Four-particle condensate in strongly coupled fermion systems

Four-particle correlations in fermion systems at finite temperatures are investigated with special attention to the formation of a condensate. Instead of the instability of the normal state with respect to the onset of pairing described by the Gorkov equation, a new equation is obtained which describes the onset of quartetting. Within a model calculation for symmetric nuclear matter, we find that below a critical density, the four-particle condensation (alpha-like quartetting) is favored over deuteron condensation (triplet pairing). This pairing-quartetting competition is expected to be a general feature of interacting fermion systems, such as the excition-biexciton system in excited semiconductors. Possible experimental consequences are pointed out.Comment: LaTeX, 11 pages, 2 figures, uses psfig.sty (included), to be published in Phys. Rev. Lett., tentatively scheduled for 13 April 1998 (Volume 80, Number 15

Need and importance of health protection training in Nepal

By investing in health protection, the health of the nation can be safeguarded from future threats of uncontrolled infectious disease epidemics and disasters

239 - What is the most effective pelvic floor muscle training type, dose, and delivery method for females with urinary incontinence? A Cochrane review with meta-analysis

Hypothesis / aims of studyWe updated the 2011 Cochrane review comparing different approaches to pelvic floor muscle training (PFMT) [1] to treat female urinary incontinence (UI) for two reasons. First, to address ongoing uncertainties as a scoping search suggested many more potentially eligible randomised controlled trials (RCTs) were published. Second, neither the previous review nor the most up-to-date alternative [2] applied ‘Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to gauge evidence certainty to underpin clinical decision-making. Therefore, we aimed to complete a systematic review and meta-analysis, using contemporary Cochrane methods, of RCTs comparing different approaches to PFMT to increase the power, accuracy, and certainty in effect estimates. We investigated differences in exercise type, dose, and intervention delivery.Study design, materials and methodsSystematic review methods were according to the Cochrane Handbook for Systematic Reviews of Interventions (version 6.4). The previous review was, as per Cochrane practice, the published protocol for the update [1].Eligible trials were RCTs (excluding cross-over RCTs) in females with UI. Trials with pregnant or postpartum participants or those with neurological conditions were excluded. To investigate different pelvic floor muscle (PFM) exercise types, eligible RCTs compared coordinated (voluntary PFM contraction with other body movement, e.g. squats), or functional (voluntary PFM contraction within activities of daily living, e.g. the Knack), or indirect (exercise to improve PFM function without voluntary PFM contraction) or combined (indirect with direct) training versus direct PFMT (repeated, isolated, voluntary PFM contractions). To investigate exercise dose, eligible trials had the same exercise type and delivery method in both trial arms but with differences in exercise dose (e.g. more versus fewer training sessions per week). For exercise intervention delivery eligible trials compared different methods of delivery/supervision (e.g. more versus less in-person clinic supervision).The Cochrane Incontinence Specialised Registry was searched on 27 September 2023, with no date or language limits. The register comprises studies identified from: the Cochrane Central Register of Controlled Trials, MEDLINE, CINAHL and handsearching. Study records were screened in Covidence. Each review stage was completed by two independent reviewers with any disagreements resolved through discussion: title and abstract screening, full text screening, data extraction onto a template revised from the previous review to include Consensus on Exercise Reporting Template PFMT (CERT-PFMT) items [3], and risk of bias (RoB) assessment using Cochrane ROB tool v1. All records were re-screened and evaluated regardless of inclusion or exclusion from the previous review. Two reviewers (JHS, MSP) cross-checked all RoB assessments, and completed the GRADE certainty of evidence ratings. Decision-rules were documented to ensure consistency.The primary outcome was incontinence or lower urinary tract symptom specific quality of life (QoL) at the primary endpoint (as defined by trialists), measured using any instrument rated A or A+ by the 7th ICI based on psychometric properties [2]. We contacted study authors if data were collected but missing, incomplete, or reported in unusable format. The secondary outcomes (incontinence episode frequency, incontinence symptom severity, patient-reported improvement, patient-reported satisfaction, and adverse events) are not reported here.A standardised mean difference (SMD) with inverse variance weighted method was used in RevMan Web 2023 for meta-analysis. Thresholds suggested by Cohen (1988) were used for interpretation: a small (> 0.2 to <0.5), moderate (> 0.5 to < 0.8), and large (> 0.8) effect. Effect sizes under 0.2 were considered unimportant even if statistically significant.Data were pooled in subgroups only; subgroups organised data by intervention and comparator. If within subgroup heterogeneity was substantial (I2 > 50%) we conducted a sensitivity analysis (low versus higher risk of selection bias, and attrition bias). If the between subgroup heterogeneity was substantial, we narratively summarised plausible explanations.ResultsAfter removing duplicates, we screened 2385 records