Protein biomarker of cell proliferation determines survival to discharge in cases of equine large colon volvulus.
Progenitor cells play critical roles in epithelial repair following ischaemic injury. Protein biomarkers have been used to identify intestinal progenitor cell subpopulations. This study aims to determine if a critical number of intestinal progenitor cells can predict tissue viability and survival to discharge of large colon volvulus (LCV) cases. The objectives were to 1) identify intestinal progenitor cell subpopulations using biomarkers: proliferating cell nuclear antigen (PCNA), sex determining region Y box 9 (SOX9), phospho-histone H3 (PHH3) and Ki-67, 2) define cut-off values for critical numbers of positive cells and 3) determine if survival to discharge is associated with cut-off values. Retrospective cohort study. Adult horses admitted to the Farm and Equine Veterinary Medical Center at NC State's Veterinary Hospital and Peterson and Smith Equine Hospital between 2006 and 2016 that underwent an exploratory coeliotomy with a diagnosis of LCV of ≥360 degrees, had pelvic flexure biopsy and that recovered from general anaesthesia were selected for inclusion in the study. Immunohistochemical analyses were performed and positive cells were counted. Optimal cut-off values were determined using receiver operator curves. A Fisher's exact test was used to associate cut-off values with survival to discharge. In this study, 23 cases of LCV ≥360° were included. Of 23 horses, 13 (57%) survived to discharge. A cut-off value of <2.1 PHH3 positive cells per crypt correctly predicted death with 100% sensitivity (95% CI; 69.15-100%) and 84.62% specificity (95% CI; 54.55-98.08%). LCV cases with <2.1 PHH3 positive cells per crypt were 96.6 times more likely to die (95% CI; 4.14-2255 and P < 0.0001). Biomarkers PCNA, SOX9 and Ki-67 did not predict short-term survival. The population size was small. PHH3 immunohistochemical analysis may assist in more accurate prediction of survival to hospital discharge of LCV cases. The summary is available in Spanish - see Supporting Information.


L-threonine injection into PPC modifies food intake, lateral hypothalamic activity, and sympathetic discharge.
Food intake and the firing rate of lateral hypothalamic neurons and nerves innervating interscapular brown adipose tissue (IBAT), along with IBAT and colonic temperatures, were monitored in male Sprague-Dawley rats fed a threonine-free diet. These variables were measured before and after a bilateral injection of L-threonine (2 nmol into each side) into the prepiriform cortex (PPC). The same variables were also monitored in 1) rats fed a threonine-free diet and injected with saline, 2) animals fed a standard diet and injected with L-threonine, and 3) rats fed a standard diet and injected with saline. The results showed that injection of L-threonine into PPC increases food intake and firing rate of lateral hypothalamic neurons, whereas it decreases the sympathetic discharge and body temperature in animals fed a threonine-free diet. No changes were found in the animals fed a standard diet. These findings suggest a correlation between 1) threonine level in the PPC and 2) lateral hypothalamic activity and sympathetic discharge to IBAT.


Building long-term family resilience through universal prevention: 10-year parent and child outcomes during the COVID-19 pandemic.
As the COVID-19 pandemic has been highly stressful for parents and children, it is clear that strategies that promote long-term family resilience are needed to protect families in future crises. One such strategy, the Family Foundations program, is focused on promoting supportive coparenting at the transition to parenthood. In a randomized trial, we tested the long-term intervention effects of Family Foundations on parent, child, and family well-being one to two months after the imposition of a national shelter-in-place public health intervention in 2020. We used regression models to test intervention impact on outcomes reported on by parents in a standard questionnaire format and a series of 8 days of daily reports. We also tested moderation of intervention impact by parent depression and coparenting relationship quality. Relative to control families, intervention families demonstrated significantly lower levels of individual and family problems (general parent hostility, harsh and aggressive parenting, coparenting conflict, sibling relationship conflict, and children's negative mood and behavior problems), and higher levels of positive family relationship quality (positive parenting, couple relationship quality, sibling relations, and family cohesion). For some outcomes, including coparenting conflict, harsh parenting, and child behavior problems, intervention effects were larger for more vulnerable families-that is, families with higher pre-pandemic levels of parent depression or lower levels of coparenting relationship quality. We conclude that targeted family prevention programming is able to promote healthy parent and child functioning during unforeseen future periods of acute stress. The long-term benefits of a universal approach to family support at the transition to parenthood indicate the need for greater investment in the dissemination of effective approaches.


Social Skills Group Training for Students with Neurodevelopmental Disabilities in Senior High School-A Qualitative Multi-Perspective Study of Social Validity.
Including students with neurodevelopmental disabilities (NDDs) in regular classrooms has become a law-enforced common practice in many high- and middle-income countries. Still, without appropriate actions supporting the implementation of inclusive pedagogical practice, students with NDDs remain at increased risk for absenteeism, bullying and underachievement. There is limited knowledge on the feasibility of social skills group training (SSGT) in naturalistic settings. Using a qualitative approach, the objective of this study was to explore the lived experiences of (i) students diagnosed with autism or attention-deficit hyperactivity disorder and those showing subclinical social difficulties receiving either SSGT or active social control activities in a regular senior high school setting, (ii) teachers providing SSGT or the active control activity and (iii) school leaders facilitating the implementation of these actions. Due to the impact of the COVID-19 pandemic, comparison between real life versus digital administration of SSGT was also examined. Within a randomized controlled pilot trial of the school-tailored SSGT SKOLKONTAKT®, the primary perspectives of 20 students, teachers and school leaders on SSGT or the social control activities were explored. All groups perceived SSGT to enhance school attendance and academic achievement of students, as well as teacher inclusion skills and the social school climate. Findings indicate that SSGT is largely feasible and socially valid, and broader implementation of SSGT in school settings appears meaningful.


Role of nickel in high rate methanol degradation in anaerobic granular sludge bioreactors.
The effect of nickel deprivation from the influent of a mesophilic (30 degrees C) methanol fed upflow anaerobic sludge bed (UASB) reactor was investigated by coupling the reactor performance to the evolution of the Methanosarcina population of the bioreactor sludge. The reactor was operated at pH 7.0 and an organic loading rate (OLR) of 5-15 g COD l(-1) day(-1) for 191 days. A clear limitation of the specific methanogenic activity (SMA) on methanol due to the absence of nickel was observed after 129 days of bioreactor operation: the SMA of the sludge in medium with the complete trace metal solution except nickel amounted to 1.164 (+/-0.167) g CH(4)-COD g VSS(-1) day(-1) compared to 2.027 (+/-0.111) g CH(4)-COD g VSS(-1) day(-1) in a medium with the complete (including nickel) trace metal solution. The methanol removal efficiency during these 129 days was 99%, no volatile fatty acid (VFA) accumulation was observed and the size of the Methanosarcina population increased compared to the seed sludge. Continuation of the UASB reactor operation with the nickel limited sludge lead to incomplete methanol removal, and thus methanol accumulation in the reactor effluent from day 142 onwards. This methanol accumulation subsequently induced an increase of the acetogenic activity in the UASB reactor on day 160. On day 165, 77% of the methanol fed to the system was converted to acetate and the Methanosarcina population size had substantially decreased. Inclusion of 0.5 muM Ni (dosed as NiCl(2)) to the influent from day 165 onwards lead to the recovery of the methanol removal efficiency to 99% without VFA accumulation within 2 days of bioreactor operation.


A self-help cessation program for smokeless tobacco users: comparison of two interventions.
While the use of smokeless tobacco products has increased, there has been a paucity of research evaluating interventions to help users quit. This study is the first large-scale randomized trial evaluating two levels of self-help cessation intervention with adult smokeless tobacco (SLT) users. Smokeless users in five Northwest states were recruited to call a toll-free number and 1069 users were randomized to receive one of two interventions, Manual Only (MAN) or Assisted Self-Help (ASH), who received a video and two support phone calls in addition to the manual. The study demonstrated that low-cost minimal interventions done by mail and phone can help a sizable proportion of SLT users quit both SLT and all tobacco use. Follow-up data at 6 months showed that subjects in the ASH condition had a significantly higher quit rate for both smokeless (23.4% vs. 18.4%, p < 0.05) and all tobacco use (21.1% vs. 16.5%, p < 0.05), using an intent-to-treat model. Further analysis revealed that use of the recommended cessation procedures mediated the effect of intervention condition on outcomes. This may be the result of phone counselors getting subjects to carry out behavioral cessation procedures. Public health implications for this intervention are discussed.


Complete loss of photoperiodic response in the rice mutant line X61 is caused by deficiency of phytochrome chromophore biosynthesis gene.
In rice (Oryza sativa), a short-day plant, photoperiod is the most favorable external signal for floral induction because of the constant seasonal change throughout the years. Compared with Arabidopsis, however, a large part of the regulation mechanism of the photoperiodic response in rice still remains unclear due mainly to the lack of induced mutant genes. An induced mutant line X61 flowers 35 days earlier than its original variety Gimbozu under a natural photoperiod in Kyoto (35°01'N). We attempted to identify the mutant gene conferring early heading to X61. Experimental results showed that the early heading of X61 was conferred by a complete loss of photoperiodic response due to a novel single recessive mutant gene se13. This locus interacts with two crucial photoperiod sensitivity loci, Se1 and E1. Wild type alleles at these two loci do not function in coexistence with se13 in a homozygous state, suggesting that Se13 is an upstream locus of the Se1 and E1 loci. Linkage analysis showed that Se13 is located in a 110 kb region between the two markers, INDEL3735_1 and INDEL3735_3 on chromosome 1. A database search suggested that the Se13 gene is identical to AK101395 (=OsHY2), which encodes phytochromobilin synthase, a key enzyme in phytochrome chromophore biosynthesis. Subsequent sequence analysis revealed that X61 harbors a 1 bp insertion in exon 1 of OsHY2, which induces a frame-shift mutation producing a premature stop codon. It is therefore considered that the complete loss of photoperiodic response of X61 is caused by a loss of function of the Se13 (OsHY2) gene involved in phytochrome chromophore biosynthesis.


