Acute hepatitis of unknown origin in children: Behind the statistics.

Since April 2022, the world has been witnessing a rapidly spreading outbreak of acute hepatitis of unknown origin in children < 16 years old that has affected several countries around the world. Most of the cases have presented with the clinical picture of severe hepatitis that has led to resorting to liver transplantation in several cases. Despite the numerous theories that have been suggested on the possible underlying etiologies of the outbreak, an association with hepatitis A-E viruses and a link to COVID-19 vaccines have been excluded. Adenovirus serotype 41 has been detected in numerous cases, which makes it the most likely underlying cause of the disease. Nevertheless, other hypotheses are being investigated to justify the severity of the clinical picture, which is not typical of this type of virus. This review aims to summarize the current knowledge about the outbreak, highlight the suggested working hypotheses, and report the public health measures undertaken to tackle the outbreak.

Rapid identification of SARS-CoV-2 strains via isothermal enzymatic recombinase amplification and nanopore sequencing.

Surveillance of the SARS-CoV-2 genome has become a crucial technique in the management of COVID-19, aiding the pandemic response and supporting effective public health interventions. Typically, whole-genomic sequencing is used along with PCR-based target enrichment techniques to identify SARS-CoV-2 variants, which is a complicated and time-consuming process that requires central laboratory facilities. Thus, there is an urgent need to develop rapid and cost-effective tools for precise on-site detection and identification of SARS-CoV-2 strains. In this study, we demonstrate the rapid diagnosis of COVID-19 and identification of SARS-CoV-2 variants by amplification and sequencing of the entire SARS-CoV-2 S gene using isothermal enzymatic recombinase amplification combined with the advanced Oxford nanopore sequencing technique. The entire procedure, from sampling to sequencing, takes less than 8 hours and can be performed with limited resources. The newly developed method has noteworthy implications for examining the transmission dynamics of the virus, detecting novel genetic variants, and assessing the effect of mutations on diagnostic approaches, antiviral treatments, and vaccines.

An in silico investigation of the toxicological effects and biological activities of 3-phenoxybenzoic acid and its metabolite products.

We aimed to elucidate the toxic effects and biological activities of 3-phenoxybenzoic acid (3PBA) and its metabolite products.Numerous in silico methods were used to identify the toxic effects and biological activities of 3PBA, including PASS online, molecular docking, ADMETlab 2.0, ADMESWISS, MetaTox, and molecular dynamic simulation.Ten metabolite products were identified via Phase II reactions (O-glucuronidation, O-sulfation, and methylation).All of the investigated compounds were followed by Lipinski's rule, indicating that they were stimulants or inducers of hazardous processes.Because of their high gastrointestinal absorption and ability to reach the blood-brain barrier, the studied compounds' physicochemical and pharmacokinetic properties matched existing evidence of harmful effects, including haematemesis, reproductive dysfunction, allergic dermatitis, toxic respiration, and neurotoxicity.The studied compounds have been linked to the apoptotic pathway, the reproductivity system, neuroendocrine disruptors, phospholipid-translocating ATPase inhibitors, and JAK2 expression.An O-glucuronidation metabolite product demonstrated higher binding affinity and interaction with CYP2C9, CYP3A4, caspase 3, and caspase 8 than 3PBA and other metabolite products, whereas metabolite products from methylation were predominant and more toxic.Our in silico findings partly meet the 3Rs principle by minimizing animal testing before more study is needed to identify the detrimental effects of 3PBA on other organs (liver, kidneys).Future research directions may involve experimental validation of in silico predictions, elucidation of molecular mechanisms, and exploration of therapeutic interventions.These findings contribute to our understanding of the toxicological profile of 3PBA and its metabolites, which has implications for risk assessment and regulatory decisions.

Key properties & pharmacokinetics of 3PBA & its metabolites were reportedMetabolite products from methylation were predominant and more toxicMain toxics: haematemesis, reproductive dysfunction, toxic respiration, dermatitis.

Serine protease inhibitor 3 (Serpin3) from Penaeus vannamei selectively interacts with Vibrio parahaemolyticus PirAvp.

