Transcriptomic analysis of PPARalpha-dependent alterations during cardiac hypertrophy.
Peroxisome proliferator-activated receptor (PPAR)alpha regulates lipid metabolism at the transcriptional level and modulates the expression of genes involved in inflammation, cell proliferation, and differentiation. Although PPARalpha has been shown to mitigate cardiac hypertrophy, knowledge about underlying mechanisms and the nature of signaling pathways involved is fragmentary and incomplete. The aim of this study was to identify the processes and signaling pathways regulated by PPARalpha in hearts challenged by a chronic pressure overload by means of whole genome transcriptomic analysis. PPARalpha-/- and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days, and left ventricular gene expression profile was determined with Affymetrix GeneChip Mouse Genome 430 2.0 arrays containing >45,000 probe sets. In unchallenged hearts, the mere lack of PPARalpha resulted in 821 differentially expressed genes, many of which are related to lipid metabolism and immune response. TAC resulted in a more pronounced cardiac hypertrophy and more extensive changes in gene expression (1,910 and 312 differentially expressed genes, respectively) in PPARalpha-/- mice than in wild-type mice. Many of the hypertrophy-related genes were related to development, signal transduction, actin filament organization, and collagen synthesis. Compared with wild-type hypertrophied hearts, PPARalpha-/- hypertrophied hearts revealed enrichment of gene clusters related to extracellular matrix remodeling, immune response, oxidative stress, and inflammatory signaling pathways. The present study therefore demonstrates that, in addition to lipid metabolism, PPARalpha is an important modulator of immune and inflammatory response in cardiac muscle.


The dendritic cell advantage: New focus for immune-based therapies.
Dendritic cells (DCs) provide a much earlier and antigen-specific means for manipulating the immune response. The best-studied function of DCs is to convert antigens into immunogens for T cells. The "DC advantage" entails a myriad of functions. DCs are more than antigen-presenting cells; they are accessories or adjuvants or catalysts for triggering and controlling immunity. Another special feature of DCs is their location and movement in the body; DCs are stationed at surfaces where antigens gain access to the body. The events that make up the life history of DCs are now being unraveled in molecular terms. As research on DCs expands, more potential functions and more sites for their manipulation are becoming apparent.


[Pharmacological study of papain from the papaya plant cultivated in Uzbekistan].
It was experimentally established that papain from papaya cultivated in Uzbekistan possesses a pronounced proteolytic activity: 0.1, 0.5, and 1% papain solutions decreased the weight of burn crust in vitro and accelerated experimental burn healing in vivo. Under clinical conditions, papain produced therapeutic effect in patients with inflammatory disorders in genitals, intestine, liver, and eye. The pharmacological effects of papain produced from Uzbek papaya are identical to those of the commercial product from Merck.


[Criteria for intoxication in the evaluation of severity of endotoxicosis, the efficiency of ozone therapy and traditional treatment in patients with diabetes mellitus complicated by pyonecrotic lesions of the lower extremities].
The severity of endotoxicosis was evaluated in 128 patients with type 2 diabetes mellitus complicated by pyonecrotic lesions of the lower extremities. There was evidence for a reduction in serum albumin concentration, which led to diminished detoxication capacities of the body. Concurrently, the effective albumin concentration and the binding capacity of both albumin and plasma became lower, which suggested higher blood toxicity. There was imbalance between the formation, accumulation and binding, utilization and elimination of toxic products, as confirmed by a rise in calculated intoxication criteria. Traditional therapy did not cause a significant reduction, which requires special detoxication therapy. Ozone therapy, an oxidative detoxication method substantially diminishes the severity of endogenous intoxication, as supported by an increase in the total concentration of albumin and its functional properties.


Antiplatelet and anticoagulant agents for secondary prevention of stroke and other thromboembolic events in people with antiphospholipid syndrome.
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial or venous thrombosis (or both) and/or pregnancy morbidity in association with the presence of antiphospholipid antibodies. The prevalence is estimated at 40 to 50 cases per 100,000 people. The most common sites of thrombosis are cerebral arteries and deep veins of the lower limbs. People with a definite APS diagnosis have an increased lifetime risk of recurrent thrombotic events. To assess the effects of antiplatelet or anticoagulant agents, or both, for the secondary prevention of recurrent thrombosis, particularly ischemic stroke, in people with antiphospholipid syndrome. We searched the Cochrane Stroke Group Trials Register (February 2017), CENTRAL (last search February 2017), MEDLINE (from 1948 to February 2017), Embase (from 1980 to February 2017), and several ongoing trials registers. We also checked the reference lists of included studies, systematic reviews, and practice guidelines, and we contacted experts in the field. We included randomized controlled trials (RCTs) that evaluated any anticoagulant or antiplatelet agent, or both, in the secondary prevention of thrombosis in people diagnosed with APS according to the criteria valid when the study took place. We did not include studies specifically addressing women with obstetrical APS. Pairs of review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias for the included studies. We resolved any discrepancies through discussion or by consulting a third review author and, in addition, one review author checked all the extracted data. We included five studies involving 419 randomized participants with APS. Only one study was at low risk of bias in all domains. One study was at low risk of bias in all domains for objective outcomes but not for quality of life (measured using the EQ-5D-5L questionnaire). We judged the other three studies to be at unclear or high risk of bias in three or more domains.The duration of intervention ranged from 180 days to a mean of 3.9 years. One study compared rivaroxaban (a novel oral anticoagulant: NOAC) with standard warfarin treatment and reported no thrombotic or major bleeding events, but it was not powered to detect such differences (low-quality evidence). Investigators reported similar rates of clinically relevant non-major bleeding (risk ratio (RR) 1.45, 95% confidence interval (CI) 0.25 to 8.33; moderate-quality evidence) and minor bleeding (RR 1.21, 95% CI 0.51 to 2.83) for participants receiving rivaroxaban and the standard vitamin K antagonists (VKA). This study also reported some small benefit with rivaroxaban over the standard VKA treatment in terms of quality of life health state measured at 180 days with the EQ-5D-5L 100 mm visual analogue scale (mean difference (MD) 7 mm, 95% CI 2.01 to 11.99; low-quality evidence) but not measured as health utility (MD 0.04, 95% CI -0.02 to 0.10 [on a scale from 0 to 1]).Two studies compared high dose VKA (warfarin) with moderate/standard intensity VKA and found no differences in the rates of any thrombotic events (RR 2.22, 95% CI 0.79 to 6.23) or major bleeding (RR 0.74, 95% CI 0.24 to 2.25) between the groups (low-quality evidence). Minor bleeding analyzed using the RR and any bleeding using the hazard ratio (HR) were more frequent in participants receiving high-intensity warfarin treatment compared to the standard-intensity therapy (RR 2.55, 95% CI 1.07 to 6.07; and HR 2.03, 95% CI 1.12 to 3.68; low-quality evidence).In one study, it was not possible to estimate the RR for stroke with a combination of VKA plus antiplatelet agent compared to a single antiplatelet agent, while for major bleeding, a single event occurred in the single antiplatelet agent group. In one study, comparing combined VKA plus antiplatelet agent with dual antiplatelet therapy, the RR of the risk of stroke over three years of observation was 5.00 (95% CI 0.26 to 98.0). In a single small study, the RR for stroke during one year of observation with a dual antiplatelet therapy compared to single antiplatelet drug was 0.14 (95% CI 0.01 to 2.60). There is not enough evidence for or against NOACs or for high-intensity VKA compared to the standard VKA therapy in the secondary prevention of thrombosis in people with APS. There is some evidence of harm for high-intensity VKA regarding minor and any bleeding. The evidence was also not sufficient to show benefit or harm for VKA plus antiplatelet agent or dual antiplatelet therapy compared to a single antiplatelet drug. Future studies should be adequately powered, with proper adherence to treatment, in order to evaluate the effects of anticoagulants, antiplatelets, or both, for secondary thrombosis prevention in APS. We have identified five ongoing trials mainly using NOACs in APS, so increasing experimental efforts are likely to yield additional evidence of clinical relevance in the near future.


Functional Outcome After Poor-Grade Subarachnoid Hemorrhage: A Single-Center Study and Systematic Literature Review.
Poor-grade subarachnoid hemorrhage (SAH) (World Federation of Neurosurgical Societies grade 4 and 5) is associated with high mortality rates and unfavorable functional outcomes. We report a single-center cohort of poor-grade SAH patients, combined with a systematic review of studies reporting functional outcome in the poor-grade SAH population. Data on a cohort of poor-grade SAH patients treated between 2009 and 2013 were retrospectively collected and combined with a systematic review (from inception to November 2015; PubMed, Embase). Two reviewers assessed the studies independently based on predefined inclusion criteria: consecutive poor-grade SAH, functional outcome measured at least 3 months after hemorrhage, and the report of patients who died before aneurysm treatment. The search yielded 329 publications, and 23 met our inclusion criteria with 2713 subjects enrolled from 1977 to 2014 in 10 countries (including 179 poor-grade patients from our cohort). Mortality rate was 60 % (1683 patients), of which 806 (29 %) died before and 877 (31 %) died after aneurysm treatment, respectively. Treatment was undertaken in 1775 patients (1775/2826-63 %): 1347 by surgical clipping (1347/1775-76 %) and 428 (428/1775-24 %) by endovascular methods. Outcome was favorable in 794 patients (28 %) and unfavorable in 1867 (66 %). When the studies were grouped into decades, favorable outcome increased from 13 % in the late 1970s to early 1980s to 35 % in the late 1980s to early 1990s, and remained unchanged thereafter. Although mortality remains high in poor-grade SAH patients, a favorable functional outcome can be achieved in approximately one-third of patients. The development of new diagnostic methods and implementation of therapeutic approaches were probably responsible for the decrease in mortality and improvement in the functional outcome from 1970 to the 1990s. The plateau in functional outcome seen thereafter might be explained by the treatment of sicker and older patients and by the lack of new therapeutic interventions specific for SAH.