Engineered vascular beds provide key signals to pancreatic hormone-producing cells.
The mechanisms underlying early islet graft failure are not entirely clear, but are thought to involve ischemic injury due to delayed vascularization. We hypothesize that blood vessels play an active role in cell-cell communications supporting islet survival and engraftment. To test this hypothesis and to uncouple endothelial cell (EC)-generated signaling stimuli from their nutritional and gas exchange functions, we developed three dimensional (3D) endothelial vessel networks in engineered pancreatic tissues prepared from islets, fibroblasts and ECs. The tri-culture setup, seeded on highly porous biocompatible polymeric scaffolds closely mimics the natural anatomical context of pancreatic vasculature. Enhanced islet survival correlating with formation of functional tube-like endothelial vessels was demonstrated. Addition of foreskin fibroblasts to islet-endothelial cultures promoted tube-like structure formation, which further supported islet survival as well as insulin secretion. Gene expression profiles of EC growth factors, extracellular matrix (ECM), morphogenes and differentiation markers were significantly different in 2D versus 3D culture systems and were further modified upon addition of fibroblasts. Implantation of prevascularized islets into diabetic mice promoted survival, integration and function of the engrafted engineered tissue, supporting the suggested role of ECs in islet survival. These findings present potential strategies for preparation of transplantable islets with increased survival prospects.


Common actions of adenosine receptor agonists in modulating human trabecular meshwork cell transport.
A(1) adenosine receptors (ARs) reduce, and A(2)ARs increase intraocular pressure, partly by differentially altering resistance to aqueous humor outflow. It is unknown whether the opposing effects of A(1)AR and A(2)AR agonists are mediated at different outflow-pathway cell targets or by opposing actions on a single cell target. We tested whether a major outflow-pathway cell, the trabecular meshwork (TM) cell might constitute the primary AR-agonist target and respond differentially to A(1), A(2A) and A(3)AR agonists. Receptor activation in human TM cells was identified by applying subtype-selective AR agonists: CPA and ADAC for A(1)ARs, CGS 21680 and DPMA for A(2A)ARs, and Cl-IB-MECA and IB-MECA for A(3)ARs. Stimulation of A(1), A(2A) and A(3)ARs elevated Ca(2+), measured with fura-2. Whole-cell patch clamping indicated that AR agonists activated ion channels non-uniformly, possibly reflecting variability in magnitude of agonist-triggered second-messenger responses. A(1), A(2A) and A(3)AR agonists all reduced volume, determined by calcein cell imaging. The endogenous source of adenosine delivery to the outflow pathway could be the TM cells since these cells were stimulated to release ATP by hypotonic perfusion. We conclude that: (1) TM cells express functional A(1), A(2A) and A(3)ARs; and (2) the reported differential effects of AR agonists on aqueous humor outflow are not mediated by differential actions on TM-cell Ca(2+) and volume, but likely by actions on separate cell targets.


AHRQ series on complex intervention systematic reviews-paper 5: advanced analytic methods.
Advanced analytic methods for synthesizing evidence about complex interventions continue to be developed. In this paper, we emphasize that the specific research question posed in the review should be used as a guide for choosing the appropriate analytic method. We present advanced analytic approaches that address four common questions that guide reviews of complex interventions: (1) How effective is the intervention? (2) For whom does the intervention work and in what contexts? (3) What happens when the intervention is implemented? and (4) What decisions are possible given the results of the synthesis? The analytic approaches presented in this paper are particularly useful when each primary study differs in components, mechanisms of action, context, implementation, timing, and many other domains.


Adenine phosphoribosyltransferase deficiency as a rare cause of renal allograft dysfunction.
Adenine phosphoribosyltransferase deficiency is a rare autosomal recessive disorder manifesting as urolithiasis or crystalline nephropathy. It leads to the generation of large amounts of poorly soluble 2,8-dihydroxyadenine excreted in urine, yielding kidney injury and in some patients, kidney failure. Early recognition of the disease, institution of xanthine analog therapy to block the formation of 2,8-dihydroxyadenine, high fluid intake, and low purine diet prevent CKD. Because of symptom variability and lack of awareness, however, the diagnosis is sometimes extremely deferred. We describe a patient with adenine phosphoribosyltransferase deficiency who was diagnosed during evaluation of a poorly functioning second kidney allograft. This report highlights the risk of renal allograft loss in patients with undiagnosed adenine phosphoribosyltransferase deficiency and the need for improved early detection of this disease.


Searching for hematopoietic stem cells. II. The heterogeneity of Thy-1.1(lo)Lin(-/lo)Sca-1+ mouse hematopoietic stem cells separated by counterflow centrifugal elutriation.
Mouse hematopoietic stem cells (HSCs) are highly enriched in the rare (approximately 0.05%) Thy-1.1(lo)Lin(-/lo)Sca-1+ fraction of hematopoietic tissues. It has been demonstrated that Thy-1.1(lo)Lin(-/lo)Sca-1+ cells are the only HSCs in C57BL/Ka-Thy-1.1 bone marrow. In this study, we separated C57/Ka-Thy-1.1 bone marrow cells by counterflow centrifugal elutriation (CCE) into four fractions and characterized Thy-1.1(lo)Lin(-/lo)Sca-1+ cells in each eluted fraction. The peak number of Thy-1.1(lo)Lin(-/lo)Sca-1+ cells was highly enriched in one eluted fraction, which was also highly enriched for day-12 to -13 CFU-S. Activities for day-13 CFU-S, radioprotection, and long-term multilineage reconstitution correlated with, and could be generally predicted by determining, the frequency of Thy-1.1(lo)Lin(-/lo)Sca-1+ cells in a given eluted fraction. However, the fraction that was highly enriched for blast cells and contained a low frequency of Thy-1.1(lo)Lin(-/lo)Sca-1+ cells, only provided short-term but not long-term radioprotection, with a predicted cell number (100 cells) that should have protected > or = 95% (PD95) of hosts. Still, when 300 Thy-1.1(lo)Lin(-/lo)Sca-1+ cells from this fraction (3 X PD95 for unfractionated HSCs) were injected, mice were radioprotected and donor cells provided long-term multilineage reconstitution. We propose that such blast cells may contain two Thy-1.1(lo)Lin(-/lo)Sca-1+ subsets, one providing short-term and the other long-term multilineage sustained hematopoiesis, the latter presumably due to HSC self-renewal.


Modeling of runoff water and runoff pesticide concentrations in upland bare soil using improved SPEC model.
The SPEC model (Predicted Environmental Concentrations in agricultural Soils) was developed and improved for the simulation of pesticide runoff. The model was applied to the Sakaecho upland bare soil field (Tokyo, Japan) to predict runoff water, sediment concentration in runoff water, pesticide concentrations in runoff water, and runoff sediment (clothianidin and imidacloprid) under artificial rainfall conditions. The results showed that the simulated time to first runoff agreed very well with the observed data. The simulated cumulative runoff, sediment yield, and imidacloprid concentration in sediment agreed well with the observed data (Nash-Sutcliffe Efficiency (NSE)>0.75). The simulated runoff rate agreed reasonably well with the observed data (NSE >0.5). The predicted clothianidin concentrations in sediment and in runoff water had acceptable agreement with the observed data (NSE >0). The results implied the model's potential to predict runoff water, sediment yield, and pesticide runoff.


Bioavailability of a heme-iron concentrate product added to chocolate biscuit filling in adolescent girls living in a rural area of Mexico.
A heme-iron concentrate product derived from swine hemoglobin was used to enrich the chocolate-flavored filling of biscuits and the bioavailability of this source of heme-iron was assessed in adolescent girls. The placebo control (PC) group consisted of 35 teenagers with the highest baseline hemoglobin concentrations. The supplemented groups were randomized to receive biscuits fortified with iron sulfate (IS, n = 37) or heme-iron concentrate (HIC, n = 40). Both groups were supplemented with 10.3 mg Fe/d for 7 wk. Blood chemistry and hematology analyses were performed at baseline and at the end of the study. The baseline prevalence of anemia (hemoglobin <12 g/dl) in the entire group was 3.9% and by the end of the study it had fallen to 2.3%. The hemoglobin levels in both supplemented groups increased (P < 0.05) during the study period from 13.6 and 13.5 g/dl for HIC and IS, respectively, at baseline to 14 g/dl at the end of the study. Serum ferritin concentrations decreased by the end of the study in both the PC and IS groups (P < 0.05), but not in the heme group. In conclusion, iron bioavailability from HIC-fortified biscuits was calculated to be 23.7% higher than that observed for IS, as shown by the differences observed in serum ferritin levels during the study. The iron contained in the heme-iron concentrate was well absorbed and tolerated by the adolescents included in the study.


Inhibitory effects of broccoli extract on Escherichia coli O157:H7 quorum sensing and in vivo virulence.
Broccoli extract (BE) has numerous beneficial effects on human health including anticancer activity. Quorum sensing (QS), mediated by self-produced autoinducer (AI) molecules, is a key process for the production of virulence determinants in pathogenic bacteria. BE suppressed AI-2 synthesis and AI-2-mediated bacterial motility in a dose-dependent manner in Escherichia coli O157:H7. In addition, expression of the ler gene that regulates AI-3 QS system was also diminished in response to treatment with BE. Furthermore, in an in vivo efficacy test using Caenorhabditis elegans as a host organism, C. elegans fed on E. coli O157:H7 in the presence of BE survived longer than those fed solely on the pathogenic bacteria. Quantitative real-time PCR analysis indicated that quercetin was the most active among the tested broccoli-derived compounds in downregulating virulence gene expression, while treatment with myricetin significantly suppressed the expression of the eae gene involved in type III secretion system. These data suggest that BE and its flavonoid constituents can inhibit expression of QS-associated genes, thereby downregulating the virulence attributes of E. coli O157:H7 both in vitro and in vivo. This study clearly elucidates BE's QS-inhibitory activity and suggests that BE has the potential to be developed as an anti-infective agent.


Multiple intracranial aneurysms associated with moyamoya disease. Case report.
A case of multiple intracranial aneurysms associated with unilateral moyamoya vessels is reported. The authors have reviewed the age, sex, initial symptoms, site of aneurysm, and operative indication in similar cases reported in the literature. It was found that aneurysms associated with moyamoya disease were frequently located in the vertebrobasilar system.