and excluded 2172 based on title/abstract. From 213 full texts retrieved, 87 were excluded, most commonly for an ineligible comparison. The remaining full texts represented 126 trials (some with more than one full text): 64 included trials, 40 eligible ongoing trials, and 22 trials awaiting classification (i.e. missing information precludes eligibility decision). Trials included 4972 participants: previous review included 21 trials, 1490 participants [1].Sixty-one RCTs were parallel designs, and three were cluster RCTs. Sample sizes ranged from 11 to 362. Nine trials recruited > 50 participants per trial arm. The nine larger trials contained 42% of participants (2090/4972) but three of them reported no outcome of interest or usable data.No trial was conducted in a low-income country. Seven were completed in lower-middle income countries but 3 reported no outcome of interest or usable data.Overall RoB rating considered selection, attrition, reporting and other bias with five at low risk overall, six at high risk, and the remainder at unclear risk. Regarding selection and attrition bias, on which sensitivity analysis was based, there were 19 low and six high risk, and 22 low and 27 high risk trials respectively. Risk of bias rating did not consider blinding because all outcomes of interest in the review were patient-reported.UI diagnoses were stress UI (n=36), stress predominant mixed UI (n=10), stress or mixed UI (n=6), stress, urgency, or mixed UI (n=7), and undefined “urinary incontinence” (n=4). Trial participants were typically aged from 45 to 65 years and parous, with no prior incontinence treatment or pelvic surgeries, or other appreciable pelvic floor dysfunction.Trials compared exercise type (27 trials; 3 subgroups), dose (11 trials, 4 subgroups) and intervention delivery (26 trials; 5 subgroups with data, and one without any usable data). Correct voluntary PFM contraction was confirmed for all women (35 trials), in one trial arm (five trials), or not mentioned.In addition to reporting only QoL here, we do not report findings from subgroups containing a single, small trial; in those instances, the number of downgrades of evidence quality precluded a certainty of evidence statement.Summary of findings is presented in Table 1.Interpretation of resultsThe number of trials, and participants, has trebled. Progress is being made toward addressing the highest priority uncertainty in incontinence research—what is the optimal PFMT protocol—identified by Buckley and colleagues using a James Lind Alliance approach in 2010. However, the specific uncertainties they mentioned—training frequency and duration, and the optimal training for different patterns of UI—remain. Too few trials investigate exercise dose or recruit females with diagnoses other than stress or stress predominant UI.There is now some moderate certainty evidence to support clinical decisions about PFMT and its delivery in mid-age and older women. There is probably not support for indirect training approaches, alone or in combination with direct PFMT. Adding a resistance device to PFMT probably adds no benefit. There is probably no important difference in incontinence QoL outcome between individual and group supervision of PFMT; a correct contraction was confirmed prior to group supervision in 3 of 6 trials (209/280 women, 75%). Using e-health for delivery of PFMT is probably better than written instructions only.To increase evidence certainty for clinical decision-making, in addition to the usual improvements in trial size, methods and reporting, we need to address important uncertainties such as those identified by Buckley and colleagues.Concluding messageOf the many methods of training that appear to be used in practice, direct PFMT is probably the intervention of choice. In-person supervision can probably be offered individually or in groups after confirmation of a correct PFM contraction. If supervision is not-in-person then e-health is probably better than written instruction.Funding None Clinical Trial No Subjects Non

Non-Coding Keratin Variants Associate with Liver Fibrosis Progression in Patients with Hemochromatosis

Background: Keratins 8 and 18 (K8/K18) are intermediate filament proteins that protect the liver from various forms of injury. Exonic K8/K18 variants associate with adverse outcome in acute liver failure and with liver fibrosis progression in patients with chronic hepatitis C infection or primary biliary cirrhosis. Given the association of K8/K18 variants with endstage liver disease and progression in several chronic liver disorders, we studied the importance of keratin variants in patients with hemochromatosis. Methods: The entire K8/K18 exonic regions were analyzed in 162 hemochromatosis patients carrying homozygous C282Y HFE (hemochromatosis gene) mutations. 234 liver-healthy subjects were used as controls. Exonic regions were PCRamplified and analyzed using denaturing high-performance liquid chromatography and DNA sequencing. Previouslygenerated transgenic mice overexpressing K8 G62C were studied for their susceptibility to iron overload. Susceptibility to iron toxicity of primary hepatocytes that express K8 wild-type and G62C was also assessed. Results: We identified amino-acid-altering keratin heterozygous variants in 10 of 162 hemochromatosis patients (6.2%) and non-coding heterozygous variants in 6 additional patients (3.7%). Two novel K8 variants (Q169E/R275W) were found. K8 R341H was the most common amino-acid altering variant (4 patients), and exclusively associated with an intronic KRT8 IVS7+10delC deletion. Intronic, but not amino-acid-altering variants associated with the development of liver fibrosis. I

