribution patterns to reveal common visual search behaviors.


Estimating time of HIV-1 infection from next-generation sequence diversity.
Estimating the time since infection (TI) in newly diagnosed HIV-1 patients is challenging, but important to understand the epidemiology of the infection. Here we explore the utility of virus diversity estimated by next-generation sequencing (NGS) as novel biomarker by using a recent genome-wide longitudinal dataset obtained from 11 untreated HIV-1-infected patients with known dates of infection. The results were validated on a second dataset from 31 patients. Virus diversity increased linearly with time, particularly at 3rd codon positions, with little inter-patient variation. The precision of the TI estimate improved with increasing sequencing depth, showing that diversity in NGS data yields superior estimates to the number of ambiguous sites in Sanger sequences, which is one of the alternative biomarkers. The full advantage of deep NGS was utilized with continuous diversity measures such as average pairwise distance or site entropy, rather than the fraction of polymorphic sites. The precision depended on the genomic region and codon position and was highest when 3rd codon positions in the entire pol gene were used. For these data, TI estimates had a mean absolute error of around 1 year. The error increased only slightly from around 0.6 years at a TI of 6 months to around 1.1 years at 6 years. Our results show that virus diversity determined by NGS can be used to estimate time since HIV-1 infection many years after the infection, in contrast to most alternative biomarkers. We provide the regression coefficients as well as web tool for TI estimation.


Tuberculosis and Silicosis Burden in Artisanal and Small-Scale Gold Miners in a Large Occupational Health Outreach Programme in Zimbabwe.
Artisanal and small-scale miners (ASMs) labour under archaic working conditions and are exposed to high levels of silica dust. Exposure to silica dust has been associated with an increased risk of tuberculosis and silicosis. ASMs are highly mobile and operate in remote areas with near absent access to health services. The main purpose of this study was to evaluate the prevalence of tuberculosis, silicosis and silico-tuberculosis among ASMs in Zimbabwe. A cross-sectional study was conducted from 1 October to 31 January 2021 on a convenient sample of 514 self-selected ASMs. We report the results from among those ASMs who attended an outreach medical facility and an occupational health clinic. Data were collected from clinical records using a precoded data proforma. Data variables included demographic (age, sex), clinical details (HIV status, GeneXpert results, outcomes of chest radiographs, history of tuberculosis) and perceived exposure to mine dust. Of the 464 miners screened for silicosis, 52 (11.2%) were diagnosed with silicosis, while 17 (4.0%) of 422 ASMs were diagnosed with tuberculosis (TB). Of the 373 ASMs tested for HIV, 90 (23.5%) were sero-positive. An HIV infection was associated with a diagnosis of silicosis. There is need for a comprehensive occupational health service package, including TB and silicosis surveillance, for ASMs in Zimbabwe. These are preliminary and limited findings, needing confirmation by more comprehensive studies.


[The levels of T lymphocytes and thymic peptide antibodies in patients with infiltrative pulmonary tuberculosis and in those with cancer diseases].
A relationship of the levels of thymic peptide antibodies to those of the population and subpopulations of T lymphocytes was studied in patients with pulmonary tuberculosis, lung or breast cancer. Indirect immunofluorescence was used to determine the count of CD3-, CD4-, CD80, CD38-, CD25-, CD71-, and CD95-lymphocytes. The levels of thymic peptide antibodies were estimated by enzyme immunoassay. Unlike cancer diseases, pulmonary tuberculosis was characterized by the combination of a significantly inverse correlation between the relative count of CD3-, CD4-, CD8-lymphocytes the levels of thymogen antibodies with a significantly direct correlation between the absolute count of CD25- and CD38-lymphocytes. The studies may recommend that the levels of thymic peptide antigens should be determined to select persons with immunodeficiency particularly those with inflammatory diseases.


Linking phenological events in migratory passerines with a changing climate: 50 years in the Laurel Highlands of Pennsylvania.
Advanced timing of both seasonal migration and reproduction in birds has been strongly associated with a warming climate for many bird species. Phenological responses to climate linking these stages may ultimately impact fitness. We analyzed five decades of banding data from 17 migratory bird species to investigate 1) how spring arrival related to timing of breeding, 2) if the interval between arrival and breeding has changed with increasing spring temperatures, and 3) whether arrival timing or breeding timing best predicted local productivity. Four of 17 species, all mid- to long-distance migrants, hatched young earlier in years when migrants arrived earlier to the breeding grounds (~1:1 day advancement). The interval between arrival on breeding grounds and appearance of juveniles shortened with warmer spring temperatures for 12 species (1-6 days for every 1°C increase) and over time for seven species (1-8 days per decade), suggesting that some migratory passerines adapt to climate change by laying more quickly after arrival or reducing the time from laying to fledging. We found more support for the former, that the rate of reproductive advancement was higher than that for arrival in warm years. Timing of spring arrival and breeding were both poor predictors of avian productivity for most migrants analyzed. Nevertheless, we found evidence that fitness benefits may occur from shifts to earlier spring arrival for the multi-brooded Song Sparrow. Our results uniquely demonstrate that co-occurring avian species are phenologically plastic in their response to climate change on their breeding grounds. If migrants continue to show a weaker response to temperatures during migration than breeding, and the window between arrival and optimal breeding shortens further, biological constraints to plasticity may limit the ability of species to adapt successfully to future warming.