Ty1 integrase is composed of an active N-terminal domain and a large disordered C-terminal module dispensable for its activity in vitro.
Long-terminal repeat (LTR) retrotransposons are genetic elements that, like retroviruses, replicate by reverse transcription of an RNA intermediate into a complementary DNA (cDNA) that is next integrated into the host genome by their own integrase. The Ty1 LTR retrotransposon has proven to be a reliable working model to investigate retroelement integration site preference. However, the low yield of recombinant Ty1 integrase production reported so far has been a major obstacle for structural studies. Here we analyze the biophysical and biochemical properties of a stable and functional recombinant Ty1 integrase highly expressed in E.coli. The recombinant protein is monomeric and has an elongated shape harboring the three-domain structure common to all retroviral integrases at the N-terminal half, an extra folded region, and a large intrinsically disordered region at the C-terminal half. Recombinant Ty1 integrase efficiently catalyzes concerted integration in vitro, and the N-terminal domain displays similar activity. These studies that will facilitate structural analyses may allow elucidating the molecular mechanisms governing Ty1 specific integration into safe places in the genome.


[Digital subtraction angiography in the diagnosis of emergency neurosurgical states].
Digital subtraction angiography (DSA) was used in the examination of 203 patients with various forms of acute diseases and injuries of the brain. The method of the examination is described and its advantages and shortcomings in each type of pathology are revealed. DSA meets the requirements placed upon angiographic examination of patients with acute diseases of the brain and craniocerebral injury and may be used successfully in the diagnosis of emergency neurosurgical conditions.


Phosphoinositides control the localization of HOPS subunit VPS41, which together with VPS33 mediates vacuole fusion in plants.
The vacuole is an essential organelle in plant cells, and its dynamic nature is important for plant growth and development. Homotypic membrane fusion is required for vacuole biogenesis, pollen germination, stomata opening, and gravity perception. Known components of the vacuole fusion machinery in eukaryotes include SNARE proteins, Rab GTPases, phosphoinositides, and the homotypic fusion and vacuolar protein sorting (HOPS) tethering complex. HOPS function is not well characterized in plants, but roles in embryogenesis and pollen tube elongation have been reported. Here, we show that Arabidopsis HOPS subunits VPS33 and VPS41 accumulate in late endosomes and that VPS41, but not VPS33, accumulates in the tonoplast via a wortmannin-sensitive process. VPS41 and VPS33 proteins bind to liposomes, but this binding is inhibited by phosphatidylinosiltol-3-phosphate [PtdIns(3)P] and PtdIns(3,5)P2, which implicates a nonconserved mechanism for HOPS recruitment in plants. Inducible knockdown of VPS41 resulted in dramatic vacuole fragmentation phenotypes and demonstrated a critical role for HOPS in vacuole fusion. Furthermore, we provide evidence for genetic interactions between VPS41 and VTI11 SNARE that regulate vacuole fusion, and the requirement of a functional SNARE complex for normal VPS41 and VPS33 localization. Finally, we provide evidence to support VPS33 and SYP22 at the initial stage for HOPS-SNARE interactions, which is similar to other eukaryotes. These results highlight both conserved and specific mechanisms for HOPS recruitment and function during vacuole fusion in plants.


The changing image of the Kurds in Turkish cities: middle-class perceptions of Kurdish migrants in Izmir.
Saraçoğlu deals with the ways in which the Kurdish migrants living in the western cities of Turkey have been identified in middle-class discourse by certain pejorative labels and stereotypes. He argues that this new Kurdish image demonstrates the ethnicization of longstanding anti-migrant sentiments in Turkey. He develops and substantiates the argument by means of qualitative data gathered in a field study in zmir between June 2006 and July 2007. The study involved ninety in-depth interviews with middle-class individuals living in the city and explored their anti-Kurdish attitudes. Through a close analysis of two of the common stereotypes that these interviewees deployed in the interviews-namely, that the Kurds were 'benefit scroungers' and that they 'disrupt urban life'- Saraçoğlu explores the formation of the urban social context in which such perceptions have emerged. Close examination of the narratives of the middle-class respondents indicates that the development of a new image of the Kurds has occurred in an urban context shaped by the neoliberal transformation of Turkish cities, on the one hand, and the internal displacement of Kurdish migrants, on the other.


Safety and Efficacy of Different Therapeutic Interventions on Prevention and Treatment of COVID-19.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes coronavirus disease 2019 (COVID-19), a respiratory illness. COVID-19 has now become a global public health crisis causing alarming numbers of morbidity and mortality. Ever since the COVID-19 pandemic started scientists, researchers, universities, companies, and institutions all around the world have been endeavoring to discover a potential treatment for COVID-19. Numerous studies and clinical trials on vaccines and drugs for the prevention and treatment of COVID-19 are underway across the world. However, the uncertainty around the efficacy and safety of various treatment regimens have become one of the biggest challenges in the battle against the SARS-CoV-2. This paper is a narrative review of articles regarding the various treatments and vaccines being tested for the SARS-CoV-2, available in the PubMed database along with Google Scholar. There are ongoing clinical trials on potential drugs such as remdesivir, favipiravir, lopinavir/ritonavir, chloroquine, and hydroxychloroquine, corticosteroids tocilizumab, azithromycin, anakinra, etc. and other therapeutic modalities like convalescent plasma therapy. Likewise, vaccines against SARS-CoV-2 are being developed and tested, including mRNA, non-replicating viral vector, DNA, protein subunit candidate vaccines, etc. Although some early-stage clinical trials and studies on these drugs and vaccines have shown positive results, definitive and conclusive results are yet to be obtained. Keywords: COVID-19; antiviral drugs; COVID-19 treatment; COVID-19 vaccine; SARS-CoV-2.


Increased requirements for essential fatty acids in atopic individuals: a review with clinical descriptions.
Patients with atopic eczema and a mixture of allergic illnesses show biochemical evidence suggesting impairment in the desaturation of linoleic acid and linolenic acid by the enzyme delta-6 dehydrogenase. Consequences of this enzyme defect are 1) diminished synthesis of the 20-carbon polyunsaturated fatty acids, which are prostaglandin precursors and 2) a reduction in the concentration of double bonds in the cell membrane. A distortion in the production of prostaglandins and leukotrienes, which might result from this block, can account for the immunological defects of atopy and a variety of clinical symptoms experienced by atopic individuals. Dietary supplementation with essential fatty acids relieves the signs and symptoms of atopic eczema, may improve other types of allergic inflammation, and may also correct coexisting symptoms as diverse as excessive thirst and dysmenorrhea. Further research is suggested to test the hypothesis that some atopic states represent a condition of essential fatty acid dependency owing to defective desaturation of dietary fatty acids.


The tarsal plate manifestation of IgG4-related disease.
To describe a clinical case of bilateral biopsy-proven IgG4-related disease confined to the tarsal plate. Interventional case report. A 58-year-old woman presented with a tarsal swelling in the lateral part of the upper eyelids, with focal ulceration and mucus. Histology revealed fibrotic inflammation with increased IgG4-positive plasma cells fulfilling the criteria of IgG4-related disease (IgG4-RD). Serum IgG4 levels were increased, and pathological fluorodeoxyglucose uptake at positron emission tomography/CT scanning was restricted to the upper eyelids. After treatment with oral and topical prednisone, the tarsal lesions markedly regressed. Periorbital IgG4-RD may be confined to the tarsal plate. Treatment with systemic and topical steroids may induce significant regression.


Striatal correlates of Bayesian beliefs in self-efficacy in adolescents and their relation to mood and autonomy: a pilot study.
Major depressive disorder often originates in adolescence and is associated with long-term functional impairment. Mechanistically characterizing this heterogeneous illness could provide important leads for optimizing treatment. Importantly, reward learning is known to be disrupted in depression. In this pilot fMRI study of 21 adolescents (16-20 years), we assessed how reward network disruption impacts specifically on Bayesian belief representations of self-efficacy (SE-B) and their associated uncertainty (SE-U), using a modified instrumental learning task probing activation induced by the opportunity to choose, and an optimal Hierarchical Gaussian Filter computational model. SE-U engaged caudate, nucleus accumbens (NAcc), precuneus, posterior parietal and dorsolateral prefrontal cortex (PFWE < 0.005). Sparse partial least squares analysis identified SE-U striatal activation as associating with one's sense of perceived choice and depressive symptoms, particularly anhedonia and negative feelings about oneself. As Bayesian uncertainty modulates belief flexibility and their capacity to steer future actions, this suggests that these striatal signals may be informative developmentally, longitudinally and in assessing response to treatment.


Clusters of maternal depressive symptoms in South Western Sydney, Australia.
The purpose of this study is to explore the spatial distribution of perinatal depressive symptoms in South Western Sydney, Australia, and to identify any clusters that could inform subsequent qualitative, ecological and multilevel studies and local public health interventions. A routine survey of mothers with newborn infants was commenced in 2000. The survey included the Edinburgh Postnatal Depression Scale (EPDS). Mothers (n=15,389) delivering in 2002 and 2003 were assessed at 2-3 weeks after delivery for risk factors for depressive symptoms. The binary outcome variables were EPDS>9 and EPDS>12. EPDS>9 and EPDS>12 was mapped for 101 suburbs using likelihood standardised morbidity ratios (SMRs) and Bayesian log-normal models with conditional autoregressive (CAR) components. Open domain software SaTScan™ was used to test for the presence of clusters. The Bayesian methods identified clusters of depressive symptoms in north-east, north-west and southern areas of the study region. The northern clusters were statistically significant using SaTScan™. There were two high risk clusters of EPDS>9 (radius 4.3 and 5.6 km, both p<0.001) and two high risk clusters of EPDS>12 (radius 1.8 km p=0.003 and radius 3.97 km p=0.012). The clusters were in regions known to be socially disadvantaged and with high rates of non-English speaking migrants. The study findings will be used to inform future qualitative and epidemiological research, and to plan interagency early intervention services for women, children and their families.