MicroRNA-155 Deficiency Attenuates Liver Steatosis and Fibrosis without Reducing Inflammation in a Mouse Model of Steatohepatitis

BACKGROUND & AIM: MicroRNAs (miRs) regulate hepatic steatosis, inflammation and fibrosis. Fibrosis is the consequence of chronic tissue damage and inflammation. We hypothesized that deficiency of miR-155, a master regulator of inflammation, attenuates steatohepatitis and fibrosis. METHODS: Wild type (WT) and miR-155-deficient (KO) mice were fed methionine-choline-deficient (MCD) or -supplemented (MCS) control diet for 5 weeks. Liver injury, inflammation, steatosis and fibrosis were assessed. RESULTS: MCD diet resulted in steatohepatitis and increased miR-155 expression in total liver, hepatocytes and Kupffer cells. Steatosis and expression of genes involved in fatty acid metabolism were attenuated in miR-155 KO mice after MCD feeding. In contrast, miR-155 deficiency failed to attenuate inflammatory cell infiltration, nuclear factor kappa beta (NF-kappaB) activation and enhanced the expression of the pro-inflammatory cytokines tumor necrosis factor alpha (TNFalpha) and monocyte chemoattractant protein-1 (MCP1) in MCD diet-fed mice. We found a significant attenuation of apoptosis (cleaved caspase-3) and reduction in collagen and alpha smooth muscle actin (alphaSMA) levels in miR-155 KO mice compared to WTs on MCD diet. In addition, we found attenuation of platelet derived growth factor (PDGF), a pro-fibrotic cytokine; SMAD family member 3 (Smad3), a protein involved in transforming growth factor-beta (TGFbeta) signal transduction and vimentin, a mesenchymal marker and indirect indicator of epithelial-to-mesenchymal transition (EMT) in miR-155 KO mice. Nuclear binding of CCAAT enhancer binding protein beta (C/EBPbeta) a miR-155 target involved in EMT was significantly increased in miR-155 KO compared to WT mice. CONCLUSIONS: Our novel data demonstrate that miR-155 deficiency can reduce steatosis and fibrosis without decreasing inflammation in steatohepatitis

The SV40 Late Protein VP4 Is a Viroporin that Forms Pores to Disrupt Membranes for Viral Release

Nonenveloped viruses are generally released by the timely lysis of the host cell by a poorly understood process. For the nonenveloped virus SV40, virions assemble in the nucleus and then must be released from the host cell without being encapsulated by cellular membranes. This process appears to involve the well-controlled insertion of viral proteins into host cellular membranes rendering them permeable to large molecules. VP4 is a newly identified SV40 gene product that is expressed at late times during the viral life cycle that corresponds to the time of cell lysis. To investigate the role of this late expressed protein in viral release, water-soluble VP4 was expressed and purified as a GST fusion protein from bacteria. Purified VP4 was found to efficiently bind biological membranes and support their disruption. VP4 perforated membranes by directly interacting with the membrane bilayer as demonstrated by flotation assays and the release of fluorescent markers encapsulated into large unilamellar vesicles or liposomes. The central hydrophobic domain of VP4 was essential for membrane binding and disruption. VP4 displayed a preference for membranes comprised of lipids that replicated the composition of the plasma membranes over that of nuclear membranes. Phosphatidylethanolamine, a lipid found at high levels in bacterial membranes, was inhibitory against the membrane perforation activity of VP4. The disruption of membranes by VP4 involved the formation of pores of ∼3 nm inner diameter in mammalian cells including permissive SV40 host cells. Altogether, these results support a central role of VP4 acting as a viroporin in the perforation of cellular membranes to trigger SV40 viral release

Release of Intracellular Calcium Stores Facilitates Coxsackievirus Entry into Polarized Endothelial Cells