Acute Hepatopancreatic Necrosis Disease (AHPND) represents a significant challenge in the field of shrimp aquaculture. This disease is primarily caused by Vibrio parahaemolyticus strains harbouring the pVA1 plasmid encoding the PirAvp and PirBvp toxins. To combat this epidemic and mitigate its devastating consequences, it is crucial to identify and characterize the receptors responsible for the binding of these pathogenic toxins. Our studied discovered that Penaeus vannamei's Serine protease inhibitor 3 (PvSerpin3) derived from shrimp hepatopancreatic tissues could bind to recombinant PirAvp , confirming its role as a novel PirAvp -binding protein (PA BP). Through comprehensive computational methods, we revealed two truncated PirAvp -binding proteins derived from PvSerpin3 called Serpin3(13) and Serpin3(22), which had higher affinity to PirAvp than the full-length PvSerpin3. The PA BP genes were amplified from a cDNA library that was reversed from total RNA extracted from shrimp, cloned and expressed in Escherichia coli. Three PA BP inclusion bodies were refolded to obtain the soluble form, and the recovery efficacy was found to be 100% for Serpin3 and Serpin3(13), while Serpin3(22) had a recovery efficacy of roundly 50%. Co-Immunoprecipitation (co-IP) and dot blot assays substantiated the interaction of these recombinant PA BPs with both recombinant PirAvp and VPAHPND (XN89)-producing natural toxins.

Wearing masks as a protective measure for children against traffic-related air pollution: A comparison of perceptions between school children and their caregivers in Ho Chi Minh City, Vietnam.

BACKGROUND: Traffic-related air pollution (TRAP) problems are unlikely to be solved in the short term, making it imperative to educate children on protective measures to mitigate the negative impact on their health. Children and their caregivers may hold differing views on wearing a face mask as a safeguard against air pollution. While many studies have focused on predicting children's health-protective behaviours against air pollution, few have explored the differences in perceptions between children and their caregivers. OBJECTIVES: To examine this, we conducted a study that compared the health beliefs of two generations and evaluated the factors that influence the use of masks by children to reduce air pollution exposure. METHODS: The study was conducted in 24 secondary schools and involved 8420 children aged 13-14 and their caregivers. We used a Health Belief Model (HBM)-based instrument containing 17-item self-administered health beliefs questionnaires to gather data. The results were analysed using hierarchical logistic regression to determine the probability of children frequently wearing masks to protect against TRAP. RESULTS: Our study showed both children and caregivers recognised that several factors could influence mask-wearing among children: discomfort or difficulty breathing while wearing a mask and forgetting to bring a mask when going outside; perceived threats of the poor quality of air and children's respiratory health problems; and cues to mask use (i.e., seeing most of their friends wearing facemasks and ease of finding masks in local stores). However, only children were significantly concerned with public perception of their appearance while wearing a mask. Females were more likely to wear masks, and caregivers with higher levels of education were more likely to encourage their children to wear masks. Children who commuted to schools by walking, biking, or motorbiking were also more accepting of mask-wearing than those who travelled by car or bus. CONCLUSIONS: Children and their caregivers hold different perceptions of wearing masks to protect against air pollution. Children are more susceptible to social judgements regarding their appearance when wearing a mask.

Burden of asthma-like symptoms and a lack of recognition of asthma in Vietnamese children.

OBJECTIVE: Lack of recognition of asthma in childhood results in unmet asthma treatment needs and leads to the risk of sub-optimal respiratory health. The present study assessed the prevalence of asthmatic under-recognition in middle school children in Vietnam. METHODS: We conducted a school-based survey among 15,112 Vietnamese children. Most of them are aged from 13 to 14. Schools and students were recruited using multi-stage sampling. Respiratory symptoms were collected via self-report using a standardized tool from the International Study of Asthma and Allergies in Childhood. Under-recognition of asthma was defined as a presence of at least one asthma-like symptom but a negative response to having ever asthma. Associations were investigated using logistic regression. RESULTS: Prevalence of asthma-like symptoms was 27.3% and prevalence of physician-diagnosed asthma was 8.5%. Over 80% of symptomatic children were not diagnosed with asthma. Under-recognition of asthma was found more in girls (adjusted odds ratio; aOR = 1.75; 95%CI: 1.54 to 1.98). CONCLUSIONS: Asthma is significantly under-recognized in Vietnamese middle-school children. Urgent action is required to improve the recognition of asthma in Vietnam.