Successful Management of Gorham-Stout Disease in the Cervical Spine by Combined Conservative and Surgical Treatments: A Case Report.
Gorham-Stout disease (GSD) is a rare condition characterized by intraosseous proliferation of endothelial-lined vessels and progressive osteolysis. The precise etiology and pathophysiology of the disease remain poorly understood. Current therapeutic options for GSD include chemotherapy, radiotherapy, and surgical resection, but the surgical treatment of GSD is difficult, especially in the spinal lesion. The indication of wide-margined resection was limited because of anatomical features. Herein, we report a case of GSD of the cervical spine in which the lesions were successfully stabilized with combined conservative and surgical treatments. A 15-year-old male patient was admitted because of severe neck pain. The patient presented no neurological deficiency. However, the radiological findings revealed osteolytic lesions on the laminae and vertebrae between C1 to C5. An open biopsy confirmed an irregular, thin-walled vessel formation in the bone trabeculae, which was diagnosed as GSD. Conservative treatment was initiated with chemotherapy and radiotherapy. After one and a half year, the osteolytic condition had regressed. Spinal fusion surgery was then performed from C2 to C5 to prevent for progression of the cervical kyphotic changes, and spinal fusion was confirmed 7 months after the surgery. The patient showed no recurrence of GSD in the 5-year follow-up period after surgery. We were able to provide successful treatment by giving priority to the combined conservative treatments. If a patient has no severe deformity or progressive neurologic deficits, it might be better to prioritize conservative treatments and to perform the surgery after the osteolytic changes have stopped.


Aspects of oral morphology as decision factors in mini-implant supported overdenture.
Evaluation of some morphological oral aspects perceived as decision factors in complete edentulism treatment by mini-implants overdenture. An observational study was conducted on a sample of 24 patients (average age of 61 years), through clinical and imagistic methods. The variables taken into consideration were: age, gender, alveolar mucosa status, bone offer, mini-implants characteristics, insertion torque and loading type. 117 mini-implants were applied, 59% to the lower jaw and 41% to the upper jaw. On average, there were inserted 5.33 implants to maxilla and 4.6 to mandible. Fifty-seven percent of implants were applied in the interforaminal area. The implants used had 10 mm (28.2%) and 13 mm (71.8%). In only 41% patients, the ridge width was higher than 5 mm (value necessary for conventional implant application). Diameters of implant used were: 1.8 mm (2.56%), 2.1 mm (25.64%) and 2.4 mm (71.8%). Smaller diameters were used in mandible. Only in 16.67% of patients was possible the transmucosal insertion. Bone density was D2 and D3 for men, and D3 and D4 for women. Immediate loading was achieved in 20.5% patients. Mini-implant supported overdenture can be an alternative to conventional denture and conventional implant overdenture. Its advantages derives from implants' characteristics (smaller diameter, variable length, O-ring retention system), which adapts better to the particular edentulous conditions. Insertion technique implies less surgical trauma. Choosing implants' size, number, topography, and the loading method have a great variety, depending on anatomical feature (bone offer, mucosa and relationship with the nearby anatomical structures), functional features and patients' wishes.


Characterization of the in vitro transcriptional activity of polymorphic alleles of the human monoamine oxidase-B gene.
The activity of monoamine oxidase-B (MAO-B) enzyme has a high degree of heritability, although no common genetic polymorphisms are present in the MAO-B coding region. The only known polymorphisms in MAO-B gene are a C-1,114T in the 5' region, a variable number of GT repeats in intron 2, and a G/A change in intron 13. The genetically determined differences in MAO-B activity among subjects most likely derive from functional differences conferred by these three MAO-B genetic polymorphisms, or by polymorphisms in trans-acting factors that regulate MAO-B expression. In order to identify differences in transcriptional activity conferred by the MAO-B genetic variants, we cloned alternative alleles at the three polymorphic loci in -1,114, intron 2 and intron 13, and tested them in transfection-luciferase assays in HepG2 hepatoma and 1321N1 astrocytoma cells. The mutant -1,114 allele T had higher activity than allele C in both cell lines, when cloned in pGL3Enhancer. Significant differences in trascriptional activity by intron 2 GT repeat allele were also observed, and varied by cell type and reporter construct. Allele G of intron 13 had significantly higher activity than allele A in both cell lines. These results indicate transcriptional activity differences between MAO-B variant alleles that are naturally occurring in the population.


A fragmented code: The moral and structural context for providing assistance with injection drug use initiation in San Diego, USA.
Injection drug use initiation is shaped by social networks and structural contexts, with people who inject drugs often assisting in this process. We sought to explore the norms and contexts linked to assisting others to initiate injection drug use in San Diego, USA, to inform the development of structural interventions to prevent this phenomenon. We undertook qualitative interviews with a purposive sample of people who inject drugs and had reported assisting others to initiate injection (n = 17) and a sub-sample of people who inject drugs (n = 4) who had not reported initiating others to triangulate accounts. We analyzed data thematically and abductively. Respondents' accounts of providing initiation assistance were consistent with themes and motives reported in other contexts: of seeking to reduce harm to the 'initiate', responding to requests for help, fostering pleasure, accessing resources, and claims that initiation assistance was unintentional. We developed analysis of these themes to explore initiation assistance as governed by a 'moral code'. We delineate a fragmented moral code which includes a range of meanings and social contexts that shape initiation assistance. We also show how assistance is happening within a structural context that limits discussion of injection drug use, reflecting a prevailing silence on drug use linked to stigma and criminalization. In San Diego, the assistance of others to initiate injection drug use is governed by a fragmented moral code situated within particular social norms and contexts. Interventions that address the social and structural conditions shaped by and shaping this code may be beneficial, in tandem with efforts to support safe injection and the reduction of injection-related harms.


De novo generation of white adipocytes from the myeloid lineage via mesenchymal intermediates is age, adipose depot, and gender specific.
It is generally assumed that white adipocytes arise from resident adipose tissue mesenchymal progenitor cells. We challenge this paradigm by defining a hematopoietic origin for both the de novo development of a subset of white adipocytes in adults and a previously uncharacterized adipose tissue resident mesenchymal progenitor population. Lineage and cytogenetic analysis revealed that bone marrow progenitor (BMP)-derived adipocytes and adipocyte progenitors arise from hematopoietic cells via the myeloid lineage in the absence of cell fusion. Global gene expression analysis indicated that the BMP-derived fat cells are bona fide adipocytes but differ from conventional white or brown adipocytes in decreased expression of genes involved in mitochondrial biogenesis and lipid oxidation, and increased inflammatory gene expression. The BMP-derived adipocytes accumulate with age, occur in higher numbers in visceral than in subcutaneous fat, and in female versus male mice. BMP-derived adipocytes may, therefore, account in part for adipose depot heterogeneity and detrimental changes in adipose metabolism and inflammation with aging and adiposity.


The effect of edothelium on the response to propofol on bovine coronary artery rings.
In this study, the effect of propofol on isolated bovine coronary artery tone was studied in artery rings precontracted with PGF2a. Propofol, in concentrations of 10-6-10-5 M did not change vascular smooth muscle tone, but at high concentrations (10-4-10-1 M) produced relaxation in rings with intact endothelium. In rings denuded of endothelium or treated with methylene blue, propofol produced relaxation at 10-3-10-1 M concentrations, but there was a significant decrease in relaxation compared to endothelium intact rings. In the presence of a calcium agonist (Bay K 8644; 10-5 M), propofol produced constriction in rings denuded of endothelium. These results suggest that high concentrations of propofol may have vasorelaxant effect on bovine coronary artery and that these effects may be due to actions on the endothelium and mediated by calcium channels.


Identification and repair of intraoperative cerebrospinal fluid leaks in endonasal transsphenoidal pituitary surgery: surgical experience in a series of 1002 patients.
OBJECTIVE Cerebrospinal fluid (CSF) rhinorrhea is among the most common complications following transsphenoidal surgery for sellar region lesions. The aim of this study was to review the authors' institutional experience in identifying, repairing, and treating CSF leaks associated with direct endonasal transsphenoidal operations. METHODS The authors performed a retrospective review of cases involving surgical treatment of pituitary adenomas and other sellar lesions at the University of Southern California between December 1995 and March 2016. Inclusion criteria included all pathology of the sellar region approached via a direct microscopic or endoscopic endonasal transsphenoidal approach. Demographics, pathology, intraoperative and postoperative CSF leak rates, and other complications were recorded and analyzed. A literature review of the incidence of CSF leaks associated with the direct endonasal transsphenoidal approach to pituitary lesions was conducted. RESULTS A total of 1002 patients met the inclusion criteria and their cases were subsequently analyzed. Preoperative diagnoses included pituitary adenomas in 855 cases (85.4%), Rathke's cleft cyst in 94 (9.4%), and other sellar lesions in 53 (5.2%). Lesions with a diameter ≥ 1 cm made up 49% of the series. Intraoperative repair of an identified CSF leak was performed in 375 cases (37.4%) using autologous fat, fascia, or both. An additional 92 patients (9.2%) underwent empirical sellar reconstruction without evidence of an intraoperative CSF leak. Postoperative CSF leaks developed in 26 patients (2.6%), including 13 (1.3% of the overall group) in whom no intraoperative leak was identified. Among the 26 patients who developed a postoperative CSF leak, 13 were noted to have intraoperative leak and underwent sellar repair while the remaining 13 did not have an intraoperative leak or sellar repair. No patients who underwent empirical sellar repair without an intraoperative leak developed a postoperative leak. Eight patients underwent additional surgery (0.8% reoperation rate) for CSF leak repair, and 18 were successfully treated with lumbar drainage or lumbar puncture alone. The incidence of postoperative CSF rhinorrhea in this series was compared with that in 11 other reported series that met inclusion criteria, with incidence rates ranging between 0.6% and 12.1%. CONCLUSIONS In this large series, half of the patients who developed postoperative CSF rhinorrhea had no evidence of intraoperative CSF leakage. Unidentified intraoperative CSF leaks and/or delayed development of CSF fistulas are equally important sources of postoperative CSF rhinorrhea as the lack of employing effective CSF leak repair methods. Empirical sellar reconstruction in the absence of an intraoperative CSF leak may be of benefit following resection of large tumors, especially if the arachnoid is thinned out and herniates into the sella.