Purification and certain properties of a bacteriocin from Streptococcus mutans.
An inhibition factor from Streptococcus mutans strain C3603 (serotype c) was purified and isolated, and its properties indicated that it was a bacteriocin. Bacteriocin C3603 is a basic protein with a pI value of 10 and a molecular weight of 4,800. The activity of this bacteriocin was not affected by pH over a range of 1.0 to 12.0 or by storage at 100 degrees C for 10 min at pH 2.0 to 7.0 or storage at 121 degrees C for 15 min at pH 4.0. Pronase; papain, phospholipase C, trypsin, and alpha-amylase had no effect on the activity of the bacteriocin, whereas alpha-chymotrypsin and pancreatin were partially active against it. Bacteriocin activity was greater against certain S. mutans strains of serotypes b, c, e, and f than against certain S. mutans strains of serotypes a, d, and g. Bacteriocin C3603 was also effective against selected strains of S. sanguis, S. salivarius, S. bovis, S. faecium, S. lactis, Lactobacillus casei, L. plantarum, L. fermentum, Bifidobacterium bifidum, Bifidobacterium longum, Propionibacterium acnes, and Bacteroides melaninogenicus, but it was not effective against certain strains of Escherichia coli, Klebsiella pneumoniae, Corynebacterium parvum, and Candida albicans. The inhibition of S. mutans strains BHT and PS-14 by bacteriocin C3603 was found to be due to the bacteriocidal activity of the bacteriocin. When water or a diet containing bacteriocin C3603 was consumed by gnotobiotic and specific pathogen-free rats infected with S. mutans PS-14, the caries score was found to be significantly reduced.


On the Use of the Pearson Correlation Coefficient for Model Evaluation in Genome-Wide Prediction.
The large number of markers in genome-wide prediction demands the use of methods with regularization and model comparison based on some hold-out test prediction error measure. In quantitative genetics, it is common practice to calculate the Pearson correlation coefficient (r2 ) as a standardized measure of the predictive accuracy of a model. Based on arguments from the bias-variance trade-off theory in statistical learning, we show that shrinkage of the regression coefficients (i.e., QTL effects) reduces the prediction mean squared error (MSE) by introducing model bias compared with the ordinary least squares method. We also show that the LASSO and the adaptive LASSO (ALASSO) can reduce the model bias and prediction MSE by adding model variance. In an application of ridge regression, the LASSO and ALASSO to a simulated example based on results for 9,723 SNPs and 3,226 individuals, the best model selected was with the LASSO when r2 was used as a measure. However, when model selection was based on test MSE and coefficient of determination R2 the ALASSO proved to be the best method. Hence, use of r2 may lead to selection of the wrong model and therefore also nonoptimal ranking of phenotype predictions and genomic breeding values. Instead, we propose use of the test MSE for model selection and R2 as a standardized measure of the accuracy.


[Sports injuries of the nervous system].
Almost 1% of all Germans suffer sports injuries each year, almost 5% of all peripheral nerve lesions are due to sports. A review is given on various activities detailing the specific risks for traumata of the central and peripheral nervous system. Specifically these are volleyball, handball, basketball, American football, soccer, bowling, hockey, baseball, tennis, golf, javelin, fencing, wrestling, judo, boxing, running, jumping, dancing, mountain climbing, weight lifting, gymnastics, horse-back riding, swimming, rowing, skiing, skating, shooting, (motor) biking, car racing, flying, and sports for the disabled. The knowledge of typical traumata should enable the neurologist to rapidly and reliably recognize related lesions and to contribute to their prevention or improvement.


Enhancement of spontaneous mitotic recombination by the meiotic mutant spo11-1 in Saccharomyces cerevisiae.
Both nonreciprocal and reciprocal mitotic recombination are enhanced by the recessive mutant spo11-1, which was previously shown to affect meiosis by decreasing recombination and increasing nondisjunction. The mitotic effects are not distributed equally in all chromosomal regions. The genotypes of mitotic recombinants in spo11-1/spo11-1 diploid cells provide further evidence that widely spaced chromosomal markers undergo coincident conversion in mitosis.


Gynecologic care of the female-to-male transgender man.
Transgender men are a vulnerable population whose health care needs have been difficult to identify because of limited research and an inability to identify the population. Limited evidence suggests that transgender men are at increased risk of having polycystic ovarian syndrome, contracting HIV, experiencing violence, and committing suicide. This qualitative study, conducted through face-to-face interviews of a convenient sample, was a three-part interview containing a demographic and health questionnaire, the Norbeck Social Support Questionnaire, as well as the Health Care Relationship Trust Scale. Audio recordings and written notes were reviewed and common themes were identified via content analysis. Six self-identified transgender men between the ages of 19 and 45 years were enrolled in the study. Participants were at varying degrees of social and medical transition. Four major themes were identified: 1) receiving gynecologic care was perceived to be important; 2) breasts caused the most gender identity conflict; 3) transgender men struggle with revealing their gender identity to health care providers; and 4) the male/female boxes on health intake forms, as well as pronoun usage by medical staff, were barriers to receiving health care. This gynecologic health care needs assessment of transgender men begins to characterize the barriers transgender men face when seeking health care.


[Heparin complexes with DNA: formation, properties and methylation in vitro].
Heparin complexes with DNA were obtained in vitro, the components being taken in weight ratios of 1 : 6 or 1 : 12, respectively. The complexes obtained exhibited the anticoagulating activity and antipolymerizing properties in the presence of a fibrin-monomer and an ability to dissolve nonstabilized fibrin. An intravenous injection of these complexes to rats increased the total and non-enzymatic fibrinolytic activity of blood plasma and its anticoagulating properties, while an intravenous injection of DNA caused only a short-term hypercoagulating effect. The DNA modified by heparin altered its acceptor abilities in an in vitro methylation reaction in the presence of DNA-methylases from animal and bacterial cells. Incorporation of methyl groups into DNA showed a decrease, apparently due to heparin blocking of some methylable sequences. An addition of heparin to a system containing purified DNA, DNA-methylase and S-adenosylmethionine was accompanied by a concentration-dependent inhibition of the methyl group incorporation into DNA.


Neuronal Fibers and Neurotransmitter Receptor Expression in the Human Endolymphatic Sac.
Recent studies suggest that the human endolymphatic sac (ES) may have multiple functions, including an ion-transport capacity comparable to the kidney, an immunological capacity and a possible natriuretic capacity. Further, there have been speculations of a yet undefined role in intracranial pressure homeostasis. The anatomical location towards the sigmoid sinus would suggest a possible endo- and/or paracrine signaling. However, neuronal connections may also apply, but it remains very scarcely explored in the human ES. DNA micro-arrays and immunohistochemistry were used for analyses of fresh human ES tissue samples. A total of 30 tissue samples from the human ES were obtained during translabyrinthine surgery for vestibular schwannoma. Microarray technology was used to investigate tissue sample gene expression, using adjacent dura mater as control. The expression of genes specific for neuronal signaling was determined and results for selected key molecules verified by immunohistochemistry. Transmission electron microscopy was used for ultrastructural analysis. For the transmission electron microscopy analysis, a direct innervation of the ES was observed with unmyelinated fibers imbedded in the ES epithelial lining. The microarrays confirmed, that several molecules involved in neuronal signaling were found expressed significantly in the ES DNA profile, such as the Cholecystokinin peptide and related receptors, Dopamine receptors 2 and 5, vesicular monoamine transporter 2 (VMAT2), plasma monoamine transporter (PMAT), and Serotonin 1D. All peptides were verified by immunohistochemistry. Based on global gene expression profiling and immuno-histochemical labeling, we conclude that the human ES expresses neuropeptide receptors and monoamine transporters. Combined with the ultrastructural demonstration of unmyelinated axons imbedded within the epithelial lining, the findings suggest that neuro-signaling mechanisms are involved in functions exerted by the ES.


Evaluation of the expression of C-kit (CD117) in ependymomas and oligodendrogliomas.
C-kit is a proto-oncogene located on the long arm of chromosome 4. Its product, CD117, is a specific immunohistochemical (IHQ) marker that is associated with response to a potent tyrosine kinase inhibitor therapy with STI-571 (Gleevec®) in chronic myelogenous leukemia and GISTs. In our study, we aimed to evaluate the expression of CD117 in glial tumors as this finding may guide therapeutic approaches for these brain tumors. Ependymomas and oligodendrogliomas, in formalin fixed and paraffin embedded blocks were assayed for CD117 immunoreactivity using anti-c-kit (CD117, DAKO). GISTs were used as positive control. We observed immunoreactivity of CD117 protein in 25.5% of tumors in both histological types. In oligodendrogliomas, there was an association between older age at diagnosis and positivity for CD117 (P=0.039). In addition, we observed an association between higher tumor grade (grade III) and positivity for CD117 (P=0.007). No clinical association was observed in ependymomas (P>0.05). This study encourages further investigations, considering that CD117 may be a possible oncogenic factor in some glial tumors. In this case, tumors that express this marker may eventually benefit from a therapy with selective inhibitors of receptor kinases.


Personality and body dissatisfaction: An updated systematic review with meta-analysis.
This research synthesis explored whether major personality dimensions relate to body dissatisfaction. A comprehensive literature search identified 26 studies (37 independent samples) that met inclusion criteria (364 effect sizes; n = 39,109). Data were analyzed using inverse-variance weighted random effects meta-analysis. Mean effect sizes from 30 individual meta-analyses provided evidence that neuroticism (r = .30), extraversion (r = -.17) and conscientiousness (r = -.16), and to a lesser extent openness (r = -.10) and agreeableness (r = -.08), relate to body dissatisfaction. Effect sizes were smaller in models that controlled for body mass index, with non-significant effects for openness and agreeableness. There was some evidence of publication bias and substantial heterogeneity in computed averages. Random effects meta-regression showed that the association between neuroticism and body dissatisfaction decreased as the sample age increased. Measurement was the most important moderator across personality dimensions, with measures of appearance evaluation and body appreciation often showing smaller associations than other measures of body dissatisfaction. Effect sizes were not moderated by sample sex or world-region. Overall, findings show that higher levels of neuroticism, and lower levels of extraversion and conscientiousness, are associated with a greater risk of body dissatisfaction in men and women irrespective of actual body weight.


Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12).
To evaluate the in vitro activity of ceftolozane/tazobactam and comparator agents tested against contemporary Gram-negative bacteria. Ceftolozane/tazobactam is an antipseudomonal cephalosporin combined with a well-established β-lactamase inhibitor. A total of 10 532 Gram-negative organisms (2191 Pseudomonas aeruginosa and 8341 Enterobacteriaceae) were consecutively collected from 31 medical centres located in 13 European countries plus Turkey and Israel. The organisms were tested for susceptibility by broth microdilution methods as described by the CLSI M07-A9 document and the results interpreted according to EUCAST as well as CLSI breakpoint criteria. Selected ceftazidime- and/or meropenem-resistant P. aeruginosa isolates were screened for the presence of β-lactamase genes by PCR. P. aeruginosa exhibited high rates of multidrug-resistant (31.9%) and extensively drug-resistant (24.6%) isolates and 11.6% of isolates were susceptible only to colistin. When tested against P. aeruginosa, ceftolozane/tazobactam (MIC(50), 1 mg/L) was generally 4-fold more active than ceftazidime (MIC(50), 4 mg/L) and inhibited >90% of isolates with an MIC of ≤8 mg/L in nine countries. In contrast, the highest susceptibility rates observed for ceftazidime and meropenem, respectively, were 86.0%/86.0% (UK) and 85.2%/86.1% (Ireland) (67.2%/67.1% overall). Ceftolozane/tazobactam (MIC(50/90), 0.25/2 mg/L; 93.7% and 95.2% inhibited at ≤4 and ≤8 mg/L, respectively), meropenem [MIC(50/90), ≤0.06/≤0.06 mg/L; 98.0% susceptible (EUCAST)] and tigecycline [MIC(50/90), 0.12/1 mg/L; 94.1% susceptible (EUCAST)] were the most active compounds tested against Enterobacteriaceae. Ceftolozane/tazobactam was the most active β-lactam agent tested against P. aeruginosa and demonstrated higher in vitro activity than currently available cephalosporins and piperacillin/tazobactam when tested against Enterobacteriaceae.


Safety of plasma volume expanders.
Hypovolemia from a range of etiologies can lead to severe morbidity and mortality unless blood volume and tissue perfusion are restored. The treatment of hypovolemia has included the improvement and restoration of blood volume loss by the intravenous infusion of plasma expanding therapeutic agents. These have included crystalloid and/or colloid solutions, and a brisk controversy as to which modality is better has engaged therapeutics for the past 30 years. In addition, those favoring either modality have debated which crystalloid, and which colloid, is better. This area was given a dramatic turn a decade ago when a Cochrane meta-analysis concluded that albumin, a historically important plasma expander, resulted in increased mortality when administered to critically ill patients. Although subsequently modified by other studies, the Cochrane meta-analysis has served to generate an ongoing interest in the safety of plasma expanders. This review will assess the safety of these therapies from the viewpoint of the heterogeneous range of clinical indications for which they are used.


Quantitative proteomics and protein network analysis of hippocampal synapses of CaMKIIalpha mutant mice.
Quantitative analysis of synaptic proteomes from specific brain regions is important for our understanding of the molecular basis of neuroplasticity and brain disorders. In the present study we have optimized comparative synaptic proteome analysis to quantitate proteins of the synaptic membrane fraction isolated from the hippocampus of wild type mice and 3'UTR-calcium/calmodulin-dependent kinase II alpha mutant mice. Synaptic proteins were solubilized in 0.85% RapiGest and digested with trypsin without prior dilution of the detergent, and the peptides from two groups of wild type mice and two groups of CaMKIIalpha 3'UTR mutants were tagged with iTRAQ reagents 114, 115, 116, and 117, respectively. The experiment was repeated once with independent biological replicates. Peptides were fractionated with tandem liquid chromatography and collected off-line onto MALDI metal plates. The first iTRAQ experiment was analyzed on an ABI 4700 proteomics analyzer, and the second experiment was analyzed on an ABI 4800 proteomics analyzer. Using the criteria that the proteins should be matched with at least three peptides with the highest CI% of a peptide at least 95%, 623 and 259 proteins were quantified by a 4800 proteomics analyzer and a 4700 proteomics analyzer, respectively, from which 249 proteins overlapped in the two experiments. There was a 3 fold decrease of calcium/calmodulin-dependent kinase II alpha in the synaptic membrane fraction of the 3'UTR mutant mice. No other major changes were observed, suggesting that the synapse protein constituents of the mutant mice were not substantially altered. A first draft of a synaptic protein interaction network has been constructed using commercial available software, and the synaptic proteins were organized into 10 (interconnecting) functional groups belonging to the pre- and postsynaptic compartments, e.g., receptors and ion channels, scaffolding proteins, cytoskeletal proteins, signaling proteins, adhesion molecules, and proteins of synaptic vesicles and those involved in membrane recycling.


How Worries about Interpersonal Relationships, Academic Performance, Family Support, and Classmate Social Capital Influence Suicidal Ideation among Adolescents in Japan.
Suicide is an important public health issue for adolescents. To investigate the risk and protective factors for adolescent suicide, a cross-sectional questionnaire-based survey was conducted at a junior high school (n = 379) in Japan in 2018. After obtaining survey data, we conducted univariate and logistic regression analyses to test for associations between suicidal ideation and several factors, including worries (i.e., about school life, interpersonal relationships at school, family life, interpersonal relationships at home, and academic performance), perceived support from school staff and family members, and social capital. In this context, the existence of trustful relationships between classmates was used as indicators of social capital. The results showed that the prevalence of suicidal ideation was 10.5%. The risk of suicidal ideation was increased by worries about 1) interpersonal relationships at school, 2) interpersonal relationships at home, and 3) academic performance, but was decreased by social support from family members and trusting relationships. Further, the rate of suicidal ideation was higher among students who expressed all these three worries when compared to those who expressed two or fewer worries. In addition, looking at students who expressed all these three worries simultaneously, the rate of suicidal ideation was higher among those with lower levels of support from family members and fewer trustful relationships. Our results suggest that the prevention of adolescent suicide should include strategies for reducing worries about interpersonal relationships at school/home and academic performance while finding ways to enhance family support and classmate social capital.


Visible-light-driven catalytic oxidation of aldehydes and alcohols to nitriles by 4-acetamido-TEMPO using ammonium carbamate as a nitrogen source.
A mild and efficient route to prepare nitriles from aldehydes by combining photoredox catalysis with oxoammonium cations is reported. The reaction is performed using ammonium carbamate as the nitrogen source. The practicality of the method is increased by the extension of the dual catalytic system to one-pot two-step conversion of alcohols to nitriles.


Wrist pain in a young gymnast: unusual radiographic findings and MRI evidence of growth plate injury.
A 10-yr-old gymnast, training well below the elite level, reported a 3-wk history of bilateral dorsal wrist pain. Physical examination and radiographic findings were consistent with stress injury to the distal radial growth plates. The patient's radiographs also displayed rare findings including cleft radial and ulnar epiphyses, as well as epiphyseal spur formation. Magnetic resonance imaging (MRI) demonstrated evidence of metaphyseal and epiphyseal ischemia of the growth plate. The patient responded well to conservative treatment, including ice, splinting, and activity modification. This case illustrates several potentially confusing radiographic abnormalities and the emerging role of MRI in evaluating wrist pain in young gymnasts.


E-health for older people: the use of technology in health promotion.
To meet the needs of frail older people and to promote functional longevity, providing health education and disease prevention to the elderly is important. The present study describes the development, implementation, and evaluation of an e-health program for older persons. The objective of the 4-week e-health program was to improve elders' autonomous access to and use of health-related information in the form of physical exercise videography from a government-sponsored Web site. The content of the program included participants' mastery of basic computing skills and accessing and enhancing participants' interest in seeking health-related knowledge and information via the Internet. Data were collected in weeks 1 (pretest) and 4 (posttest) using questionnaires and open-ended questions. Thirty older people participated in the study (9 males, 21 females, aged 65-80 years, with the mean age of 72). Participants' mastery of basic computer operating skills increased significantly (p < 0.05); they were able to access health information via the Internet and had gained health-related knowledge by week 4 posttest (p < 0.05). The overall learning experience was positive. In conclusion, the collaboration of community partners in sponsoring a technology-based e-health program would be an effective way to provide health education to older people.


G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 is Upregulated in Rat DRGs and Spinal Cord After Peripheral Nerve Injury.
G protein-gated inwardly rectifying potassium (GIRK) channels are involved in the regulation of neuronal excitability. Four GIRK subunits (GIRK1-4) are expressed in rat dorsal root ganglia (DRGs). Recently, we have characterized the expression of GIRK1 and -2, and both are downregulated in rat DRGs and spinal cord after a complete sciatic nerve transection (axotomy). Here, we aimed to study the neurochemical characteristics of GIRK3, and its regulation in rat DRGs and spinal cord induced by nerve injury. A sciatic nerve axotomy was performed to study the influences of injury on GIRK3 expression in DRGs and spinal cord. A dorsal root rhizotomy and a sciatic nerve crush were employed to study the axonal transport of GIRK3 protein, respectively. Immunohistochemistry analysis was employed for investigating the neurochemical characteristics of GIRK3. In control DRGs, ~18% of neuron profiles (NPs) were GIRK3-positive (+), and ~41%, ~48% and ~45% of GIRK3+ NPs were CGRP+, IB4+ and NF200+, respectively. GIRK3-like immunoreactivity was observed in glabrous skin of hind paws and axons originating from DRG neurons. Fourteen days after axotomy, more than one-third of DRG NPs were GIRK3+, and among these ~51% and ~56% coexpressed galanin and neuropeptide Y, respectively. In control animals, a small group of interneurons found in the dorsal horn was GIRK3+. In addition, GIRK3+ processes could be observed in superficial laminae of spinal dorsal horn. After nerve injury, the intensity of GIRK3-like immunoreactivity in the superficial layers was increased. Evidence based on rhizotomy and sciatic nerve crush indicated both anterograde and retrograde transport of GIRK3. Our study demonstrates that GIRK3 is expressed in sensory neurons and spinal cord. GIRK3 has both anterograde and retrograde axonal transport. GIRK3 expression can be regulated by peripheral nerve injury.


Potential mechanisms and implications for the formation of tau oligomeric strains.
The culmination of many years of increasing research into the toxicity of tau aggregation in neurodegenerative disease has led to the consensus that soluble, oligomeric forms of tau are likely the most toxic entities in disease. While tauopathies overlap in the presence of tau pathology, each disease has a unique combination of symptoms and pathological features; however, most study into tau has grouped tau oligomers and studied them as a homogenous population. Established evidence from the prion field combined with the most recent tau and amyloidogenic protein research suggests that tau is a prion-like protein, capable of seeding the spread of pathology throughout the brain. Thus, it is likely that tau may also form prion-like strains or diverse conformational structures that may differ by disease and underlie some of the differences in symptoms and pathology in neurodegenerative tauopathies. The development of techniques and new technology for the detection of tau oligomeric strains may, therefore, lead to more efficacious diagnostic and treatment strategies for neurodegenerative disease. [Formula: see text].