Mussel - Inspired biosorbent combined with graphene oxide for removal of organic pollutants from aqueous solutions.

In this work, we develop a mussel-inspired biosorbent combined with graphene oxide for removal of organic dyes in water sources. The composite was prepared via self-polymerization of dopamine in weak alkaline solution containing graphene oxide at ambient condition. Morphological and structural studies revealed that polydopamine has gradually grown to cover the surface of graphene oxide flakes, partially reduced these flakes, and somehow form many grains (size around 20 nm) on the flakes instead of making very large aggregates as usual. The mass ratio between two components of the composite was also investigated to find the optimal one which provides enough surface area (20 m2.g-1) and maintain adhesive sites in order to ensure high-efficiency removal of organic molecules. The adsorption kinetics and isotherms of as-prepared adsorbent towards methylene blue were found to fit well with pseudo-first order kinetics model and Langmuir isotherm. The maximum adsorption capacity (qm) and Langmuir constant (kL) were estimated to be 270 mg.g-1 and 0.49 L. mg-1. The as-prepared bio-sorbent is very promising for remediation of water sources contaminated with cationic organic molecules and heavy metal ions.

Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease.

BACKGROUND: In recent years, many studies have focused on the intestinal environment to elucidate pathogenesis of various diseases, including kidney diseases. Impairment of the intestinal barrier function, the "leaky gut," reportedly contributes to pathologic processes in some disorders. Mitochondrial antiviral signaling protein (MAVS), a component of innate immunity, maintains intestinal integrity. The effects of disrupted intestinal homeostasis associated with MAVS signaling in diabetic kidney disease remains unclear. METHODS: To evaluate the contribution of intestinal barrier impairment to kidney injury under diabetic conditions, we induced diabetic kidney disease in wild-type and MAVS knockout mice through unilateral nephrectomy and streptozotocin treatment. We then assessed effects on the kidney, intestinal injuries, and bacterial translocation. RESULTS: MAVS knockout diabetic mice showed more severe glomerular and tubular injuries compared with wild-type diabetic mice. Owing to impaired intestinal integrity, the presence of intestine-derived Klebsiella oxytoca and elevated IL-17 were detected in the circulation and kidneys of diabetic mice, especially in diabetic MAVS knockout mice. Stimulation of tubular epithelial cells with K. oxytoca activated MAVS pathways and the phosphorylation of Stat3 and ERK1/2, leading to the production of kidney injury molecule-1 (KIM-1). Nevertheless, MAVS inhibition induced inflammation in the intestinal epithelial cells and KIM-1 production in tubular epithelial cells under K. oxytoca supernatant or IL-17 stimulation. Treatment with neutralizing anti-IL-17 antibody treatment had renoprotective effects. In contrast, LPS administration accelerated kidney injury in the murine diabetic kidney disease model. CONCLUSIONS: Impaired MAVS signaling both in the kidney and intestine contributes to the disrupted homeostasis, leading to diabetic kidney disease progression. Controlling intestinal homeostasis may offer a novel therapeutic approach for this condition.

The cervicovaginal mucus barrier to HIV-1 is diminished in bacterial vaginosis.