Evaluation of High-Sensitivity Cardiac Troponin T Levels in Japanese Patients Recently Recovered From Coronavirus Disease 2019.
Several studies have reported elevated troponin levels in coronavirus disease 2019 (COVID-19) patients, so we investigated myocardial damage by measuring high-sensitivity troponin T (hsTnT) levels and analyzed the relationship with comorbidities.Methods and Results:Of 209 patients who recently recovered from COVID-19, 65% had an elevated hsTnT level that was higher than levels in patients with acute phase infection despite most patients (79%) having a mild illness. The hsTnT levels correlated with disease severity, sex, comorbidities, and ACEi and ARB use. Myocardial damage occurs in the recovery phase of COVID-19, and its evaluation, regardless of patient age, should be considered.


Over-the-counter delta5 anabolic steroids 5-androsen-3,17-dione; 5-androsten-3beta, 17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione: excretion studies in men.
Studies of urinary steroids were performed in males after oral administration of 5-androsten-3,17-dione; 5-androsten-3beta,17beta-diol; dehydroepiandrosterone; and 19-nor-5-androsten-3,17-dione. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol; and dehydroepiandrosterone amplify most endogenous steroids, but to a lesser extent than their delta4 analogues do. Especially affected are androsterone, etiocholanolone, dehydroandrosterone, dehydroepiandrosterone, and isomeric 5-androstendiols. 5-Androsten-3,17-dione; 5-androsten-3beta,17beta-diol; and dehydroepiandrosterone elevate the urinary testosterone to epitestosterone (T/E) ratio by a factor of 2-3 a few hours after administration. This may cause a positive T/E test (> 6) for individuals with normal T/E ratios higher than 2. Most of the steroids return to their original concentrations in less than 24 h. Etiocholanolone and 5beta-androstan-3alpha,17beta-diol remain elevated for several days. A reduced androsterone to etiocholanolone (A/E) ratio may be an indication of delta5 steroids abuse. 19-Nor-5-androsten-3,17-dione has a similar effect, except that all metabolites in urine are 19-nor exogenous steroids. Identification criteria for 19-nor-5-androsten-3,17-dione may be the same as nandrolone, that is, detection of 19-norandrosterone and 19-noretiocholanolone. Specific abundant metabolites of 19-nor-5-androsten-3,17-dione are 19-nordehydroandrosterone and 19-nordehydroepiandrosterone. In the later stages of excretion, higher concentration of 1 9-noreticholanolone relative to 19-norandrosterone specifically indicates administration of 19-nor delta5 steroids.


A Balanced Investment Portfolio For Equitable Health And Well-Being Is An Imperative, And Within Reach.
Health investments, defined as formal expenditures to either produce or care for health, in the US are extremely inefficient and have yet to unlock the country's full potential for equitable health and well-being. A major reason for such poor performance is that the US health investment portfolio is out of balance, with too much spent on certain aspects of health care and not enough spent to ensure social, economic, and environmental conditions that are vital to maintaining health and well-being. This commentary summarizes the evidence for this assertion, along with the opportunities and challenges involved in rebalancing investments in ways that would improve overall population health, reduce health gaps, and help build a culture of health for all Americans.


Spatiotemporal regulation of ATP and Ca2+ dynamics in vertebrate rod and cone ribbon synapses.
In conventional neurons, Ca2+ enters presynaptic terminals during an action potential and its increased local concentration triggers transient exocytosis. In contrast, vertebrate photoreceptors are nonspiking neurons that maintain sustained depolarization and neurotransmitter release from ribbon synapses in darkness and produce light-dependent graded hyperpolarizing responses. Rods transmit single photon responses with high fidelity, whereas cones are less sensitive and exhibit faster response kinetics. These differences are likely due to variations in presynaptic Ca2+ dynamics. Metabolic coupling and cross-talk between mitochondria, endoplasmic reticulum (ER), plasma membrane Ca2+ ATPase (PMCA), and Na+-Ca2+ exchanger (NCX) coordinately control presynaptic ATP production and Ca2+ dynamics. The goal of our structural and functional studies was to determine the spatiotemporal regulation of ATP and Ca2+ dynamics in rod spherules and cone pedicles. Central retina tissue from C57BL/6 mice was used. Laser scanning confocal microscopy (LSCM) experiments were conducted on fixed-frozen vertical sections. Primary antibodies were selected for their tissue/cellular specificity and ability to recognize single, multiple or all splice variants of selected isoforms. Electron microscopy (EM) and 3-D electron tomography (ET) studies used our standard procedures on thin- and thick-sectioned retinas, respectively. Calibrated fluo-3-Ca2+ imaging experiments of dark- and light-adapted rod and cone terminals in retinal slices were conducted. Confocal microscopy showed that mitochondria, ER, PMCA, and NCX1 exhibited distinct retinal lamination patterns and differential distribution in photoreceptor synapses. Antibodies for three distinct mitochondrial compartments differentially labeled retinal areas with high metabolic demand: rod and cone inner segments, previously undescribed cone juxtanuclear mitochondria and the two plexiform layers. Rod spherule membranes uniformly and intensely stained for PMCA, whereas the larger cone pedicles preferentially stained for NCX1 at their active zones and PMCA near their mitochondria. EM and ET revealed that mitochondria in rod spherules and cone pedicles differed markedly in their number, location, size, volume, and total cristae surface area, and cristae junction diameter. Rod spherules had one large ovoid mitochondrion located near its active zone, whereas cone pedicles averaged five medium-sized mitochondria clustered far from their active zones. Most spherules had one ribbon synapse, whereas pedicles contained numerous ribbon synapses. Fluo-3 imaging studies revealed that during darkness rod spherules maintained a lower [Ca2+] than cone pedicles, whereas during light adaptation pedicles rapidly lowered their [Ca2+] below that observed in spherules. These findings indicate that ATP demand and mitochondrial ATP production are greater in cone pedicles than rod spherules. Rod spherules employ high affinity/low turnover PMCA and their mitochondrion to maintain a relatively low [Ca2+] in darkness, which increases their sensitivity and signal-to-noise ratio. In contrast, cone pedicles utilize low affinity/high turnover NCX to rapidly lower their high [Ca2+] during light adaptation, which increases their response kinetics. Spatiotemporal fluo-3-Ca2+ imaging results support our immunocytochemical results. The clustering of cone pedicle mitochondria likely provides increased protection from Ca2+ overload and permeability transition. In summary, these novel studies reveal that several integrated cellular and subcellular components interact to regulate ATP and Ca2+ dynamics in rod and cone synaptic terminals. These results should provide a greater understanding of in vivo photoreceptor synaptic terminal exocytosis/endocytosis, Ca2+ overload and therapies for retinal degenerations.


Analysis of FIM instrument scores for patients admitted to an inpatient cardiac rehabilitation program.
To evaluate in an inpatient cardiac rehabilitation program (a phase IB) whether length of stay (LOS), discharge to home, and improvement in physical function differed between patients with lower and higher degrees of functional independence on admission. A retrospective study. A public acute long-term care hospital. All cardiac rehabilitation patients (N = 143) admitted to the hospital from January 1998 through June 1999. Patients were divided into a higher- and a lower-functioning group by using the admission FIM instrument scores above and below the midpoint of 72. Comparisons in LOS, discharge disposition, and functional gains between these 2 groups were then performed. Not applicable. FIM scores, FIM change, FIM gains per week, LOS, and discharge disposition. Total FIM scores at discharge were significantly higher than those on admission (25%, P <.0001). The median value of total FIM gains per week was 7.78 with a stay of 17 days and a home discharge rate of 76%. The higher-functioning group (n = 106) differed from the lower group (n = 37) with shorter stay (15 vs 23d, P <.0001), greater FIM gains per week (8.6 vs 4.8, P =.002), and greater likelihood of discharge to home or community (84% vs 54%, P <.001). The average incremental FIM change in each group was the same. In multivariate analysis, both admission (P =.001) and discharge (P <.001) FIM scores were the best predictors of patients' discharge disposition to home. Admission FIM scores are important predictors for the clinical course and discharge outcomes of cardiac rehabilitation patients, with those with higher admission FIM scores having a shorter LOS and greater likelihood of discharge to home. The admission FIM scores can help to establish realistic goals.


The Boston keratoprosthesis in 2 patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
To report the results of Boston keratoprosthesis in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Case 1 is a 36-year-old woman with APECED and ocular history of corneal ulcers in both eyes who presented with severe dry eyes. Her ocular examination showed diffuse corneal vascularization and stromal scarring in the left eye. She underwent Boston type 1 keratoprosthesis, cataract extraction, and sulcus intraocular lens implant in the left eye to improve visual acuity. Case 2 is a 49-year-old man with possible APECED and ocular history of phlyctenular keratitis, recurrent corneal erosions, and scarring presented with dense corneal vascularization and scarring in both eyes. He underwent a Boston type 1 keratoprosthesis, clear lens extraction, and posterior chamber intraocular lens implant in the right eye. The surgeries were uneventful. On postoperative day 1, visual acuity of 20/40 was achieved in both patients and it remained stable during the 2-year follow-up period. There were no postoperative complications seen in either patient. APECED is a rare disorder, which can be associated with bilateral keratitis or diffuse corneal vascularization in addition to systemic findings and ectodermal signs. The Boston type 1 keratoprosthesis is a promising treatment option to improve visual acuity in patients with APECED with corneal involvement.


Microfluidic applications on circulating tumor cell isolation and biomimicking of cancer metastasis.
The prognosis of malignant tumors is challenged by insufficient means to effectively detect tumors at early stage. Liquid biopsy using circulating tumor cells (CTCs) as biomarkers demonstrates a promising solution to tackle the challenge, because CTCs play a critical role in cancer metastatic process via intravasation, circulation, extravasation, and formation of secondary tumor. However, the effectiveness of the solution is compromised by rarity, heterogeneity, and vulnerability associated with CTCs. Among a plethora of novel approaches for CTC isolation and enrichment, microfluidics leads to isolation and detection of CTCs in a cost-effective and operation-friendly way. Development of microfluidics also makes it feasible to model the cancer metastasis in vitro using a microfluidic system to mimick the in vivo microenvironment, thereby enabling analysis and monitor of tumor metastasis. This paper aims to review the latest advances for exploring the dual-roles microfluidics has played in early cancer diagnosis via CTC isolation and investigating the role of CTCs in cancer metastasis; the merits and drawbacks for dominating microfluidics-based CTC isolation methods are discussed; biomimicking cancer metastasis using microfluidics are presented with example applications on modelling of tumor microenvironment, tumor cell dissemination, tumor migration, and tumor angiogenesis. The future perspectives and challenges are discussed.