Integrative physiological, critical plant endogenous hormones, and transcriptomic analyses reveal the difenoconazole stress response mechanism in wheat (Triticum aestivum L.).
Difenoconazole (DFN) is widely utilized as a fungicide in wheat production. However, its accumulation in plant tissues has a profound impact on the physiological functions of wheat plants, thus severely threatening wheat growth and even jeopardizing human health. This study aims to comprehensively analyze the dynamic dissipation patterns of DFN, along with an investigation into the physiological, hormonal, and transcriptomic responses of wheat seedlings exposed to DFN. The results demonstrated that exposure of wheat roots to DFN (10 mg/kg in soil) led to a significant accumulation of DFN in wheat plants, with the DFN content in roots being notably higher than that in leaves. Accumulating DFN triggered an increase in reactive oxygen species content, malonaldehyde content, and antioxidant enzyme activities, while concurrently inhibiting photosynthesis. Transcriptome analysis further revealed that the number of differentially expressed genes was greater in roots compared with leaves under DFN stress. Key genes in roots and leaves that exhibited a positive response to DFN-induced stress were identified through weighted gene co-expression network analysis. Metabolic pathway analysis indicated that these key genes mainly encode proteins involved in glutathione metabolism, plant hormone signaling, amino acid metabolism, and detoxification/defense pathways. Further results indicated that abscisic acid and salicylic acid play vital roles in the detoxification of leaf and root DFN, respectively. In brief, the abovementioned findings contribute to a deeper understanding of the detrimental effects of DFN on wheat seedlings, while shedding light on the molecular mechanisms underlying the responses of wheat root and leaves to DFN exposure.


Laparoscopic excision of a schwannoma arising in the psoas muscle.
Schwannoma occurring in the psoas muscle is rare. We report a 49-year-old male who presented to the orthopaedic oncosurgery team with persistent lower back pain radiating to the right lower limb following a fall on the back a few months ago. Magnetic resonance imaging revealed a well-defined lesion in the right psoas muscle at the level of third lumbar vertebra (L3). He underwent a laparoscopic excision of this mass using one 10 mm and two 5 mm ports. Intraoperative frozen section after a complete excision showed this to be a benign schwannoma. He was discharged the day after surgery. His symptoms gradually reduced over a period of time and he remains well 3 years after surgery. This case highlights the feasibility and safety of minimally invasive treatment of this rare tumour.


Cutaneous and systemic infection with Scedosporium apiospermum.
We present a case of cutaneous and systemic infection with Scedosporium apiospermum occurring in a patient with systemic lupus erythematosus. Scedosporium apiospermum is a rare cause of systemic mycosis but is associated with a high rate of mortality in immunocompromised hosts. Because the patient presented in an advanced state of infection, supportive measures were unsuccessful and definitive diagnosis could not be made until postmortem examination. We discuss the presentation, pathology, diagnosis, and treatment strategies for Scedosporium infection.


Cytoplasmic incompatibility management to support Incompatible Insect Technique against Aedes albopictus.
The transinfection of the endosymbiotic bacterium Wolbachia provides a method to produce functionally sterile males to be used to suppress mosquito vectors. ARwP is a wPip Wolbachia infected Aedes albopictus which exhibits a bidirectional incompatibility pattern with wild-types. We coupled a modelistic approach with laboratory experiments to test ARwP as a control tool and evaluate the possible occurrence of population replacement following the release of ARwP females in a wild-type (SANG) population. Repeated male-only releases were simulated and tested in the laboratory in comparison with releases contaminated with 1% ARwP females. Model simulations also investigated how migration affects the outcome of contaminated releases. Finally, the mean level of egg fertility and the long-term evolution of populations constituted by two Wolbachia infection types were studied by testing SANG and ARwP Ae. albopictus and performing more general model simulations. The model was parametrized with laboratory data and simulations were compared with results of biological trials. Small populations of ARwP males and females were theoretically and experimentally demonstrated to rapidly become extinct when released in larger SANG populations. Male-only releases at a 5:1 ratio with respect to the wild-type males led to a complete suppression of the SANG population in a few generations. Contaminated releases were efficient as well but led to population replacement in the long term, when the wild-type population approached eradication. Migration significantly contrasted this trend as a 5% population turnover was sufficient to avoid any risk of population replacement. At equal frequencies between ARwP and SANG individuals, the mean egg fertility of the overall population was more than halved and suppression was self-sustaining until one of the two infection types extinguished. In the case of bidirectional incompatibility patterns, the repeated release of incompatible males with small percentages of contaminant females could lead to population replacement in confined environments while it could be managed to target high efficiency and sustainability in wild-type suppression when systems are open to migration. This possibility is discussed based on various contexts and taking into consideration the possibility of integration with other control methods such as SIT and the use of larvicides.


A systematic investigation of forensic hair decontamination procedures and their limitations.
The effectiveness of decontamination procedures used for the removal of external drug contamination in forensic hair analysis is an ongoing debate. This investigation evaluated wash methods complying with Society of Hair Testing (SoHT) guidelines and their capacity to remove cocaine (COC) and methamphetamine (MA) from artificially contaminated hair. The most effective decontamination method was determined using a systematic approach, involving (1) an initial washing solvent screen, (2) optimization of wash duration, (3) comparison of sequential wash methods, and (4) reanalysis of clinical hair samples. For analysis, hair was subjected to micro-pulverized methanolic extraction prior to quantitation by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Methanol (MeOH) and 0.1 M phosphate buffer (pH 6) were the most effective organic and aqueous solvents, respectively, removing 28%-38% of COC and 16%-31% of MA. Wash durations longer than 30-60 minutes did not remove additional amounts, and a more efficient sequential wash method was subsequently developed. Despite this, the interpretation of reportable results relative to the SoHT cut-off levels was unchanged for most clinical hair samples reanalyzed after washing by agitation for 30 minutes with MeOH. These findings highlight the inability of decontamination solvents to completely remove external COC and MA contamination from hair, including wash methods adhering to SoHT guidelines.


Binding of ligands originates small perturbations on the microscopic thermodynamic properties of a multicentre redox protein.
NMR and visible spectroscopy coupled to redox measurements were used to determine the equilibrium thermodynamic properties of the four haems in cytochrome c3 under conditions in which the protein was bound to ligands, the small anion phosphate and the protein rubredoxin with the iron in the active site replaced by zinc. Comparison of these results with data for the isolated cytochrome shows that binding of ligands causes only small changes in the reduction potentials of the haems and their pairwise interactions, and also that the redox-sensitive acid-base centre responsible for the redox-Bohr effect is essentially unaffected. Although neither of the ligands tested is a physiological partner of cytochrome c3, the small changes observed for the thermodynamic properties of cytochrome c3 bound to these ligands vs. the unbound state, indicate that the thermodynamic properties measured for the isolated protein are relevant for a physiological interpretation of the role of this cytochrome in the bioenergetic metabolism of Desulfovibrio.


A Functional Magnetic Resonance Imaging Study Using Dynamic Amplitude of Low-Frequency Fluctuation to Assess Brain Activity in Patients with Moyamoya Disease.
Introduction: The purpose of this study was to monitor and record the dynamic brain activity of patients with moyamoya disease (MMD), as well as to study the relationship between brain abnormalities and presenting clinical features. Methods: A total of 16 patients with MMD (2 males and 14 females) were invited to participate in the study, as were healthy controls (HCs) with the same number and sex ratio. In this study, the dynamic amplitude of low-frequency fluctuation (dALFF) was utilized to assess changes in spontaneous brain activity. Moreover, we also used correlation analysis to study the relationship among the measured mean of dALFF, behavioral performances, and the retinal nerve fiber layer and the Hospital Anxiety and Depression Scale (HADS) score to explore the potential relationship between MMD and anxiety and depression. Results: Our study reveals that in MMD, dALFF levels decreased in the left lingual gyrus, right insula, and occipital lobe. Discussion: In this study, we found and discussed the potential relationship between the abnormal activities in multiple brain regions and related functional network disorders in patients with MMD, as well as the damage to brain regions that process emotion and vision, in the hopes of providing more ideas for the clinical diagnosis and treatment of MMD.


NMDA as well as non-NMDA receptors in phrenic nucleus mediate respiratory effects of carotid chemoreflex.
An in vivo model was used to identify the transmitter/receptor mechanisms in the phrenic nucleus that mediate carotid chemoreceptor responses. Adult male Wistar rats, anesthetized with urethan, were fixed in a stereotaxic instrument, and the blood pressure and heart rate were monitored. The rats were immobilized and artificially ventilated to maintain the end-tidal CO2 at 4.5-5%. The vagus nerves were bilaterally sectioned, and a pneumothorax was produced. Activity was recorded from one of the phrenic nerves. The spinal cord was exposed from C1 to T1 vertebral level. The dorsal and ventral rootlets of spinal nerves C3, C5, and C6, ipsilateral to the phrenic nerve from which electrical activity was recorded, were sectioned; the dorsal and ventral roots of spinal nerve C4 were left intact. Thus the phrenic nerve bursts recorded in this preparation represented output from a portion of the phrenic nucleus located in the ipsilateral C4 spinal segment. Carotid chemoreceptor stimulation by N2 inhalation increased the amplitude as well as the frequency of phrenic nerve bursts. Microinjections (50 nl) of a specific N-methyl-d-aspartic acid (NMDA) receptor antagonist (D(-)-2-amino-7-phosphonoheptanoic acid, AP-7, 50-100 mM) into the phrenic nucleus decreased the N2-induced increase in amplitude, but not the frequency, of phrenic nerve bursts. Likewise microinjections of a specific non-NMDA receptor antagonist (1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzoquinoxaline-7-sulfonamid e, NBQX, 0.5-1 mM) into the phrenic nucleus decreased the N2-induced increase in phrenic nerve burst amplitude. When AP-7 and NBQX were microinjected into the phrenic nucleus sequentially within an interval of 5 min, a drastic reduction in the N2-induced increase in phrenic nerve burst amplitude was observed. These observations suggest that both NMDA and non-NMDA receptors located in the phrenic nucleus are involved in the mediation of phrenic nerve responses to the carotid chemoreceptor stimulation.