Clinical characteristics and prognostic factors in Chinese patients with Hodgkin's lymphoma.
The aim of our study is to investigate the clinical characteristics and prognostic factors in Chinese Hodgkin's lymphoma patients. It is known that clinical characteristics and epidemiology of Hodgkin's lymphoma in China are different from Western countries. In total, 137 consecutive, previously untreated patients with Hodgkin's lymphoma at Sun Yat-Sen University Cancer Center were enrolled. Among these patients, 92 were male and 45 were female, with a median age of 28 (range: 2-76) years. The bimodal age curve of classical Hodgkin's lymphoma analyzed from our patients was not obvious as the Western population, showing an early peak in 25 years and a second peak in 45 years. Most of the patients (41.6%) were classified as nodular sclerosis classic Hodgkin's lymphoma. Results showed that the 5-year overall survival, event-free survival, and disease-free survival rates were 97.7, 85.0, and 94.0%, respectively. Lymphopenia at diagnosis was related to poorer overall survival (P = 0.015) and event-free survival (P < 0.001) in all-stage Hodgkin's lymphoma patients. Multivariate analysis showed that lymphopenia as an independent unfavorable prognostic factor influenced event-free survival (P = 0.015). The international prognostic score ≥ 5 was also the only independent prognostic factor of disease-free survival in advanced-stage patients (P = 0.046). Our findings demonstrated that some clinical characteristics of Hodgkin's lymphoma in China were different from those in the Western countries. Lymphopenia was an effective prognostic predictor in both early stage and advanced stage.


In vivo MRI using real-time production of hyperpolarized 129Xe.
MR imaging of hyperpolarized (HP) nuclei is challenging because they are typically delivered in a single dose of nonrenewable magnetization, from which the entire image must be derived. This problem can be overcome with HP (129)Xe, which can be produced sufficiently rapidly to deliver in dilute form (1%) continuously and on-demand. We demonstrate a real-time in vivo delivery of HP (129)Xe mixture to rats, a capability we now routinely use for setting frequency, transmitter gain, shimming, testing pulse sequences, scout imaging, and spectroscopy. Compared to images acquired using conventional fully concentrated (129)Xe, real-time (129)Xe images have 26-fold less signal, but clearly depict ventilation abnormalities. Real-time (129)Xe MRI could be useful for time-course studies involving acute injury or response to treatment. Ultimately, real-time (129)Xe MRI could be done with more highly concentrated (129)Xe, which could increase the signal-to-noise ratio by 100 relative to these results to enable a new class of gas imaging applications.


Executive cognitive impairment detected by simple bedside testing is associated with poor glycaemic control in type 2 diabetes.
Cognitive impairment in people with type 2 diabetes is a barrier to successful disease management. We sought to determine whether impaired executive function as detected by a battery of simple bedside cognitive tests of executive function was associated with inadequate glycaemic control. People with type 2 diabetes attending a tertiary referral diabetic clinic who consented to participate in the study underwent a brief battery of cognitive testing (the Bedside Executive Screening Test) designed to detect executive function impairment. Glycaemic control was determined using blood glycated haemoglobin levels (HBA(1c)). Inadequate glycaemic control was defined as HBA(1c) > or =7%. Executive function impairment was detected in 51 (52%) of the 98 study participants. The presence of executive function impairment was significantly associated with poor glycaemic control (HBA(1c) > or =7%) (odds ratio 4.9, 95% confidence interval 1.3 - 18.8, p=0.019). There were no significant differences between patients with and without executive function impairment with regard to age, target organ damage, patient reported adherence, and hypoglycaemic therapy. Patients with a lower level of education were more likely to demonstrate executive impairment when glycaemic control was poor (p=0.013). Executive function impairment is common in a population of people with difficult-to-manage type 2 diabetes. The presence of executive impairment is significantly associated with poor glycaemic control.


Comparative Phenotypic and Genotypic Analysis of Swiss and Finnish Listeria monocytogenes Isolates with Respect to Benzalkonium Chloride Resistance.
Reduced susceptibility of Listeria monocytogenes to benzalkonium chloride (BC), a quaternary ammonium compound widely used in food processing and hospital environments, is a growing public health and food safety concern. The minimal inhibitory concentration of BC on 392 L. monocytogenes strains from Switzerland (CH) and Finland (FIN) was determined. Within this strain collection, benzalkonium chloride resistance was observed in 12.3% (24/195) of Swiss and 10.6% (21/197) of Finnish strains. In both countries, the highest prevalence of BC-resistant strains (CH: 29.4%; FIN: 38.9%) was detected among serotype 1/2c strains. Based on PCR analysis, genes coding for the qacH efflux pump system were detected for most of the BC-resistant strains (CH: 62.5%; FIN: 52.4%). Some Swiss BC-resistant strains harbored genes coding for the bcrABC (16.7%) efflux pump system, while one Finnish BC-resistant strain harbored the emrE gene previously only described among BC-resistant L. monocytogenes strains from Canada. Interestingly, a subset of BC-resistant strains (CH: 5/24, 20.8%; FIN: 9/21, 42.8%) lacked genes for efflux pumps currently known to confer BC resistance in L. monocytogenes. BC resistance analysis in presence of reserpine showed that the resistance was completely or partially efflux pump dependent in 10 out of the 14 strains lacking the known BC resistance genes. Sequence types 155 and ST403 were over-representated among these strains suggesting that these strains might share similar but yet unknown mechanisms of BC resistance.