Transformation of human cathelicidin LL-37 into selective, stable, and potent antimicrobial compounds.
This Letter reports a family of novel antimicrobial compounds obtained by combining peptide library screening with structure-based design. Library screening led to the identification of a human LL-37 peptide resistant to chymotrypsin. This d-amino-acid-containing peptide template was active against Escherichia coli but not methicillin-resistant Staphylococcus aureus (MRSA). It possesses a unique nonclassic amphipathic structure with hydrophobic defects. By repairing the hydrophobic defects, the peptide (17BIPHE2) gained activity against the ESKAPE pathogens, including Enterococcus faecium, S. aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species. In vitro, 17BIPHE2 could disrupt bacterial membranes and bind to DNA. In vivo, the peptide prevented staphylococcal biofilm formation in a mouse model of catheter-associated infection. Meanwhile, it boosted the innate immune response to further combat the infection. Because these peptides are potent, cell-selective, and stable to several proteases, they may be utilized to combat one or more ESKAPE pathogens.


Suicide in Elementary School-Aged Children and Early Adolescents.
Suicide in elementary school-aged children is not well studied, despite a recent increase in the suicide rate among US black children. The objectives of this study were to describe characteristics and precipitating circumstances of suicide in elementary school-aged children relative to early adolescent decedents and identify potential within-group racial differences. We analyzed National Violent Death Reporting System (NVDRS) surveillance data capturing suicide deaths from 2003 to 2012 for 17 US states. Participants included all suicide decedents aged 5 to 14 years (N = 693). Age group comparisons (5-11 years and 12-14 years) were conducted by using the χ2 test or Fisher's exact test, as appropriate. Compared with early adolescents who died by suicide, children who died by suicide were more commonly male, black, died by hanging/strangulation/suffocation, and died at home. Children who died by suicide more often experienced relationship problems with family members/friends (60.3% vs 46.0%; P = .02) and less often experienced boyfriend/girlfriend problems (0% vs 16.0%; P < .001) or left a suicide note (7.7% vs 30.2%; P < .001). Among suicide decedents with known mental health problems (n = 210), childhood decedents more often experienced attention-deficit disorder with or without hyperactivity (59.3% vs 29.0%; P = .002) and less often experienced depression/dysthymia (33.3% vs 65.6%; P = .001) compared with early adolescent decedents. These findings raise questions about impulsive responding to psychosocial adversity in younger suicide decedents, and they suggest a need for both common and developmentally-specific suicide prevention strategies during the elementary school-aged and early adolescent years. Further research should investigate factors associated with the recent increase in suicide rates among black children.


The Impact of Hypertension and Use of Calcium Channel Blockers on Tuberculosis Treatment Outcomes.
Hypertension induces systemic inflammation, but its impact on the outcome of infectious diseases like tuberculosis (TB) is unknown. Calcium channel blockers (CCB) improve TB treatment outcomes in preclinical models, but their effect in patients with TB remain unclear. This retrospective cohort study, including all patients > 18 years receiving treatment for culture-confirmed, drug-sensitive TB from 2000 to 2016 at the National Taiwan University Hospital, assessed the association of hypertension and CCB use with all-cause and infection-related mortality during the first 9 months of TB treatment, as well as sputum smear microscopy and sputum culture positivity at 2 and 6 months. Of the 2894 patients, 1052 (36.4%) had hypertension. A multivariable analysis revealed that hypertension was associated with increased mortality due to all causes (hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.23-1.99) and infections (HR, 1.87; 95% CI, 1.34-2.6), but there were no statistical differences in microbiological outcomes when stratified based on hypertensive group. Dihydropyridine-CCB (DHP-CCB) use was associated only with reduced all-cause mortality (HR, 0.67; 95% CI, .45-.98) by univariable Cox regression. There were no associations between DHP-CCB use and infection-related mortality (HR, 0.78; 95% CI, .46-1.34) or microbiological outcomes in univariable or multivariable regression analyses. Patients with hypertension have increased all-cause mortality and infection-related mortality during the 9 months following TB treatment initiation. DHP-CCB use may lower all-cause mortality in TB patients with hypertension. The presence of hypertension or the use of CCB did not result in a significant change in microbiological outcomes.


The biological features and prognosis of breast cancer diagnosed during pregnancy: a case-control study.
Breast cancer during pregnancy (BCP) is relatively rare and is associated with controversies about its biology and prognosis. Hence, we designed a case-control study to examine tumor features and outcome in a series of BCP patients diagnosed and treated in a single institution. We identified 65 patients diagnosed with BCP and for each; we selected two non-pregnant breast cancer patients, who were matched for age, year of surgery, stage, and neoadjuvant chemotherapy. We then compared the differences in pathology, immunohistochemical features (ER, PR, HER2 and ki-67), disease-free (DFS) and overall survival (OS). We did not find any significant differences in tumor characteristics between the two groups. However, at a median follow-up of four years, BCP patients had an inferior DFS (HR 2.3; 95% CI 1.3-4.2), after adjustment for possible confounding covariates. No difference in OS was observed. However, upon restricting the analysis to patients who did not receive neoadjuvant chemotherapy, patients with BCP had inferior OS as well (HR 2.6; 95% CI 1.0-6.5). No association between induction of abortion and prognosis was observed. While we did not observe any differences in tumor features, BCP patients have poorer prognosis compared to age and stage-matched control. Further studies should try to elucidate reasons for such poor outcome.


[Mechanism of action of piracetam on cerebral circulation].
The experimental data show that piracetam exerts a marked effect on cerebral hemodynamics producing a lowering of cerebral artery tonus and an increase of local blood flow. In addition, an increase of GABA content is noted, particularly following an experimentally-induced disorder of cerebral blood circulation. A stable dilatation of the mean capillary diameter, a decrease of the number of non-functioning capillaries in the brain cortex after piracetam administration indicate an important role of piracetam as a cyclic analogue of GABA in regulation and compensation of disordered cerebral hemodynamics.


Automated Glycan Sequencing from Tandem Mass Spectra of N-Linked Glycopeptides.
Mass spectrometry has become a routine experimental tool for proteomic biomarker analysis of human blood samples, partly due to the large availability of informatics tools. As one of the most common protein post-translational modifications (PTMs) in mammals, protein glycosylation has been observed to alter in multiple human diseases and thus may potentially be candidate markers of disease progression. While mass spectrometry instrumentation has seen advancements in capabilities, discovering glycosylation-related markers using existing software is currently not straightforward. Complete characterization of protein glycosylation requires the identification of intact glycopeptides in samples, including identification of the modification site as well as the structure of the attached glycans. In this paper, we present GlycoSeq, an open-source software tool that implements a heuristic iterated glycan sequencing algorithm coupled with prior knowledge for automated elucidation of the glycan structure within a glycopeptide from its collision-induced dissociation tandem mass spectrum. GlycoSeq employs rules of glycosidic linkage as defined by glycan synthetic pathways to eliminate improbable glycan structures and build reasonable glycan trees. We tested the tool on two sets of tandem mass spectra of N-linked glycopeptides cell lines acquired from breast cancer patients. After employing enzymatic specificity within the N-linked glycan synthetic pathway, the sequencing results of GlycoSeq were highly consistent with the manually curated glycan structures. Hence, GlycoSeq is ready to be used for the characterization of glycan structures in glycopeptides from MS/MS analysis. GlycoSeq is released as open source software at https://github.com/chpaul/GlycoSeq/ .


Natural history of a bighorn sheep pneumonia epizootic: Source of infection, course of disease, and pathogen clearance.
A respiratory disease epizootic at the National Bison Range (NBR) in Montana in 2016-2017 caused an 85% decline in the bighorn sheep population, documented by observations of its unmarked but individually identifiable members, the subjects of an ongoing long-term study. The index case was likely one of a small group of young bighorn sheep on a short-term exploratory foray in early summer of 2016. Disease subsequently spread through the population, with peak mortality in September and October and continuing signs of respiratory disease and sporadic mortality of all age classes through early July 2017. Body condition scores and clinical signs suggested that the disease affected ewe groups before rams, although by the end of the epizootic, ram mortality (90% of 71) exceeded ewe mortality (79% of 84). Microbiological sampling 10 years to 3 months prior to the epizootic had documented no evidence of infection or exposure to Mycoplasma ovipneumoniae at NBR, but during the epizootic, a single genetic strain of M. ovipneumoniae was detected in affected animals. Retrospective screening of domestic sheep flocks near the NBR identified the same genetic strain in one flock, presumptively the source of the epizootic infection. Evidence of fatal lamb pneumonia was observed during the first two lambing seasons following the epizootic but was absent during the third season following the death of the last identified M. ovipneumoniae carrier ewe. Monitoring of life-history traits prior to the epizootic provided no evidence that environmentally and/or demographically induced nutritional or other stress contributed to the epizootic. Furthermore, the epizootic occurred despite proactive management actions undertaken to reduce risk of disease and increase resilience in this population. This closely observed bighorn sheep epizootic uniquely illustrates the natural history of the disease including the (presumptive) source of spillover, course, severity, and eventual pathogen clearance.


Oncogenic Roles Of A Histone Methyltransferase SETDB2 In AML1-ETO Positive AML.
AML1-ETO produced by t(8;21) abnomality has multiple effects on the leukemogenesis of acute myeloid leukemia (AML). SET domain, bifurcated 2 (SETDB2) can mediate gene silencing by trimethylation of the ninth lysine residue of histone H3 protein (H3K9) of the promoter and has been confirmed as an oncogene in many cancers. The role of SETDB2 in AML1-ETO positive AML is not clear. Quantitative reverse transcription PCR was performed to measure SETDB2 expression in bone marrow from AML patients and healthy people. Kaplan-Meier analysis was performed to investigate the effect of SETDB2 on prognosis of AML patients. Dual luciferase reporter gene assay, chromatin immunoprecipitation were performed to investigate the regulatory mechanism of AML1-ETO on SETDB2. CCK-8 and colony formation assay were performed to measure the effect of SETDB2 on leukemic cells. SETDB2 is highly expressed in AML1-ETO positive AML. The overall survival, event-free and relapse-free survival rate of patients with high SETDB2 expression was lower than those of patients with low SETDB2 expression. SETDB2 is epigenetically upregulated by AML1-ETO fusion protein. Downregulation of SETDB2 expression significantly inhibits the proliferation and clonality of leukemic cells and promotes the sensitivity of leukemic cells to an epigenetic inhibitor JQ1. AML1-ETO/SETDB2 is a novel epigenetic pathway of leukemogenesis and SETDB2 is a potential therapeutic target of t(8;21) AML.