Reduction of protein synthesis and statin-induced cardiomyocyte cell death.
The objective of this study was to determine whether an HMG Co A reductase inhibitor (statin) reduces protein synthesis in cardiomyocytes and whether this action maybe an underlying mechanism for statin-induced cell death. Cardiomyocytes from embryonic chick heart were maintained in culture. Cells exposed to lovastatin for 4 h showed a concentration dependent reduction in protein synthesis as assessed by [3H] leucine incorporation and [35S] methionine incorporation. Compared to control, lovastatin 100 microM, which produced a 25% increase in cell death, induced a three-fold reduction in methionine incorporation. [35S] methionine autoradiography showed little (new) protein synthesis at concentrations of lovastatin of 70 microM or higher; an effect that was not limited to specific proteins. Cardiomyocytes treated with lovastatin showed morphologic changes in the nucleoli consistent with insufficient protein synthesis. These cardiomyocytes manifested cell death under conditions of reduced protein synthesis. Interruption of protein synthesis with cycloheximide, a ribosomal RNA transcription inhibitor or reduction in protein substrate availability by lowering the media concentration of fetal calf serum was associated with a concentration-dependent reductions in cell viability. Importantly, stimulation of protein synthesis by higher concentrations of fetal calf serum limited lovastatin-induced cell death. These data suggest that statin-induced inhibition of protein synthesis is an underlying mechanism for statin-induced cell death.


Reverse Monte Carlo modeling in confined systems.
An extension of the well established Reverse Monte Carlo (RMC) method for modeling systems under close confinement has been developed. The method overcomes limitations induced by close confinement in systems such as fluids adsorbed in microporous materials. As a test of the method, we investigate a model system of (36)Ar adsorbed into two zeolites with significantly different pore sizes: Silicalite-I (a pure silica form of ZSM-5 zeolite, characterized by relatively narrow channels forming a 3D network) at partial and full loadings and siliceous Faujasite (which exhibits relatively wide channels and large cavities). The model systems are simulated using grand canonical Monte Carlo and, in each case, its structure factor is used as input for the proposed method, which shows a rapid convergence and yields an adsorbate microscopic structure in good agreement with that of the model system, even to the level of three body correlations, when these are induced by the confining media. The application to experimental systems is straightforward incorporating factors such as the experimental resolution and appropriate q-sampling, along the lines of previous experiences of RMC modeling of powder diffraction data including Bragg and diffuse scattering.


Phellinus linteus polysaccharides: A review on their preparation, structure-activity relationships, and drug delivery systems.
Phellinus linteus polysaccharides exhibit antitumor, immunomodulatory, anti-inflammatory, and antioxidant properties, mitigate insulin resistance, and enhance the diversity and abundance of gut microbiota. However, the bioactivities of P. linteus polysaccharides vary owing to the complex structure, thereby, limiting their application. Various processing strategies have been employed to modify them for improving the functional properties and yield. Herein, we compare the primary modes of extraction and purification employed to improve the yield and purity, review the structure-activity relationships, and discuss the application of P. linteus polysaccharides using nano-carriers for the encapsulation and delivery of various drugs to improve bioactivity. The limitations and future perspectives are also discussed. Exploring the bioactivity, structure-activity relationship, processing methods, and delivery routes of P. linteus polysaccharides will facilitate the development of functional foods and dietary supplements rich in P. linteus polysaccharides.


Varicocele treatment: a 2-centers comparison between non microsurgical open correction, laparoscopic approach and retrograde percutaneous sclerotization on 463 cases.
To determine whether there are differences in sperm parameters improvement after different varicocele correction techniques. To determine the role of age in sperm parameters improvement. 2 different European centers collected pre- and postoperative sperm parameters of patients undergoing varicocele correction. Among 463 evaluated patients, 367 were included. Patients were divided in procedure-related and age-related groups. Ivanissevich inguinal open surgical procedure (OS), lymphatic-sparing laparoscopic approach (LSL) and retrograde percutaneous transfemoral sclerotization (RPS) were performed. As outcome measurements sperm count (millions/mL, SC) and percentage of mobile sperms were analyzed. Univariate and multivariate regression between the defined groups; bivariate regression analysis between age and sperm count and motility. Number of patients: OS 78; LSL 85; RPS 204. Mean age 30.2 (SD 6.83); postoperative SC increased from 18.2 to 30.1 (CI 95% 27.3-32.9; p < 0,001); motility from 25.6 to 32.56% (30.9-34.2; p < 0.001). OS: SC varied from 16.9 to 18.2 (p < 0.001); sperm motility from 29% to 33% (p < 0.001). LSL: SC from 15.5 to 17.2 (p < 0.001); motility from 27 to 31% (p < 0.001). RPS: SC from 18.9 to 36.2 (p < 0.001); motility from 24% to 32% (p < 0.001). Univariate and multivariate analysis confirmed the significant difference of SC variation in RPS, compared to the other groups (p < 0.001). No significance between LSL and OS (p = 0.826). No significant differences regarding motility (p = 0.8). Varicocele correction is confirmed useful in improving sperm parameters; sclerotization technique leads to a better sperm improvement compared to other studied procedures; improvement in seminal parameters is not affected by age of the patients treated.


Desmopressin Acetate Before Percutaneous Ultrasound-Guided Kidney Biopsy in Patients with Renal Failure - Is it Really Beneficial?
The most common complication of percutaneous renal biopsy is bleeding, which can be seen in up to one-third of cases. The aim of this study was to evaluate the effect of prebiopsy administration of intranasal desmopressin acetate in reducing the incidence of biopsy-related bleeding complications in patients with significant renal dysfunction who underwent renal biopsy. This was a retrospective, observational study of percutaneous native renal biopsies performed at our center from July 2014 to June 2018. Bleeding complication rates of patients with renal failure (estimated glomerular filtration rate [eGFR] <30 mL/minute/1.73 m2) who received desmopressin and those who did not receive desmopressin were compared. Desmopressin administration before renal biopsy in patients with eGFR <30 mL/minute/1.73 m2 was associated with a significant reduction of bleeding complications (major and minor together; P = 0.025) and no significant reduction in major complications (P = 0.616) or intervention rates (P = 0.251) when compared with a group that did not receive desmopressin. While prebiopsy intranasal desmopressin use was associated with a significant reduction of overall bleeding complications including major and minor complications, there was no reduction in the rate of other major complications and interventions.


Costly infidelity: low lifetime fitness of extra-pair offspring in a passerine bird.
Extra-pair copulation (EPC) is widespread in socially monogamous species, but its evolutionary benefits remain controversial. Indirect genetic benefit hypotheses postulate that females engage in EPC to produce higher quality extra-pair offspring (EPO) than within-pair offspring (WPO). In contrast, the sexual conflict hypothesis posits that EPC is beneficial to males but not to females. Thus, under the sexual conflict hypothesis, EPO are predicted to be no fitter than WPO. We tested these two hypotheses in a 12-year dataset with complete life-history and pedigree information from an isolated island population of house sparrows (Passer domesticus). We compared fitness components of EPO and two types of WPO: (1) WPO from genetically polyandrous "unfaithful" mothers, and (2) WPO from genetically monogamous mothers. We found that all three groups of offspring had similar probabilities of hatching and nestling survival. Unexpectedly, EPO had the lowest probability of recruiting into the breeding population and the lowest lifetime reproductive output. Our results indicate that EPO incurred indirect genetic costs, rather than benefits, which is contrary to indirect benefit models. Importantly, the indirect costs we observed are also underappreciated in current sexual conflict models. Our results call for improved theoretical frameworks that incorporate indirect costs by extending current sexual conflict models.


Gastrointestinal motility disturbances in celiac disease.
It is quite frequent to recognize celiac patients who show gastrointestinal motor abnormalities in clinical practice. In fact, in 30 to 60% of patients, physical examination and dyspeptic symptoms (epigastric discomfort, early satiety) suggest a gastrointestinal motility disorder. Consistent data are now available on the presence of a disturbed motility of the esophagus, stomach, small intestine, gallbladder, and colon of untreated celiac patients. Gastrointestinal abnormalities differ in different gastrointestinal districts. In fact, esophageal transit, gastric and gallbladder emptying, and orocecal transit time are delayed, while colonic transit is faster. These findings are related to the complex interactions among reduced absorption of food constituent (in particular, fat), neurologic alteration, and hormonal derangement. Motility disorders of the gut are also a predisposing factor in the development of small intestinal bacterial overgrowth and may contribute both to development of symptoms in some untreated celiacs and to the persistence of symptoms after gluten-free diet in some of them. All these alterations fortunately disappear after gluten-free diet, and patients return to well being status. Whatever the initial event in the pathogenesis of the celiac lesions may be, we know for certain at this time that gastrointestinal disturbances play an important role in the genesis of gastrointestinal symptoms in celiac disease and that surveillance for celiac disease in patients complaining of dysmotility-like dyspeptic symptoms should be increased.


Big brains, small worlds: material culture and the evolution of the mind.
New developments in neuroimaging have demonstrated that the basic capacities underpinning human social skills are shared by our closest extant primate relatives. The challenge for archaeologists is to explain how complex human societies evolved from this shared pattern of face-to-face social interaction. We argue that a key process was the gradual incorporation of material culture into social networks over the course of hominin evolution. Here we use three long-term processes in hominin evolution-encephalization, the global human diaspora and sedentism/agriculture-to illustrate how the cultural transmission of material culture allowed the 'scaling up' of face-to-face social interactions to the global societies known today. We conclude that future research by neuroimagers and archaeologists will need to investigate the cognitive mechanisms behind human engagement with material culture as well as other persons.


Postmortem Study of Cause of Death Among Children Hospitalized With Respiratory Illness in Kenya.
In resource-limited settings, acute respiratory infections continue to be the leading cause of death in young children. We conducted postmortem investigations in children <5 years hospitalized with a clinical diagnosis of respiratory disease at Kenya's largest referral hospital. We collected respiratory and other tissues postmortem to examine pathologic processes using histology, molecular and immunohistochemistry assays. Nasopharyngeal, trachea, bronchi and lung specimens were tested using 21-target respiratory pathogen real-time reverse transcription polymerase chain reaction assays deployed on Taqman Array Cards. Expert panels reviewed all findings to determine causes of death and associated pathogens. From 2014 to 2015, we investigated 64 pediatric deaths (median age 7 months). Pneumonia was determined as cause of death in 70% (42/52) of cases where death was associated with an infectious disease process. The main etiologies of pneumonia deaths were respiratory syncytial virus (RSV) (n = 7, 19%), Pneumocystis jirovecii (n = 7, 19%), influenza A (n = 5, 14%) and Streptococcus pneumoniae (n = 5, 14%)-10% of cases had multi-pathogen involvement. Among the other 10 deaths associated with a nonpneumonia infectious process, 4 did not have an etiology assigned, the others were associated with miliary tuberculosis (2), cerebral thrombosis due to HIV (1), Enterobacteriaceae (1), rotavirus (1), and 1 case of respiratory infection with severe hypokalemia associated with RSV. In spite of well-established vaccination programs in Kenya, some deaths were still vaccine preventable. Accelerated development of RSV monoclonal antibodies and vaccines, introduction of seasonal influenza vaccination, and maintenance or improved uptake of existing vaccines can contribute to further reductions in childhood mortality.