Group B coxsackieviruses (CVB) are associated with viral-induced heart disease and are among the leading causes of aseptic meningitis worldwide. Here we show that CVB entry into polarized brain microvasculature and aortic endothelial cells triggers a depletion of intracellular calcium stores initiated through viral attachment to the apical attachment factor decay-accelerating factor. Calcium release was dependent upon a signaling cascade that required the activity of the Src family of tyrosine kinases, phospholipase C, and the inositol 1,4,5-trisphosphate receptor isoform 3. CVB-mediated calcium release was required for the activation of calpain-2, a calcium-dependent cysteine protease, which controlled the vesicular trafficking of internalized CVB particles. These data point to a specific role for calcium signaling in CVB entry into polarized endothelial monolayers and highlight the unique signaling mechanisms used by these viruses to cross endothelial barriers

Morbillivirus Glycoprotein Expression Induces ER Stress, Alters Ca2+ Homeostasis and Results in the Release of Vasostatin

Although the pathology of Morbillivirus in the central nervous system (CNS) is well described, the molecular basis of neurodegenerative events still remains poorly understood. As a model to explore Morbillivirus-mediated CNS dysfunctions, we used canine distemper virus (CDV) that we inoculated into two different cell systems: a monkey cell line (Vero) and rat primary hippocampal neurons. Importantly, the recombinant CDV used in these studies not only efficiently infects both cell types but recapitulates the uncommon, non-cytolytic cell-to-cell spread mediated by virulent CDVs in brain of dogs. Here, we demonstrated that both CDV surface glycoproteins (F and H) markedly accumulated in the endoplasmic reticulum (ER). This accumulation triggered an ER stress, characterized by increased expression of the ER resident chaperon calnexin and the proapoptotic transcription factor CHOP/GADD 153. The expression of calreticulin (CRT), another ER resident chaperon critically involved in the response to misfolded proteins and in Ca2+ homeostasis, was also upregulated. Transient expression of recombinant CDV F and H surface glycoproteins in Vero cells and primary hippocampal neurons further confirmed a correlation between their accumulation in the ER, CRT upregulation, ER stress and disruption of ER Ca2+ homeostasis. Furthermore, CDV infection induced CRT fragmentation with re-localisation of a CRT amino-terminal fragment, also known as vasostatin, on the surface of infected and neighbouring non-infected cells. Altogether, these results suggest that ER stress, CRT fragmentation and re-localization on the cell surface may contribute to cytotoxic effects and ensuing cell dysfunctions triggered by Morbillivirus, a mechanism that might potentially be relevant for other neurotropic viruses

Health Behaviours, Socioeconomic Status, and Mortality: Further Analyses of the British Whitehall II and the French GAZEL Prospective Cohorts

Background: Differences in morbidity and mortality between socioeconomic groups constitute one of the most consistent findings of epidemiologic research. However, research on social inequalities in health has yet to provide a comprehensive understanding of the mechanisms underlying this association. In recent analysis, we showed health behaviours, assessed longitudinally over the follow-up, to explain a major proportion of the association of socioeconomic status (SES) with mortality in the British Whitehall II study. However, whether health behaviours are equally important mediators of the SES-mortality association in different cultural settings remains unknown. In the present paper, we examine this issue in Whitehall II and another prospective European cohort, the French GAZEL study.Methods and Findings: We included 9,771 participants from the Whitehall II study and 17,760 from the GAZEL study. Over the follow-up (mean 19.5 y in Whitehall II and 16.5 y in GAZEL), health behaviours (smoking, alcohol consumption, diet, and physical activity), were assessed longitudinally. Occupation (in the main analysis), education, and income (supplementary analysis) were the markers of SES. The socioeconomic gradient in smoking was greater (p < 0.001) in Whitehall II (odds ratio [OR] = 3.68, 95% confidence interval [CI] 3.11-4.36) than in GAZEL (OR = 1.33, 95% CI 1.18-1.49); this was also true for unhealthy diet (OR = 7.42, 95% CI 5.19-10.60 in Whitehall II and OR = 1.31, 95% CI 1.15-1.49 in GAZEL, p < 0.001). Socioeconomic differences in mortality were similar in the two cohorts, a hazard ratio of 1.62 (95% CI 1.28-2.05) in Whitehall II and 1.94 in GAZEL (95% CI 1.58-2.39) for lowest versus highest occupational position. Health behaviours attenuated the association of SES with mortality by 75% (95% CI 44%-149%) in Whitehall II but only by 19% (95% CI 13%-29%) in GAZEL. Analysis using education and income yielded similar results.Conclusions: Health behaviours were strong predictors of mortality in both cohorts but their association with SES was remarkably different. Thus, health behaviours are likely to be major contributors of socioeconomic differences in health only in contexts with a marked social characterisation of health behaviours