Posttrabeculectomy endophthalmitis caused by Moraxella nonliquefaciens.
Moraxella nonliquefaciens, a commensal organism of the upper respiratory tract, is generally considered to have low pathogenic potential. We report here two cases of severe endophthalmitis occurring 9 years and 2 months after glaucoma filtration surgery, respectively. Apart from sulfonamide, very low MICs were recorded for several antibiotics tested. Identification was based on phenotypic characteristics in combination with sequencing of the 16S rRNA gene.


Recognition of lipopeptides by Toll-like receptors.
Toll-like receptors (TLRs) recognize specific molecular patterns present only in micro-organisms and thereby activate innate immune cells. TLR2 is essential for the recognition of peptidoglycan and lipoprotein/lipopeptides. Lipoprotein/lipopeptides are observed in cell walls of a variety of micro-organisms. Host immune cells recognize the specific patterns of lipoprotein/lipopeptides through the association of TLR2 with other TLRs. TLR1 and TLR6 are highly homologous to TLR2 in structure. TLR6-deficient mice showed an impaired response to mycoplasmal lipopeptides that are diacylated, whereas TLR1-deficient mice were defective in their response to bacterial lipopeptides that are triacylated. TLR2-deficient mice did not show any inflammatory response to either type of lipopeptide. The functional association of TLR2 with TLR1 or TLR6 has been demonstrated. Thus, TLR1 and TLR6 are involved in the discrimination of a subtle difference between triacyl and diacyl lipopeptides through interaction with TLR2.


Beta-endorphin, Met-enkephalin and corresponding opioid receptors within synovium of patients with joint trauma, osteoarthritis and rheumatoid arthritis.
Intra-articularly applied opioid agonists or antagonists modulate pain after knee surgery and in chronic arthritis. Therefore, the expression of beta-endorphin (END), Met-enkephalin (ENK), and mu and delta opioid receptors (ORs) within synovium of patients with joint trauma (JT), osteoarthritis (OA) and rheumatoid arthritis (RA) were examined. Synovial samples were subjected to double immunohistochemical analysis of opioid peptides with immune cell markers, and of ORs with the neuronal markers calcitonin gene-related peptide (CGRP) and tyrosine hydroxylase (TH). END and ENK were expressed by macrophage-like (CD68(+)) and fibroblast-like (CD68(-)) cells within synovial lining layers of all disorders. In the sublining layers, END and ENK were mostly expressed by granulocytes in patients with JT, and by macrophages/monocytes, lymphocytes and plasma cells in those with OA and RA. Overall, END- and ENK-immunoreactive (IR) cells were more abundant in patients with RA than in those with OA and JT. ORs were found on nerve fibres and immune cells in all patients. OR-IR nerve fibres were significantly more abundant in patients with RA than in those with OA and JT. muORs and deltaORs were coexpressed with CGRP but not with TH. Parallel to the severity of inflammation, END and ENK in immune cells and their receptors on sensory nerve terminals are more abundant in patients with RA than in those with JT and OA. These findings are consistent with the notion that, with prolonged and enhanced inflammation, the immune and peripheral nervous systems upregulate sensory nerves expressing ORs and their ligands to counterbalance pain and inflammation.


Cost containment and the physician.
The rapid rise in health care costs is receiving a good deal of attention these days. Proposed responses include the deliberate rationing of expensive medical technologies, such as organ transplantation, and a redirection of our efforts toward preventive care. Although preventive care may improve our health, it cannot be assumed to reduce medical costs, since a later death may be as expensive as an earlier one. I suggest that a major and rapidly growing component of medical costs stems from the widespread application of tests and procedures when they are of no demonstrated benefit and may even be harmful. Identifying and curtailing such unnecessary medical care, rather than rationing beneficial technologies, should be the thrust of cost-containment efforts. Fee schedules should be revised so that they neither encourage nor discourage the use of tests and procedures; we should undertake systematic studies to assess technologies and practices; and we should make every effort to discourage the practice of defensive medicine. The involvement of physicians in rationing is not only premature; it is also inconsistent with our role as advocates for the health of our patients.


The yeast spindle pole body component Spc72p interacts with Stu2p and is required for proper microtubule assembly.
We have previously shown that Stu2p is a microtubule-binding protein and a component of the Saccharomyces cerevisiae spindle pole body (SPB). Here we report the identification of Spc72p, a protein that interacts with Stu2p. Stu2p and Spc72p associate in the two-hybrid system and can be coimmunoprecipitated from yeast extracts. Stu2p and Spc72p also interact with themselves, suggesting the possibility of a multimeric Stu2p-Spc72p complex. Spc72p is an essential component of the SPB and is able to associate with a preexisting SPB, indicating that there is a dynamic exchange between soluble and SPB forms of Spc72p. Unlike Stu2p, Spc72p does not bind microtubules in vitro, and was not observed to localize along microtubules in vivo. A temperature-sensitive spc72 mutation causes defects in SPB morphology. In addition, most spc72 mutant cells lack cytoplasmic microtubules; the few cytoplasmic microtubules that are observed are excessively long, and some of these are unattached to the SPB. spc72 cells are able to duplicate and separate their SPBs to form a bipolar spindle, but spindle elongation and chromosome segregation rarely occur. The chromosome segregation block does not arrest the cell cycle; instead, spc72 cells undergo cytokinesis, producing aploid cells and polyploid cells that contain multiple SPBs.


Epithelial cells and fibroblasts.
Chronic obstructive pulmonary disease (COPD) is characterized by acute and chronic alterations in the cellular composition structure of the airways and alveoli. Much attention has been focused on the increase in inflammatory cells present both within the airway lumen and within the airway wall. The parenchymal cells of the airway are intimately involved in the recruitment and activation of these inflammatory cells. Conversely, the behaviour of parenchymal cells can be modulated by inflammatory cells. The parenchymal cells can also alter the structural elements present within the airway leading to architecture changes which can impair lung function. Finally, epithelial cells and fibroblasts can directly modify each other's behaviour. The activity of these cells, therefore, undoubtedly can play a variety of roles in the pathophysiologic processes which underlie COPD.


Effectiveness of clinical Pilates and home exercises in sagittal cervical disorientation: randomized controlled study.
Aim: To compare effects of clinical Pilates and home exercises on postural disorders, strength and endurance of deep cervical flexors (DCF), cervical range of motion (CROM), pain intensity and functional disability in sagittal cervical disorientation. Patients & methods: Fourty six patients were included and divided into two groups. Clinical Pilates group performed stabilization based exercise and home exercise group performed conventional exercises. Results: Craniovertebral, head tilt, cervicothoracic angles and strength and endurance of DCF muscles had improvement in favor of clinical Pilates group (p < 0.05). There was no difference between groups in terms of right-left acromial distance, pain intensity, functional disability and CROM parameters (p > 0.05). Conclusion: Clinical Pilates exercises have been found to provide clinically significant improvements in craniovertebral, head tilt, cervicothoracic angles and strength and endurance of DCF muscles. However, in the increase of CROM, decreasing pain severity and functional impairment parameters there was no superiority of both exercise training. Clinical trial registration number: NCT03352921 (Clinicaltrials.gov).


A new variant nummular headache: large diameter accompanied with bitrigeminal hyperalgesia and successful treatment with carbamazepine.
Nummular headache (NH) is defined as a focal head pain that is exclusively felt in a small area, which is typically 1-6 cm in diameter. Neurological examinations are normal in all patients, but this report describes a new variant. A patient was identified who presented with focal head pain that was approximately 8 cm in diameter and bitrigeminal hyperalgesia on neurological examination. Treatment with carbamazepine provided significant analgesic relief in terms of both the frequency and intensity of pain. The findings enlarge the clinical diversity of this headache disorder. The pathogenic mechanisms of NH may be similar to trigeminal neuralgia in particular patients.


Very-Low-Density Lipoprotein of Metabolic Syndrome Modulates Gap Junctions and Slows Cardiac Conduction.
Very-low-density lipoproteins (VLDL) is a hallmark of metabolic syndrome (MetS) and each manifestation of MetS is related to atrial fibrillation (AF) risks. Slowed atrial conduction is a mechanism of AF in MetS. We hypothesized that VLDL can modulate and reduce atrial gap junctions. VLDLs were separated from normal (Normal-VLDL) and MetS (MetS-VLDL) individuals. VLDLs (15 µg/g) and equivalent volumes of saline (CTL) were injected respectively to C57BL/6 mice for 6 weeks. Electrocardiograms demonstrated that MetS-VLDL induced prolongation of P wave (P = 0.041), PR intervals (P = 0.014), QRS duration and QTc interval (both P = 0.003), but Normal-VLDL did not. Optical mapping of perfused hearts confirmed slowed conduction on atria and ventricles of MetS-VLDL mice. Slowed cardiac conduction was associated with significant atrial and ventricular remodeling, along with systolic dysfunction and comparable intra-cardiac fibrosis. MetS-VLDL induced downregulation of Cx40 and Cx43 at transcriptional, translational and tissue levels, and it also enhanced O-GlcNAcylation of Cx40 and Cx43. Protein structure analyses predicted O-GlcNAcylation at serine 18 of Cx40 and Cx43 which may impair stability of gap junctions. In conclusion, MetS-VLDL modulates gap junctions and delays both atrial and ventricular conduction. VLDL may contribute to the pathophysiology of atrial fibrillation and ventricular arrhythmias in MetS.