Quantitative proteomics of a B12 -dependent alga grown in coculture with bacteria reveals metabolic tradeoffs required for mutualism.
The unicellular green alga Lobomonas rostrata requires an external supply of vitamin B12 (cobalamin) for growth, which it can obtain in stable laboratory cultures from the soil bacterium Mesorhizobium loti in exchange for photosynthate. We investigated changes in protein expression in the alga that allow it to engage in this mutualism. We used quantitative isobaric tagging (iTRAQ) proteomics to determine the L. rostrata proteome grown axenically with B12 supplementation or in coculture with M. loti. Data are available via ProteomeXchange (PXD005046). Using the related Chlamydomonas reinhardtii as a reference genome, 588 algal proteins could be identified. Enzymes of amino acid biosynthesis were higher in coculture than in axenic culture, and this was reflected in increased amounts of total cellular protein and several free amino acids. A number of heat shock proteins were also elevated. Conversely, photosynthetic proteins and those of chloroplast protein synthesis were significantly lower in L. rostrata cells in coculture. These observations were confirmed by measurement of electron transfer rates in cells grown under the two conditions. The results indicate that, despite the stability of the mutualism, L. rostrata experiences stress in coculture with M. loti, and must adjust its metabolism accordingly.


"You always end up feeling like you're some hypochondriac": intimate partner violence survivors' experiences addressing depression and pain.
Little is known regarding how providers should use information about intimate partner violence (IPV) to care for depressed patients. Our objective was to explore what depressed IPV survivors believe about the relationship between abuse, mental health, and physical symptoms and to elicit their recommendations for addressing depression. Focus group study. Adult, English-speaking, female, Internal Medicine clinic patients with depressive symptoms and a history of IPV. Thematic analysis using an inductive approach (consistent with grounded theory), at a semantic level, with an essentialist paradigm. Twenty three women participated in 5 focus groups. Although selected because of their depression, participants often felt their greatest concerns were physical. They acknowledged that their abuse history, depression, and physical complaints compound each other. They appreciated the need for health care workers to know about their depression and IPV history to get a "full picture" of their health, but they were often hesitant to discuss such issues with providers because of their fear that such information would make providers think their symptoms were "all in their head" or would encourage providers to discount their pain. Participants discussed difficulties related to trust and control in relationships with providers and gave recommendations as to how providers can earn their trust. Understanding a patient's IPV history may allow providers to develop a better therapeutic relationship. To treat depression adequately, it is important for providers to reassure patients that they believe their physical symptoms; to communicate respect for patients' intelligence, experience, and complexity; and to share control.


Endo-N-acetyl-beta-D-glucosaminidase activity in rat liver. Studies on substrate specificity, enzyme inhibition, subcellular localization and partial purification.
Endo-N-acetyl-beta-D-glucosaminidase (EC 18.104.22.168, endoglucosaminidase) has been partially purified (520-fold with respect to the cytoplasmic activity) by using concanavalin A-Sepharose, CM-Sephadex and Bio-Gel P-150 chromatography. From the influence of exogenous glycopeptides on the endoglucosaminidase activity it can be concluded that this activity consists of one enzyme hydrolysing both N-acetyl-lactosaminic-type and oligomannosidic-type substrates. Glycoproteins present in the homogenate inhibit the endoglucosaminidase activity. On re-examination of the subcellular distribution of endoglucosaminidase (after removal of inhibiting glycoproteins from the respective subcellular fractions), its cytoplasmic localization was confirmed.


Resurgent current of voltage-gated Na(+) channels.
Resurgent Na(+) current results from a distinctive form of Na(+) channel gating, originally identified in cerebellar Purkinje neurons. In these neurons, the tetrodotoxin-sensitive voltage-gated Na(+) channels responsible for action potential firing have specialized mechanisms that reduce the likelihood that they accumulate in fast inactivated states, thereby shortening refractory periods and permitting rapid, repetitive, and/or burst firing. Under voltage clamp, step depolarizations evoke transient Na(+) currents that rapidly activate and quickly decay, and step repolarizations elicit slower channel reopening, or a 'resurgent' current. The generation of resurgent current depends on a factor in the Na(+) channel complex, probably a subunit such as NaVβ4 (Scn4b), which blocks open Na(+) channels at positive voltages, competing with the fast inactivation gate, and unblocks at negative voltages, permitting recovery from an open channel block along with a flow of current. Following its initial discovery, resurgent Na(+) current has been found in nearly 20 types of neurons. Emerging research suggests that resurgent current is preferentially increased in a variety of clinical conditions associated with altered cellular excitability. Here we review the biophysical, molecular and structural mechanisms of resurgent current and their relation to the normal functions of excitable cells as well as pathophysiology.


Invited review: motor unit estimation: methods, results, and present status.
The renewed interest in motor unit estimation (counting) has coincided with the introduction of computer-based methodology and with the application of the technique to proximal as well as distal muscles. The advantages and disadvantages of the different methods are considered, together with the assumptions inherent in this type of examination. In normal subjects, the extensor digitorum brevis (EDB) muscle has approximately 200 motor units while each of the intrinsic muscles of the hand has about 100 units; larger muscles in the limbs contain greater numbers of units. Beyond the age of 60 years, there is a decline in the number of functioning motor units in both proximal and distal muscles. In denervating disorders, motor unit estimation is useful for diagnosis and assessment; abnormal values may often be observed in muscles judged clinically to be unaffected. Serial studies have enabled the rate of motor unit loss to be determined in ALS and in spinal muscular atrophy. Depletion of motor units has also been found following upper motoneuron lesions caused by injury to the spinal cord or by cerebral hemorrhage; trans-synaptic dysfunction has been presumed responsible. Rather surprisingly, reduced numbers of motor units have been observed in a variety of myopathic disorders; of these, the most consistent abnormalities have been reported in myotonic muscular dystrophy.


Single photon emission computerized tomography increases the sensitivity of indium-111-pentetreotide scintigraphy in detecting abdominal carcinoids.
Somatostatin (sms) receptors have been identified in carcinoids (c), so enabling their visualization with 111In-pentetreotide scintigraphy. The aim of this study was to evaluate if single photon emission computerized tomography (SPECT) can increase the sensitivity of sms receptor scintigraphy in the detection of abdominal c. 26 patients (pts) with a present, or previously operated, abdominal carcinoid were submitted to SPECT over the abdomen and multiple planar views after the injection of 111In-pentetreotide. Magnetic resonance imaging and computed tomography were also performed. In 19 pts abnormal sites of uptake were found by SPECT which localized 13 abdominal extrahepatic (in 11 pts) and 45 hepatic lesions (in 15 pts). No pathologic accumulation was seen in 7 pts in complete remission after surgery. Planar images visualized 7 abdominal extrahepatic (in 6 pts) and 26 liver tumor sites (in 10 pts), conventional procedures detected 5 abdominal extrahepatic (in 4 pts) and 36 hepatic lesions (in 10 pts). 111In-pentetreotide SPECT is more sensitive than planar scanning and conventional methods to detect abdominal c, and so may play a major role in the early and accurate mapping of tumour spread.


The effect of pH on the exchangeability with deuterium of protons coupled to molybdenum(V) in the active and the desulpho forms of xanthine oxidase.
The effect of pH variation on the exchangeability with deuterium of protons strongly coupled to Mo(V) in the active and desulpho forms of xanthine oxidase was studied by e.p.r. and rapid freezing, in extension of the work of Gutteridge, Tanner & Bray [Biochem. J. (1978) 175, 887-897]. Above neutrality, exchange rates increased with increasing pH. Detailed studies were made on the desulpho enzyme under a variety of conditions, and exchange rate constants at 22 degrees C ranged from 0.16s -1 at pH 6.6 to 1.6s -1 at pH 11.3. The mechanism of proton exchange in the enzyme is discussed. The interpretation by the above workers that the strongly coupled proton of the active enzyme is on sulphur and that of the desulpho enzyme is on oxygen remains valid (and is in agreement with other work), as do their proposals for the structures of the protonated and deprotonated species. However, pK values cannot be calculated from the exchange data. It is likely that the relatively low rates of exchange observed are due to the difference of structure between the protonated and the deprotonated forms. In the case of the desulpho enzyme, an exchange mechanism, which involves the proton exchanging both as such and along with oxygen in the form of a hydroxyl ion, is discussed.


Comparison of psychophysical properties of two intraoral digital sensors on low-contrast perceptibility.
The psychophysical properties of a new complementary metal oxide semi-conductor-based detector, ProSensor® (Planmeca Oy, Helsinki, Finland), in terms of dose response function and perceptibility curve test were performed and compared with those of a charged couple device-based sensor, Dixi® (Planmeca Oy). Dose response functions at 66 kVp for a Dixi and a ProSensor were determined by means of multiple exposures to a homogeneous X-ray field covering the whole exposure range. The entry dose of each exposure was measured and registered. The mean grey level in each image was plotted as function of the corresponding exposures for both digital systems. Radiographs of a test object containing ten holes of increasing depth were obtained throughout the exposure range of the two digital sensors at 66 kVp. 12 observers were asked to register the number of perceptible holes in each radiograph. Based on the mean value of the observers' evaluation, the perceptibility curves were constructed, and the integral value under the perceptibility curves were compared between two intraoral sensors. The results based on dose response function showed that the ProSensor was more sensitive than the Dixi sensor. Paired t-test showed that the minimal perceptible low-contrast details were significantly higher for the ProSensor than for the Dixi sensor (p < 0.001). The integrals below the two perceptibility curves were 33.4 and 69.2 for the Dixi and ProSensor, respectively. Applying the new ProSensor may be beneficial to patients owing to its reduced radiation dose and increased perception for low-contrast details in dentistry.