Genetic determinants of cell size at birth and their impact on cell cycle progression in Saccharomyces cerevisiae.
In most cases, cells must increase their size before they can divide. Hence, a small size has been used often as a phenotype for mutants that accelerate initiation of division, such as the celebrated WHI mutants of budding yeast. Recently, we measured the DNA content of all nonessential gene deletion strains in Saccharomyces cerevisiae. Surprisingly, there was little, if any, correlation between mean cell size and cell-cycle progression. Here, we examine this issue further, providing the first systematic analysis of genetic determinants of the cell size at birth. We found that although a large birth size strongly correlates with a large mean size, the converse relationship (i.e., small birth size vs. small mean size) is not as strong. Our data also suggest that mutants that are born large do not have a significant advantage for faster cell-cycle progression. In contrast, mutants that are born small are more likely to progress slower in the cell cycle. The majority of gene deletions that displayed such phenotypes affect protein synthesis or ribosome biogenesis. Overall, our data suggest that birth size may be a more informative parameter for cell-cycle progression than the mean size of a proliferating cell population. In contrast to WHI phenotype expectations, a small size is more likely to be associated with delayed cell-cycle progression.


Preliminary analysis of the risk factors for radiation pneumonitis in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy.
The aim of this study was to investigate radiation pneumonitis and its associated risk factors in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy. We conducted an analysis of patients with nonoperable stage IIIA-IV non-small-cell lung cancer who were treated with concurrent thoracic radiotherapy and erlotinib (ClinicalTrials.gov identifier: NCT00973310). The Common Terminology Criteria for Adverse Events version 3.0 grading system was applied to evaluate the incidence of radiation pneumonitis. The lung dosimetric parameters were recorded in accordance with the treatment plan, and the study endpoint was radiation pneumonitis at grade 2 or more. Among the 24 selected clinical cases, nine were identified with radiation pneumonitis of grade 2 or above (37.5%). This included four cases with grade 2 (16.7%), two cases with grade 3 (8.3%), and three cases with grade 5 (12.5%). The results showed that the planning target volume was a significant factor affecting the incidence of radiation pneumonitis. All lung dosimetric parameters exhibited statistically significant differences between patients with pneumonitis and patients without pneumonitis. The receiver operating characteristic (ROC) curve analysis showed that all lung dosimetric parameters were useful in predicting the incidence of radiation pneumonitis. In addition, the threshold values of V5, V10, V15, V20, V30, and mean lung dose were >44%, >29%, >27%, >22%, >17% and >1,027 cGy, respectively. Special attention should be paid to the adverse effects of radiation pneumonitis in concurrent thoracic radiotherapy and erlotinib treatment. Lung dosimetric parameters are important predictive factors in radiation pneumonitis.


Correlation of the Osteogenic Protein-1 (OP-1) with Age, Cartilage metabolic Markers and Antioxidants in the Osteoarthritic Patients of Sikkim.
Age and oxidative stress have been implicated as the main causes of the cartilage damage in osteoarthritis (OA). The osteogenic protein-1(OP-1), a member of the bone morphogenetic family (BMP), plays a major role in cartilage repair. To correlate the OP-1 in the synovial fluid with the age and antioxidants like superoxide dismutase (SOD), glutathione peroxidase (GPx) and uric acid (UA) in the blood and with the cartilage metabolic markers like hyaluronic acid (HA) and keratan sulphate (KS) in the synovial fluid of osteoarthritic patients. Seventy five osteoarthritic patients were taken up for the study. Heparinized blood samples were collected for the estimation of SOD, GPx and UA. Synovial fluid was aspirated for the estimation of HA, KS and OP-1. OP-1 was estimated by using a polyclonal antibody (anti-OP-1) which was produced against OP-1 in the mouse ascitic fluid by sandwich ELISA. Age and UA showed a significant correlation with OP-1. On the other hand, the correlations between OP-1 and the antioxidants (SOD and GPx) and the cartilage metabolic markers (HA and KS) were insignificant in osteoarthritic patients. The study suggests about the important role of OP-1 in cartilage aging and degeneration, which may help us in understanding the potential for the therapeutic interventions in the treatment of cartilage degenerative processes.


Efficacy and Safety of Weekly Somatrogon vs Daily Somatropin in Children With Growth Hormone Deficiency: A Phase 3 Study.
Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: -0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (-1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).