Bacterial vaginosis (BV), a condition in which the vaginal microbiota consists of community of obligate and facultative anaerobes rather than dominated by a single species of Lactobacillus, affects ~30% of women in the US. Women with BV are at 60% increased risk for HIV acquisition and are 3-times more likely to transmit HIV to an uninfected partner. As cervicovaginal mucus (CVM) is the first line of defense against mucosal pathogens and the home of the resident vaginal microbiota, we hypothesized the barrier function of CVM to HIV may be diminished in BV. Here, we characterized CVM properties including pH, lactic acid content, and Nugent score to correlate with the microbiota community composition, which was confirmed by 16S rDNA sequencing on a subset of samples. We then quantified the mobility of fluorescently-labeled HIV virions and nanoparticles to characterize the structural and adhesive barrier properties of CVM. Our analyses included women with Nugent scores categorized as intermediate (4-6) and BV (7-10), women that were either symptomatic or asymptomatic, and a small group of women before and after antibiotic treatment for symptomatic BV. Overall, we found that HIV virions had significantly increased mobility in CVM from women with BV compared to CVM from women with Lactobacillus crispatus-dominant microbiota, regardless of whether symptoms were present. We confirmed using nanoparticles and scanning electron microscopy that the impaired barrier function was due to reduced adhesive barrier properties without an obvious degradation of the physical CVM pore structure. We further confirmed a similar increase in HIV mobility in CVM from women with Lactobacillus iners-dominant microbiota, the species most associated with transitions to BV and that persists after antibiotic treatment for BV. Our findings advance the understanding of the protective role of mucus and highlight the interplay between vaginal microbiota and the innate barrier function mucus.

Characterization of an Adapted Murine Model of Intrauterine Inflammation-Induced Preterm Birth.

Preterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs, >25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. An in vivo imaging system revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI). Endotoxin concentrations in vaginal lavage fluid from SPI dams were significantly higher than from DDI dams. At equivalent LPS doses, DDI consistently induced more PTB than SPI, and DDI showed a linear dose-response, whereas SPI did not. Gene expression in myometrial tissue revealed increased levels of inflammatory markers in dams that received LPS DDI compared with LPS SPI. The SPI group showed more significant overexpression in cervical remodeling genes, likely due to the leakage of LPS from the uterine horns through the cervix. The more reliable PTB induction and uniform uterine exposure provided by this new model will be useful for further studying fetal outcomes and potential therapeutics for the prevention of inflammation-induced PTB.

Suspected heparin-induced thrombocytopenia in a COVID-19 patient on extracorporeal membrane oxygenation support: a case report.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) support can be life-saving in critically ill COVID-19 patients. However, there are many complications associated with this procedure, including Heparin-induced thrombocytopenia (HIT.) Despite its rarity in ECMO cases, HIT can lead to devastating consequences and is difficult to manage. CASE PRESENTATION: In this report, we present a case of a COVID-19 patient on ECMO support who was diagnosed with HIT and required intensive treatment. Initially, HIT was only suspected due to newly-developed thrombocytopenia and oxygenator dysfunction, with thrombi observed later. Regarding his treatment, since there was no recommended replacement to heparin available to us at the time of diagnosis, we decided to use rivaroxaban temporarily. No adverse events were recorded during that period. The patient was able to make a full recovery. CONCLUSION: HIT may jeopardize patient's care during ECMO. As COVID-19 may bring about a surge in the number of patients requiring ECMO support, we need consented guidance to optimize treatment in this specific situation.

Fear of falling and cognitive impairment in elderly with different social support levels: findings from a community survey in Central Vietnam.

BACKGROUND: Fear of falling (FoF) in the elderly is one of the major public health concerns in this era of aging of the population. As there is limited evidence on how cognitive function may differ by social support level in relation to FoF among the elderly, this cross-sectional study aims to investigate the prevalence of FoF and the associations between cognitive impairment and FoF by the social support level, after adjustments for potential confounders. METHODS: Data from the "Health needs assessment of elderly in Thua Thien Hue Province, Vietnam in 2018" survey of 725 elderly aged 60 years or older were used for analysis. FoF was assessed using the Fall Efficacy Scale-International. High FoF was defined as a score above 28. The Multidimensional Scale of Perceived Social Support was used to measure the perception of support. Logistic regression analysis was performed to investigate the association between cognitive function and FoF by social support levels (p < 0.05). RESULTS: The prevalence of high FoF among the elderly was 40.8%. Female gender, advanced age, a marital status of single or formerly married, living alone, history of injury, history of falls, chronic diseases (arthritis and/or hypertension), limitations of the IADL and BADL, visual difficulty and walking difficulty, low social support, and cognitive impairment were all significantly associated with a high FoF. After adjustments for the age, gender, marital status, history of falls and health-related factors, cognitive impairment remained significantly associated with a high FoF among the elderly with a low to moderate social support level (OR = 2.97, 95% CI 1.49-5.89), but not in those with a high social support level. CONCLUSIONS: A high FoF was associated with impairment of cognitive function among the elderly who perceived themselves as having low or moderate support levels, even after adjustments for socio demographic and physical functional factors. However, this association was not observed among the elderly who perceived themselves as having high social support levels. Fall prevention programs for the elderly with various levels of social support should be carefully devised, keeping in mind the cognitive function levels of the target recipients.