Allelic expression analysis of the osteoarthritis susceptibility gene COL11A1 in human joint tissues.
The single nucleotide polymorphism (SNP) rs2615977 is associated with osteoarthritis (OA) and is located in intron 31 of COL11A1, a strong candidate gene for this degenerative musculoskeletal disease. Furthermore, the common non-synonymous COL11A1 SNP rs1676486 is associated with another degenerative musculoskeletal disease, lumbar disc herniation (LDH). rs1676486 is a C-T transition mediating its affect on LDH susceptibility by modulating COL11A1 expression. The risk T-allele of rs1676486 leads to reduced expression of the COL11A1 transcript, a phenomenon known as allelic expression imbalance (AEI). We were keen therefore to assess whether the effect that rs1676486 has on COL11A1 expression in LDH is also observed in OA and whether the rs2615977 association to OA also marked AEI. Using RNA from OA cartilage, we assessed whether either SNP correlated with COL11A1 AEI by 1) measuring COL11A1 expression and stratifying the data by genotype at each SNP; and 2) quantifying the mRNA transcribed from each allele of the two SNPs. We also assessed whether rs1676486 was associated with OA susceptibility using a case-control cohort of over 18,000 individuals. We observed significant AEI at rs1676486 (p < 0.0001) with the T-allele correlating with reduced COL11A1 expression. This corresponded with observations in LDH but the SNP was not associated with OA. We did not observe AEI at rs2615977. COL11A1 is subject to AEI in OA cartilage. AEI at rs1676486 is a risk factor for LDH, but not for OA. These two diseases therefore share a common functional phenotype, namely AEI of COL11A1, but this appears to be a disease risk only in LDH. Other functional effects on COL11A1 presumably account for the OA susceptibility that maps to this gene.


Pentapeptides derived from Abeta 1-42 protect neurons from the modulatory effect of Abeta fibrils--an in vitro and in vivo electrophysiological study.
Short fragments and fragment analogues of beta-amyloid 1-42 peptide (Abeta1-42) display a protective effect against Abeta-mediated neurotoxicity. After consideration of our earlier results with in vitro bioassay of synthetic Abeta-recognition peptides and toxic fibrillar amyloids, five pentapeptides were selected as putative neuroprotective agents: Phe-Arg-His-Asp-Ser amide (Abeta4-8) and Gly-Arg-His-Asp-Ser amide (an analogue of Abeta4-8), Leu-Pro-Tyr-Phe-Asp amide (an analogue of Abeta17-21), Arg-Ile-Ile-Gly-Leu amide (an analogue of Abeta30-34), and Arg-Val-Val-Ile-Ala amide (an analogue of Abeta38-42). In vitro electrophysiological experiments on rat brain slices demonstrated that four of these peptides counteracted with the field excitatory postsynaptic potential-attenuating effect of Abeta1-42; only Arg-Val-Val-Ile-Ala amide proved inactive. In in vivo experiments using extracellular single-unit recordings combined with iontophoresis, all these pentapeptides except Arg-Val-Val-Ile-Ala amide protected neurons from the NMDA response-enhancing effect of Abeta1-42 in the hippocampal CA1 region. These results suggest that Abeta recognition sequences may serve as leads for the design of novel neuroprotective compounds.


Endovascular treatment of cranial venous sinus obstruction resulting in pseudotumor syndrome. Report of three cases.
It is probable that a significant number of cases of pseudotumor syndrome (PTS) occur because of cranial venous outflow obstruction, yet reports of direct treatment of the obstruction are few and inconclusive. In this study the authors report three cases of PTS with angiographically confirmed venous sinus obstruction treated by direct, endovascular procedures; urokinase infusion in two and balloon venoplasty in one. Two patients suffered transient complications that resolved satisfactorily. All three showed initial resolution of the signs and symptoms of PTS but one relapsed after 8 months and required surgical treatment. The possible role and methods of treatment of cranial venous outflow obstruction in PTS are discussed.


Both products of the fosB gene, FosB and its short form, FosB/SF, are transcriptional activators in fibroblasts.
We demonstrate that a member of the fos family, the fosB gene, gives rise to two transcripts by alternative splicing of exon 4, generating two proteins, FosB of 338 amino acids and a short form, FosB/SF, which contains the DNA binding and dimerization domains but not the 101 amino acids of the C terminus. FosB/SF activates an AP-1-chloramphenicol acetyltransferase construct in NIH 3T3 cells, as determined by transient and stable transfections, although more weakly than does FosB. In contrast to FosB, FosB/SF has lost its ability to repress the dyad symmetry element of the c-fos gene. FosB/SF when expressed in excess to FosB can downmodulate the activity of FosB. Constitutive expression of high levels of FosB/SF in NIH 3T3 cells has no significant inhibitory effect in the induction of cell proliferation or cell cycle progression, indicating that FosB/SF is not a negative regulator of cell growth. This conclusion is further confirmed by the observation that the majority of the Jun molecules are complexed with FosB/SF in the FosB/SF-overexpressing cells.


[Comparative studies on detection of Chlamydophila psittaci and Chlamydophila abortus in meat turkey flocks using cell culture, ELISA, and PCR].
The prevalence of chlamydia in 10 meat turkey flocks was investigated. As samples served of each moment of collection and sex of the animals 10 cloacal swabs which were taken at the age of 1, 4, 8 and 12 (females) or 16 weeks (males) and at the time of slaughter at the age of 16 or 20 weeks. Spleen samples were taken at the time of slaughter, additionally. These were pooled making 1 pool out of 5 individual samples. The cloacal and spleen pools were examined by nested PCR (nPCR), Capture-ELISA and Capture Blocking-ELISA directly as well as after isolation attempts in cell cultures. The most sensitive method to detect chlamydia, with 6 isolates proved to be the isolation by cell culture followed by detection using nPCR. Not corresponding to the results of the nPCR were 4 positive reactions found by the Capture-ELISA which could in no case be affirmed by Capture-Blocking-ELISA. The direct examination of cloacal swab pools by nPCR proved positive in only 2 cases. In contrast to this the examination of these samples by Capture-ELISA showed a high percentage of 71.9% positive results, of which only 2 cases were confirmed by nPCR and none by Capture-Blocking-ELISA. Of the 8 Chlamydia positive results in the nPCR 7 could be classified by DNA sequencing to Cp. abortus and only one to Cp. psittaci.


Cell-mediated lympholysis responses against autologous cells modified with haptenic sulfhydryl reagents. II. Analysis of the genetic control and H-2-restricted pattern of cytotoxic responses to sulfhydryl and amino reactive reagents.
N-iodoacetyl-N'-(5-sulfonic-1-naphthyl)ethylene-diamine modified autologous cells are shown to induce respective high and low AED-self CTL responses by spleen cells from H-2b and H-2k mice. The lysis mediated by effector populations from both haplotypes was highly H-2 restricted. Cytotoxic responses induced by a 2nd sulfhydryl- (SH) specific reagent, dithionitrobenzoic acid (DTNB), were shown not to be cross-reactive at the effector cell level with AED-self but exhibited the same high and low CTL response patterns as those induced against AED-self. These Ir-effects reported for the 2 SH reactive compounds are discussed in relation to the opposite Ir-patterns demonstrated against a number of amino (NH2) reactive compounds. The difference of self-recognition sites is suggested to account for the contrasting results observed in the response patterns induced by SH- and NH2-reactive compounds. The AED-self CTL response was found to exhibit Kk-self over Db-self Ir regulation. Thus, this latter type of genetic control appears to function independently of whether the hapten is an SH- or NH2-reactive compound.


Guillain-Barré Syndrome During Ongoing Zika Virus Transmission - Puerto Rico, January 1-July 31, 2016.
Guillain-Barré syndrome (GBS) is a postinfectious autoimmune disorder characterized by bilateral flaccid limb weakness attributable to peripheral nerve damage (1). Increased GBS incidence has been reported in countries with local transmission of Zika virus, a flavivirus transmitted primarily by certain Aedes species mosquitoes (2). In Puerto Rico, three arthropod-borne viruses (arboviruses) are currently circulating: Zika, dengue, and chikungunya. The first locally acquired Zika virus infection in Puerto Rico was reported in December 2015 (3). In February 2016, the Puerto Rico Department of Health (PRDH), with assistance from CDC, implemented the GBS Passive Surveillance System (GBPSS) to identify new cases of suspected GBS (4). Fifty-six suspected cases of GBS with onset of neurologic signs during January 1-July 31, 2016, were identified. Thirty-four (61%) patients had evidence of Zika virus or flavivirus infection; the median age of these patients was 55 years (range = 21-88 years), and 20 (59%) patients were female. These 34 patients were residents of seven of eight PRDH public health regions. All 34 patients were hospitalized and treated with intravenous immunoglobulin G (IVIg), the standard treatment for GBS; 21 (62%) required intensive care unit admission, including 12 (35%) who required endotracheal intubation and mechanical ventilation. One patient died of septic shock after treatment for GBS. Additionally, 26 cases of neurologic conditions other than GBS were reported through GBPSS, including seven (27%) in patients with evidence of Zika virus or flavivirus infection. Residents of and travelers to Puerto Rico and countries with active Zika virus transmission should follow recommendations for prevention of Zika virus infections.* Persons with signs or symptoms consistent with GBS should promptly seek medical attention. Health care providers in areas with ongoing local transmission seeing patients with neurologic illnesses should consider GBS and report suspected cases to public health authorities.


Effects of sample preparation on chemistry, cytotoxicity, and inflammatory responses induced by air particulate matter.
Methanol is used for high-efficiency extraction of air particulate (PM) mass from the sampling substrate in the high-volume cascade impactor. Sonication is needed during extraction and when dissolving dried PM samples in liquids used in exposure studies. We investigated the effects of these procedures on the PM chemistry and PM-induced cytotoxic and inflammatory responses in mouse macrophages. Untreated and methanol-treated ambient air reference PM samples (SRM1649a, EHC-93) and diesel PM (SRM1650) were tested after different sonication durations (530 min). Furthermore, the time dependency of the responses to SRM1649a, EHC-93, and a fine PM sample from Helsinki was investigated. Methanol pretreatment increased on average by 24% and 21% the recovery of water-soluble metals from SRM1649a and EHC-93, but not SRM1650. It had no systematic effect on the recoveries of inorganic secondary ions (NO3-, SO4(2-), NH4+) or the sum of genotoxic PAH compounds from the three reference samples. Nitric oxide (NO) response to SRM1650 was strongly enhanced by methanol pretreatment, whereas the cytotoxic or inflammatory responses to the ambient air PM samples (EHC-93, SRM1649a) were only slightly modified. Sonication duration was a modifying factor only in connection to SRM1650. Maximal interleukin (IL)-1 production was observed earlier (8 h) than maximal tumor necrosis factor (TNF) alpha and IL-6 productions (24 h), which indicates the importance to know the optimal time points for measurement of the selected response parameters. In conclusion, methanol extraction and reasonable sonication duration are not likely to modify the cytotoxic and inflammatory potency of ambient air PM samples, but some responses to air PM, rich in organic compounds, can be modified.