The pretubulysin-induced exposure of collagen is caused by endothelial cell retraction that results in an increased adhesion and decreased transmigration of tumor cells.
Microtubule-targeting agents (MTAs) are the most widely used chemotherapeutic drugs. Pretubulysin (PT), a biosynthetic precursor of the myxobacterial tubulysins, was recently identified as a novel MTA. Besides its strong anti-tumoral activities, PT attenuates tumor angiogenesis, exerts anti-vascular actions on tumor vessels and decreases cancer metastasis formation in vivo. The aim of the present study was to analyze the impact of PT on the interaction of endothelial and tumor cells in vitro to gain insights into the mechanism underlying its anti-metastatic effect. The influence of PT on tumor cell adhesion and transmigration onto/through the endothelium as well as its influence on cell adhesion molecules and the chemokine system CXCL12/CXCR4 was investigated. Treatment of human endothelial cells with PT increased the adhesion of breast cancer cells to the endothelial monolayer, whereas their transmigration through the endothelium was strongly reduced. Interestingly, the PT-induced upregulation of ICAM-1, VCAM-1 and CXCL12 were dispensable for the PT-evoked tumor cell adhesion. Tumor cells preferred to adhere to collagen exposed within PT-triggered endothelial gaps via β1-integrins on the tumor cell surface. Taken together, our study provides, at least in part, an explanation for the anti-metastatic potential of PT.


Assessment of Causal Direction Between Gut Microbiota-Dependent Metabolites and Cardiometabolic Health: A Bidirectional Mendelian Randomization Analysis.
We examined the causal direction between gut microbiota-dependent metabolite trimethylamine N-oxide (TMAO) or its predecessors and cardiometabolic diseases, such as risk of type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), myocardial infarction (MI), stroke, atrial fibrillation (AF), and chronic kidney disease (CKD). We used genetic variants as instruments to test the causal associations. Genetically predicted higher TMAO and carnitine were not associated with higher odds of T2DM, AF, CAD, MI, stroke, and CKD after Bonferroni correction (P ≤ 0.0005). However, we observed that genetically increased choline showed a suggestive association with higher risk of T2DM (odds ratio 1.84 [95% CI 1.00-3.42] per 10 units, P = 0.05). In contrast, genetically predicted higher betaine (0.68 [0.48-0.95] per 10 units, P = 0.023) was suggestively associated with a lower risk of T2DM. We observed a suggestive association of genetically increased choline with a lower level of body fat percentage (β ± SE -0.28 ± 0.11, P = 0.013) but a higher estimated glomerular filtration rate (0.10 ± 0.05, P = 0.034). We further found that T2DM (0.130 ± 0.036, P < 0.0001) and CKD (0.483 ± 0.168, P = 0.004) were causally associated with higher TMAO levels. Our Mendelian randomization findings support that T2DM and kidney disease increase TMAO levels and that observational evidence for cardiovascular diseases may be due to confounding or reverse causality.


Critical role of Emx2 in the pluripotency - differentiation transition in male gonocytes via regulation of FGF9/NODAL pathway.
Emx2 deletion impairs the growth and maintenance of the genital ridge. However, its role in subsequent germ cell differentiation during embryonic stages is unknown. Using a tamoxifen-inducible Cre-loxP mouse model (Emx2(flox/flox), Cre-ER(TM), hereafter called as Emx2 knockdown), we showed that germ cell differentiation was impaired in Emx2-knockdown testes. Representative characteristics of male germ cell differentiation, including a reduced ability to form embryonic germ (EG) cell colonies in vitro, down-regulation of pluripotency markers and G1/G0 arrest, did not occur in Emx2-knockdown testes. Furthermore, FGF9 and NODAL signalling occurred at abnormally high levels in Emx2-knockdown testes. Both blocking FGF9 signalling with SU5402 and inhibiting NODAL signalling with SB431542 allowed germ cells from Emx2-knockdown testes to differentiate in vitro Therefore, EMX2 in somatic cells is required to trigger germ cell differentiation in XY foetuses, posterior to its previously reported role in the growth and maintenance of the genital ridge.


Why are young and old repetitive elements distributed differently in the human genome?
Alu elements are not distributed homogeneously throughout the human genome: old elements are preferentially found in the GC-rich parts of the genome, while young Alus are more often found in the GC-poor parts of the genome. The process giving rise to this differential distribution remains poorly understood. Here we investigate whether this pattern could be due to a preferential degradation of Alu elements integrated in GC-poor regions by small indel mutations. We aligned 5.1 Mb of human and chimpanzee sequences and examined whether the rate of insertion and deletion inside Alu elements differed according to the base composition surrounding them. We found that Alu elements are not preferentially degraded in GC-poor regions by indel events. We also looked at whether very young L1 elements show the same change in distribution compared to older ones. This analysis indicated that L1 elements also show a shift in their distribution, although we could not assess it as precisely as for Alu elements. We propose that the differential distribution of Alu elements is likely to be due to a change in their pattern of insertion or their probability of fixation through evolutionary time.


Effect of somatostatin on the growth of gastrointestinal mucosa and pancreas in rats. Role of endogenous gastrin.
This study was undertaken to determine the influence of somatostatin on the growth of gastric, duodenal, and pancreatic tissue in rats placed on liquid diet. In the first part of the study animals were fed an elemental liquid diet for 10 days and then killed, and the growth of the oxyntic gland area of the stomach, 2 cm segments of duodenum and pancreatic tissue was determined. Feeding an elemental diet caused a decrease in organ weight, nucleic acid contents and serum gastrin level. Subsequent addition of pentagastrin prevented this reduction in organ weight and RNA and DNA contents while somatostatin failed to affect the decrease in growth parameters or serum gastrin level in tests with or without addition of pentagastrin. In a second part of the study, sham operated and antrectomised rats were used. Antrectomy caused a significant decrease in serum gastrin concentration and resulted in a significant reduction in the weight and RNA and DNA contents of the tissue tested. As in liquid diet, subsequent administration of pentagastrin prevented the reduction in the growth parameters both in tests with and without somatostatin. These results suggest that somatostatin inhibits the growth of the gastroduodenal mucosa by a mechanism involving, at least in part, the suppression of gastrin release.


German validation of the conners adult ADHD rating scale-self-report: confirmation of factor structure in a large sample of participants with ADHD.
The Conners Adult ADHD Rating Scales (CAARS) assess symptoms specific to adults that are frequently used and have been translated into German. The current study tests the factor structure of the CAARS in a large sample of German adults with ADHD and compares the means of the CAARS subscales with those of healthy German controls. CAARS were completed by 466 participants with ADHD and 851 healthy control participants. Confirmatory factor analysis was used to establish model fit with the American original. Comparisons between participants with ADHD and healthy controls and influences of gender, age, and degree of education were analyzed. Confirmatory factor analysis showed a very good fit with the model for the American original. Differences between ADHD participants and healthy controls on all Conners Adult ADHD Rating Scales-Self-Report (CAARS-S) subscales were substantial and significant. The factor structure of the original American model was successfully replicated in this sample of adult German ADHD participants.


Pepsin-related molecules secreted by trophoblast.
The pregnancy-associated glycoproteins (PAGs) were first described as placental antigens of cattle that were also present in the blood serum of the mother after implantation. Molecular cloning studies have shown that they are members of the aspartic proteinase gene family and closely related to the pepsinogens. An enzymatic role seems unlikely, as at least some of them have mutations likely to render them enzymatically inactive. Nevertheless, these molecules have retained the substrate-binding cleft of the pepsins and are expressed abundantly in trophectoderm, particularly in the invasive binucleate cell component. There may be as many as 100 PAG genes in cattle and sheep, many of which are transcribed. PAGs are also products of the placenta of the pig, a species whose progenitors diverged from the ruminants at least 55 million years ago. There is even evidence for PAG-like molecules outside the Artiodactyla. Although their function remains elusive, it seems unlikely that these placentally expressed molecules are simply oddities in view of their long-term evolutionary survival and conspicuous presence at the fetal-maternal interface.


Laughing through this pain: medical clowning during examination of sexually abused children: an innovative approach.
This study examined the role of medical clowns during medical examinations of children who were sexually abused. Three case studies are described, illustrating diverse interactions among the victimized child, the medical clown, and the medical forensical examiner during medical forensic examinations held at the Tene Center for Sexually Abused Children, Poria-Pade Medical Center, Israel. The results indicated that medical clowns play a unique role both in lowering anxiety and fear among children before and during the unpleasant forensic examination as well as in mitigating potential retraumatization of the sexual abuse event resulting from the medical examination. The medical clown was found to assist in creating a pleasant and calm atmosphere, thus improving the child's cooperation during the examination.


Leaf day respiration: low CO2 flux but high significance for metabolism and carbon balance.
Contents 986 I. 987 II. 987 III. 988 IV. 991 V. 992 VI. 995 VII. 997 VIII. 998 References 998 SUMMARY: It has been 75 yr since leaf respiratory metabolism in the light (day respiration) was identified as a low-flux metabolic pathway that accompanies photosynthesis. In principle, it provides carbon backbones for nitrogen assimilation and evolves CO2 and thus impacts on plant carbon and nitrogen balances. However, for a long time, uncertainties have remained as to whether techniques used to measure day respiratory efflux were valid and whether day respiration responded to environmental gaseous conditions. In the past few years, significant advances have been made using carbon isotopes, 'omics' analyses and surveys of respiration rates in mesocosms or ecosystems. There is substantial evidence that day respiration should be viewed as a highly dynamic metabolic pathway that interacts with photosynthesis and photorespiration and responds to atmospheric CO2 mole fraction. The view of leaf day respiration as a constant and/or negligible parameter of net carbon exchange is now outdated and it should now be regarded as a central actor of plant carbon-use efficiency.


Guided self-help in primary care mental health: meta-synthesis of qualitative studies of patient experience.
There is a gap between the supply of trained cognitive-behavioural therapists to treat depression and demand for care in the community. There is interest in the potential of self-help interventions, which require less input from a therapist. However, the design of effective self-help interventions is complex. Qualitative research can help to explore some of this complexity. The study aimed to identify qualitative studies of patient experience of depression management in primary care, synthesise these studies to develop an explanatory framework, and then apply this framework to the development of a guided self-help intervention for depression. A meta-synthesis was conducted of published qualitative research. The synthesis revealed a number of themes, including the nature of personal experience in depression; help-seeking in primary care; control and helplessness in engagement with treatment; stigma associated with treatment; and patients' understandings of self-help interventions. This meta-synthesis of qualitative studies provided a useful explanatory framework for the development of effective and acceptable guided self-help interventions for depression.