Relationships among cyberbullying, parental attitudes, self-harm and suicidal behavior among adolescents: results from a school-based survey in Vietnam.

BACKGROUND: The rapid and widespread development of social networking sites has created a venue for an increase in cyberbullying among adolescents. Protective mechanisms and actions must be considered, such as how proximal family factors can prevent self-harm and suicidal behaviors among adolescents exposed to cyberbullying. The present study examined the associations among cyberbullying, parental attitudes, self-harm, and suicidal behaviors after adjusting for confounding factors. METHODS: Data were obtained from a school-based survey of randomly selected grade 6 students (11 years old) performed in Hue City, Vietnam, in 2018. A total of 648 students were interviewed face-to-face using a structured questionnaire based on the Global School-based Student Health Survey (GSHS). Univariate, multivariable logistic regression analyses were performed at 95% confidence level. RESULTS: After adjusting for gender, perceived academic pressure, unhealthy behaviors, use of Internet devices, school bullying, and family living situation, a significantly higher risk of self-harm was detected among those who had experienced cyberbullying (adjusted odd ratio [AOR] = 2.97; 95% CI, 1.32-6.71). Parental acceptance retained a significant association with self-harm and suicidal behavior (P < 0.05) while parental concentration did not exhibit a significant association in a multivariable logistic regression model. In addition, suicidal ideation and suicidal planning were associated with an interaction effect between cyberbullying and parental concentration (AOR = 0.37; 95% CI, 0.15-0.94 and AOR = 0.23; 95% CI, 0.06-0.87, respectively). CONCLUSION: Cyberbullying has become an important phenomenon associated with self-harm among young adolescents in developing countries, and parental acceptance in proxy of parental attitude was positively related with severe mental health issues among adolescents. Thus, sufficient attention in efforts to promote adolescent health should be focused on family factors in the digital era of developing countries.

Optimal Nitrogen Incorporation in Nickel Silicide for Thermally Stable Contact Formation.

Nickel silicide (NiSi) is commonly used as a contact material for metal junctions but the poor thermal instability of NiSi above 600 °C has limited the further scaling down of devices and the implementation of novel schemes, such as monolithic 3-dimensional integration. This paper suggests a process to improve the thermal stability of NiSi through nitrogen incorporation during the silicidation process. The optimal level of nitrogen incorporation in NiSi reduced the nickel diffusion rate and enhanced the thermal stability by preventing the formation of a nickel disilicide phase. On the other hand, a higher level of N incorporation led to Ni3N formation, which impeded the complete transformation to NiSi. Therefore, it is essential to incorporate the optimal content of N. In this study, NiSi with 3.9% N incorporation showed superior electrical characteristics, such as the sheet resistance, junction leakage, and stable Schottky barrier height, even after high-temperature post silicidation annealing at 600 °C for 30 min.

Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection.

Oral preexposure prophylaxis (PrEP) has been approved for prophylaxis of HIV-1 transmission but is associated with high costs and issues of adherence. Protection from anal transmission of HIV using topical microbicides and methods congruent with sexual behavior offers the promise of improved adherence. We compared the pharmacokinetics (PK) and ex vivo efficacy of iso-osmolar (IOsm) and hypo-osmolar (HOsm) rectal enema formulations of tenofovir (TFV) in rhesus macaques. Single-dose PK of IOsm or HOsm high-dose (5.28 mg/ml) and low-dose (1.76 mg/ml) formulations of TFV enemas were evaluated for systemic uptake in blood, colorectal biopsy specimens, and rectal CD4+ T cells. Markedly higher TFV concentrations were observed in plasma and tissues after administration of the HOsm high-dose formulation than with all other formulations tested. TFV and TFV diphosphate (TFV-DP) concentrations in tissue correlated for the HOsm high-dose formulation, demonstrating rapid uptake and transformation of TFV to TFV-DP in tissues. TFV-DP amounts in tissues collected at 1 and 24 h were 7 times and 5 times higher, respectively (P < 0.01), than the ones collected in tissues with the IOsm formulation. The HOsm high-dose formulation prevented infection in ex vivo challenges of rectal tissues collected at 1, 24, and 72 h after the intrarectal dosing, whereas the same TFV dose formulated as an IOsm enema was less effective.