Sociodemographic differences in antiepileptic drug prescriptions to adult epilepsy patients.
According to the Swedish Health Care Act, patients should be provided with the health care they need, regardless of sociodemographic status. We investigated whether in Sweden sociodemographic differences are associated with access to expert health care and antiepileptic drug (AED) prescriptions in epilepsy. Patients with epilepsy were identified in the National Patient Register. Persons >or=18 years on continuous AED treatment in 2006 were identified in the recently established Swedish Prescribed Drug Register. Data on sociodemographic variables were obtained from several other national registers. We linked data to examine whether epilepsy patients' access to neurologists and the prescription of individual AEDs are related to sex, age, educational level, area of residence, region of birth, or income. We also assessed whether AEDs are prescribed differently to patients with epilepsy by neurologists as compared to non-neurologists. We identified 26,124 epilepsy patients in the register who were on continuous AED treatment (effective sample). Being women, young, highly educated, having high incomes, and residing in a larger city meant being more often treated by a neurologist than by other specialists. The prescriptions of AEDs differed according to gender, age, education, place of residence, and income. Lamotrigine and levetiracetam were prescribed to a larger extent by a neurologist rather than by other specialists. This nationwide cross-sectional study of epilepsy patients indicates that sociodemographic characteristics are important for access to neurologists and prescriptions of individual antiepileptic drugs. Prospective studies using patient-related outcomes are needed to analyze the consequences of these differences.


Co-evolution of tumor and immune cells during progression of multiple myeloma.
Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect "B cell-featured" plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options.


Caveolin-1 and lipids: Association and their dualism in oncogenic regulation.
Caveolin-1 (Cav-1) is a structural protein of caveolae that functions as a molecular organizer for different cellular functions including endocytosis and cellular signaling. Cancer cells take advantage of the physical position of Cav-1, as it can communicate with extracellular matrix, help to organize growth factor receptors, redistribute cholesterol and glycosphingolipids, and finally transduce signals within the cells for oncogenesis. Recent studies emphasize the exceeding involvement of Cav-1 with different lipid bodies and in altering the metabolism, especially lipid metabolism. However, the association of Cav-1 with different lipid bodies like lipid rafts, lipid droplets, cholesterols, sphingolipids, and fatty acids is remarkably dynamic. The lipid-Cav-1 alliance plays a dual role in carcinogenesis. Both cancer progression and regression are modified and affected by the type of lipid molecule's association with Cav-1. Accordingly, this Cav-1-lipid cooperation exemplifies a cancer-type-specific treatment strategy for a better prognosis of the disease. In this review, we first present Cav-1 as an oncogenic molecule and its communication via lipid raft. We discussed the involvement of Cav-1 with lipid droplets, Cholesterol, sphingolipids, gangliosides, and ceramides. Further, we describe the Cav-1-mediated altered Fatty acid metabolism in cancer and the strategic therapeutic approaches toward Cav-1 targeting.


Role of chemotherapy for advanced/recurrent gastric cancer: an individual-patient-data meta-analysis.
We conducted an individual-patient-data meta-analysis of the efficacy of chemotherapy on overall survival (OS) and progression-free survival (PFS) in advanced/recurrent gastric cancer (AGC). Our primary research question was whether the experimental arms of the trials included in the meta-analysis showed a benefit as compared with their corresponding control arms. MEDLINE (up to 2010), Cochrane Central Register of Controlled Trials, National Institutes of Health (NIH) trial registry and proceedings of major oncologic and gastrointestinal cancer meetings were searched. Randomised controlled trials for AGC closed to patient accrual before the end of 2006 were eligible. As of December 2010, individual patient data were available from 22 trials (4245 patients, representing 47% of the targeted data) of 55 eligible trials. The overall comparison of experimental arms with the corresponding control arms showed statistically significant differences in terms of both OS and PFS. Hazard ratio was 0.88 (95% confidence interval 0.82-0.94, P<0.0001) for OS and 0.81 (0.76-0.88, P<0.0001) for PFS. The results of the sub-analysis of adding a given chemotherapeutic agent to any chemotherapy confirm the results of the overall analysis, with a hazard reduction of 11% for OS (P<0.01) and 26% for PFS (P<0.0001). This meta-analysis of individual patient data shows that the additions of experimental chemotherapeutic agents to pre-existing control or standard regimens have produced a modest improvement in OS and PFS. Median survival remained below 1 year for all investigated chemotherapy regimens and none emerged as a clear standard.


Phyllodes tumour of the prostate posing diagnostic and therapeutic dilemmas.
A rare case of phyllodes tumour of the prostate of which less than 100 cases have been reported in the literature. It has an unclear clinical course and uncertain management options. In an inoperable case such as this, the authors discuss the difficulties faced with its management and the limited, possibly palliative role, of hormonal treatment using luteinising hormone-releasing hormone analogue in managing it over a medium term.


A site-specific endonuclease essential for mating-type switching in Saccharomyces cerevisiae.
We have detected two site-specific endonucleases in strains of Saccharomyces cerevisiae. One endonuclease, which we call YZ endo, is present only in yeast strains that are undergoing mating-type interconversion. The site at which YZ endo cleaves corresponds to the in vivo double-strand break occurring at the mating-type locus in yeast undergoing mating-type interconversion. YZ endo generates a site-specific double-strand break having 4-base 3' extensions terminating in 3' hydroxyl groups. The site of cleavage occurs in the Z1 region near the YZ junction of the mating-type locus. Mutant mating-type loci known to decrease the frequency of mating-type interconversion are correspondingly poor substrates for YZ endo in vitro. In vitro analysis of a number of such altered recognition sites has delimited the sequences required for cleavage. The molecular genetics of mating-type interconversion is discussed in the context of this endonucleolytic activity. The second endonuclease, which we refer to as Sce II, is present in all strains of S. cerevisiae we have examined. The cleavage site of Sce II has been determined and proves to be unrelated to the cleavage site of YZ endo.


Prenatal diagnosis of developmental and epileptic encephalopathy 9 with a 10.05-Mb microdeletion at Xq21.31q22.1 inherited from mother: A case report and literature review.
Developmental and epileptic encephalopathy 9 (DEE9) is characterized by early infantile seizures and mild-to-severe neuropsychiatric symptoms. Despite being an X-linked dominant disorder, DEE9 mainly affects heterozygous females or mosaic males, while hemizygous males are less affected. PCDH19 gene has been documented as the causative gene. Karyotyping analysis and copy number variation sequencing (CNV-seq) were performed on a pregnant woman with epilepsy, together with her husband, son, and fetus. A disease-causing microdeletion, seq[GRCh37] del(X)(q21.31q22.1) (90310001-100360000), was identified in the pregnant woman and her female fetus. The microdeletion includes the entire PCDH19 gene and is classified as "pathogenic" according to the American College of Medical Genetics and Genomics guidelines. In this case study, we have not only identified the epilepsy type of the woman as DEE9 but have also made an unfavorable prognosis for her fetus. Our findings from this prenatal case provide valuable clinical resources for prenatal diagnosis and genetic counseling, while also implying the potential of CNV-seq as a viable method for uncovering PCDH19-related epilepsy.


Timing of Breast Cancer Surgery-How Much Does It Matter?
Timing of surgical resection after breast cancer diagnosis is dependent on a variety of factors. Lengthy delays may lead to progression; however, the impact of modest delays is less clear. The aim of this study was to evaluate the impact of surgical timing on outcomes, including disease-free survival (DFS) and nodal status (NS). The cancer registry from one academic cancer hospital was retrospectively reviewed. Time from initial biopsy to surgical resection was calculated for patients with ductal carcinoma in situ (DCIS) and stage 1 and 2 invasive carcinomas. Early (0-21 days), intermediate (22-42 days), and late (43-63 days) surgery groups were evaluated for differences in NS and DFS for each cancer stage separately. A total of 3,932 patients were identified for analysis. There were no differences in DFS noted for DCIS. For stage 1, early surgery (ES) was associated with worse DFS compared to intermediate surgery (IS) (p = 0.025). There were no significant differences between ES and late surgery (LS) (p = 0.700) or IS and LS (p = 0.065). In stage II cancers, there was a significant difference in DFS in ES compared to IS (p < 0.001) and LS (p = 0.009). There was no significant difference between IS and LS (p = 0.478). Patients were more likely to undergo immediate reconstruction (p < 0.0001 for all stages) in later time-to-surgery groups, while patients in earlier groups were more likely to undergo breast conserving surgery. There was also no significant difference in NS at time of surgery in clinical stage 1 (p = 0.321) or stage 2 disease (p = 0.571). Delays of up to 60 days were not associated with worse outcomes. This study should reassure patients and surgeons that modest delays do not adversely affect breast cancer outcomes. This allows patients time to consider treatment and reconstruction options.


A single-center descriptive study of untraced sources of infection among new cases of coronavirus disease in Tokyo, Japan.
We investigated possible sources of newly infected patients with coronavirus disease (COVID-19) after the fourth wave in order to explore unknown sources. Retrospective chart review on all the confirmed patients with COVID-19 admitted to the National Center for Global Health and Medicine (NCGM) in Tokyo, Japan was conducted from May 22 through June 29, 2021. Among the 22 participants, 14 (64%) had a history of known high-risk infection behaviors. Of those, 12 reported that their activities involved eating and drinking. In addition, there were 24 high-risk situations, of those, 21 (88%) were related to indoor dining, and masks were not worn in 22 situations (92%). New source of infection has not been identified. In situations with a high known risk of infection, many cases were related to eating and drinking, and insufficient use of masks was evident. Raising risk awareness on infection prevention and control of COVID-19 is urgently needed.