Novel 3-fluoro-6-methoxyquinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV.

Novel (non-fluoroquinolone) inhibitors of bacterial type II topoisomerases (NBTIs) are an emerging class of antibacterial agents. We report an optimized series of cyclobutylaryl-substituted NBTIs. Compound 14 demonstrated excellent activity both in vitro (S. aureus MIC90=0.125µg/mL) and in vivo (systemic and tissue infections). Enhanced inhibition of Topoisomerase IV correlated with improved activity in S. aureus strains with mutations conferring resistance to NBTIs. Compound 14 also displayed an improved hERG IC50 of 85.9µM and a favorable profile in the anesthetized guinea pig model.

Association Between a Wider Availability of Health Information and Health Care Utilization in Vietnam: Cross-Sectional Study.

BACKGROUND: The rapid and widespread development of mass media sources including the Internet is occurring worldwide. Users are being confronted with a flood of health information through a wide availability of sources. Studies on how the availability of health information has triggered users' interest in utilizing health care services remain limited within the Vietnamese population. OBJECTIVE: This study examined the associations between the wider availability of sources for health information and health care utilization in Vietnam after adjusting for potential confounding variables. METHODS: The data for this study were drawn from a cross-sectional study conducted over a 6-month period in Hue, a city in central Vietnam. The participants were 993 randomly selected adults aged between 18 and 60 years. Information was collected through face-to-face interviews on the types of information sources that were consulted, including traditional media (television), Internet, and health education courses, as well as the impact of such information on health care use (emergency department visits, hospitalizations, doctor visits). Multivariable logistic regression analyses were performed at a 95% confidence level. RESULTS: The prevalence of watching television, using the Internet, and attending health education courses to obtain health information were 50.9% (505/993), 32.9% (327/993), and 8.7% (86/993), respectively. After further adjustments for self-reported health status, the presence of health insurance, and monthly income, respondents who watched television and used the Internet to obtain health information were 1.7 times more likely to visit a doctor (television: adjusted odds ratio [AOR] 1.69, 95% CI 1.30-2.19; Internet: AOR 1.64, 95% CI 1.23-2.19), and also significantly associated with inpatient hospitalization (P=.003). CONCLUSIONS: The use of widely available mass media sources (eg, television and the Internet) to obtain health information was associated with higher health care utilization. How this interest in health-related information can be used so that it will have a beneficial effect on care-seeking behavior should be a topic of concern to further health promotion in developing countries.

Hypothermia/rewarming disrupts excitation-contraction coupling in cardiomyocytes.

Hypothermia/rewarming (H/R) is poorly tolerated by the myocardium; however, the underlying intracellular basis of H/R-induced cardiac dysfunction remains elusive. We hypothesized that in cardiomyocytes, H/R disrupts excitation-contraction coupling by reducing myofilament Ca(2+) sensitivity due to an increase in cardiac troponin I (cTnI) phosphorylation. To test this hypothesis, isolated rat cardiomyocytes (13-15 cells from 6 rats per group) were electrically stimulated to evoke both cytosolic Ca(2+) ([Ca(2+)]cyto) and contractile (sarcomere shortening) responses that were simultaneously measured using an IonOptix system. Cardiomyocytes were divided into two groups: 1) those exposed to hypothermia (15°C for 2 h) followed by rewarming (35°C; H/R); or 2) time-matched normothermic (35°C) controls (CTL). Contractile dysfunction after H/R was indicated by reduced velocity and extent of sarcomere length (SL) shortening compared with time-matched controls. Throughout hypothermia, basal [Ca(2+)]cyto increased and the duration of evoked [Ca(2+)]cyto transients was prolonged. Phase-loop plots of [Ca(2+)]cyto vs. contraction were shifted rightward in cardiomyocytes during hypothermia compared with CTL, indicating a decrease in Ca(2+) sensitivity. Using Western blot, we found that H/R increases cTnI phosphorylation. These results support our overall hypothesis and suggest that H/R disrupts excitation-contraction coupling of cardiomyocytes due to increased cTnI phosphorylation and reduced Ca(2+) sensitivity.

Challenges in detection and treatment of multidrug resistant tuberculosis patients in Vietnam.

BACKGROUND: Vietnam is ranked 14(th) among 27 countries with high burden of multidrug-resistant tuberculosis (MDR-TB). In 2009, the Vietnamese government issued a policy on MDR-TB called Programmatic Management of Drug-resistant Tuberculosis (PMDT) to enhance and scale up diagnosis and treatment services for MDR-TB. Here we assess the PMDT performance in 2013 to determine the challenges to the successful identification and enrollment for treatment of MDR-TB in Vietnam. METHODS: In 35 provinces implementing PMDT, we quantified the number of MDR-TB presumptive patients tested for MDR-TB by Xpert MTB/RIF and the number of MDR-TB patients started on second-line treatment. In addition, existing reports and documents related to MDR-TB policies and guidelines in Vietnam were reviewed, supplemented with focus group discussions and in-depth interviews with MDR-TB key staff members. RESULTS: 5,668 (31.2 %) of estimated 18,165 MDR-TB presumptive cases were tested by Xpert MTB/RIF and second-line treatment was provided to 948 out of 5100 (18.7 %) of MDR-TB patients. Those tested for MDR-TB were 340/3224 (10.5 %) of TB-HIV co-infected patients and 290/2214 (13.1 %) of patients who remained sputum smear-positive after 2 and 3 months of category I TB regimen. Qualitative findings revealed the following challenges to detection and enrollment of MDR-TB in Vietnam: insufficient TB screening capacity at district hospitals where TB units were not available and poor communication and implementation of policy changes. Instructions for policy changes were not always received, and training was inconsistent between training courses. The private sector did not adequately report MDR-TB cases to the NTP. CONCLUSIONS: The proportion of MDR-TB patients diagnosed and enrolled for second-line treatment is less than 20 % of the estimated total. The low enrollment is largely due to the fact that many patients at risk are missed for MDR-TB screening. In order to detect more MDR-TB cases, Vietnam should intensify case finding of MDR-TB by a comprehensive strategy to screen for MDR-TB among new cases rather than targeting previously treated cases, in particular those with HIV co-infection and contacts of MDR-TB patients, and should engage the private sector in PMDT.

Vinculin regulates assembly of talin: ß3 integrin complexes.

Vinculin is a talin-binding protein that promotes integrin-mediated cell adhesion, but the mechanisms are not understood. Because talin is a direct activator of integrins, we asked whether and how vinculin regulates the formation of integrin: talin complexes. We report that VD1 (aa 1-258) and its talin-binding mutant, VD1A50I, bind directly and equally to several ß integrin cytoplasmic tails (ßCT). Results from competition assays show that VD1, but not VD1A50I, inhibits the interaction of talin (Tn) and talin rod (TnR), but not talin head (TnH) with ß3CT. The inhibition observed could be the result of VD1 binding to one or more of the 11 vinculin binding sites (VBSs) in the TnR domain. Our studies demonstrate that VD1 binding to amino acids 482-911, a VBS rich region, in TnR perturbs the interaction of rod with ß3CT. The integrin activation assays done using CHOA5 cells show that activated vinculin enhances αIIbß3 integrin activation and that the effect is dependent on talin. The TnR domain however shows no integrin activation unlike TnH that shows enhanced integrin activation. The overall results indicate that activated vinculin promotes talin-mediated integrin activation by binding to accessible VBSs in TnR and thus displacing the TnR from the ß3 subunit. The study presented, defines a novel direct interaction of VD1 with ß3CT and provides an attractive explanation for vinculin's ability to potentiate integrin-mediated cell adhesion through directly binding to both TnR and the integrin cytoplasmic tail.