Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse ß-cells by co-ordinating insulin biosynthesis with secretory granule formation.

OBJECTIVE: Although individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context. METHODS: MIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in ß-cells of adult mice using Ins1-CreER+. Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER. RESULTS: With a Km ≈3.5 mM, glucose rapidly (T1/2 0.9 h) increased full length (FL) CREB3L2 followed by a slower rise (T1/2 2.5 h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with ß-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi. CONCLUSION: The stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing ß-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating ß-cell failure.

ß-cell function is regulated by metabolic and epigenetic programming of islet-associated macrophages, involving Axl, Mertk, and TGFß receptor signaling.

We have exploited islet-associated macrophages (IAMs) as a model of resident macrophage function, focusing on more physiological conditions than the commonly used extremes of M1 (inflammation) versus M2 (tissue remodeling) polarization. Under steady state, murine IAMs are metabolically poised between aerobic glycolysis and oxidative phosphorylation, and thereby exert a brake on glucose-stimulated insulin secretion (GSIS). This is underpinned by epigenetic remodeling via the metabolically regulated histone demethylase Kdm5a. Conversely, GSIS is enhanced by engaging Axl receptors on IAMs, or by augmenting their oxidation of glucose. Following high-fat feeding, efferocytosis is stimulated in IAMs in conjunction with Mertk and TGFß receptor signaling. This impairs GSIS and potentially contributes to ß-cell failure in pre-diabetes. Thus, IAMs serve as relays in many more settings than currently appreciated, fine-tuning insulin secretion in response to dynamic changes in the external environment. Intervening in this nexus might represent a means of preserving ß-cell function during metabolic disease.

Electroconvulsive therapy portrayal in contemporary video games.

Electroconvulsive therapy (ECT) is an important treatment modality in psychiatry, considered to be the most effective option for pharmaco-resistant affective and psychotic disorders. Despite its great efficacy, it still remains a rather controversial method, which hinders its full potential. It is feasible to say that in part, this controversy is caused by a largely negative image of ECT displayed through media. The depiction of ECT in movies has been studied and well documented in the past. The aim of our study was to provide an overview of how ECT is represented in video games - a form of media where ECT representation has been overlooked in scientific literature so far. As with movies, most of these portrayals are negative, depicting ECT as an obsolete, aggressive or torturous treatment method.

The Very First Modification of Pleuromutilin and Lefamulin by Photoinitiated Radical Addition Reactions-Synthesis and Antibacterial Studies.

Pleuromutilin is a fungal diterpene natural product with antimicrobial properties, semisynthetic derivatives of which are used in veterinary and human medicine. The development of bacterial resistance to pleuromutilins is known to be very slow, which makes the tricyclic diterpene skeleton of pleuromutilin a very attractive starting structure for the development of new antibiotic derivatives that are unlikely to induce resistance. Here, we report the very first synthetic modifications of pleuromutilin and lefamulin at alkene position C19-C20, by two different photoinduced addition reactions, the radical thiol-ene coupling reaction, and the atom transfer radical additions (ATRAs) of perfluoroalkyl iodides. Pleuromutilin were modified with the addition of several alkyl- and aryl-thiols, thiol-containing amino acids and nucleoside and carbohydrate thiols, as well as perfluoroalkylated side chains. The antibacterial properties of the novel semisynthetic pleuromutilin derivatives were investigated on a panel of bacterial strains, including susceptible and multiresistant pathogens and normal flora members. We have identified some novel semisynthetic pleuromutilin and lefamulin derivatives with promising antimicrobial properties.

Application of polyoxymethylene passive air sampler to monitor hydrophobic organics in air around a confined disposal facility.

Volatile losses of hydrophobic organic contaminants from a confined disposal facility (CDF) containing dredged contaminated sediments is of substantial concern to surrounding communities. A partitioning passive sampling approach using polyoxymethylene (POM) was applied to measure long-term average (weeks to months) air concentrations resulting from evaporation at a CDF. Measurements at 10 locations surrounding the CDF using the POM air samplers indicated that the highest concentrations of ΣPCBs∼13 ng/m3 and ΣPAHs ∼65 ng/m3 were measured during an active dredge material placement period when the average temperature was 23 °C. The measurements were dominated by the more volatile, lower molecular weight compounds of each type. Partitioning to the POM during the post dredge material placement period with average temperature of 5 °C was corrected for temperature and the measured ∑PCBs and ∑PAHs were ∼3 ng/m3 and 45 ng/m3 respectively. The partitioning passive sampling measurements agreed well with the available weekly 24-h high-volume air samples (HVAS) averaged over the POM equilibration time for lower congener number PCBs (15, 18, 20/28 and 31) and naphthalene but were as much as 10 times lower than HVAS for high molecular weight PAHs. The difference was likely the result of the greater association of these PAHs with particulates and sources other than evaporation from the CDF. The POM air sampler achieved the goal of providing a long-term average air concentration without having to collect, analyze and average multiple HVAS samples although the technique is largely limited to the lower molecular weight PAHs and PCBs and different equilibration times for different compounds complicate its use and analysis.

Prevalence and associated factors of asymptomatic leishmaniasis: a systematic review and meta-analysis.

Asymptomatic leishmaniasis is believed to play important role in maintaining the transmission of Leishmania spp. within endemic communities. Therefore, the efforts to eliminate leishmaniasis are daunting if we cannot manage asymptomatic leishmaniasis well. To clarify the global prevalence and factors associated with the asymptomatic Leishmania infection, we assessed the prevalence of asymptomatic leishmaniasis by a systematic review followed by meta-analyses. In addition, factors associated with the asymptomatic leishmaniasis versus symptomatic were also analyzed. We included all of the original articles alluding to the human asymptomatic leishmaniasis that was confirmed by at least one laboratory diagnosis method regardless of age, sex, race, and ethnicity of the patients, study design, publication date or languages. In total, 111 original articles were chosen for the data extraction. Based on our meta-analyses of the original articles reporting asymptomatic leishmaniasis mostly in endemic areas, the prevalence of asymptomatic leishmaniasis was 11.2% [95% confidence interval (CI) 8.6%-14.4%] in general population, 36.7% [95% CI 27.6%-46.8%] in inhabitants living in the same or neighboring household to the symptomatic patients, and 11.8% [95% CI 7.1%-19%] in HIV infected patients. Among individuals with leishmaniasis, 64.9% [95% CI 54.7%-73.9%] were asymptomatic and males were more susceptible to develop symptoms, with OR=1.88, 95% CI 1.19-2.99, P=0.007. Meta-regression analysis showed no significant change in the prevalence of asymptomatic leishmaniasis during the last 40 years.

HDAC9 Is Preferentially Expressed in Dedifferentiated Hepatocellular Carcinoma Cells and Is Involved in an Anchorage-Independent Growth.

Aberrant activation of histone deacetylases (HDACs) is one of the causes of tumor cell transformation in many types of cancer, however, the critical HDAC responsible for the malignant transformation remain unclear. To identify the HDAC related to the dedifferentiation of hepatocellular carcinoma (HCC) cells, we investigated the expression profile of HDACs in differentiated and undifferentiated hepatoma cells. We found that HDAC9, a member of the class II HDAC, is preferentially expressed in undifferentiated HCC cells. Analysis of 373 HCC patients in The Cancer Genome Atlas (TCGA) database revealed that the expression of HDAC9 mRNA positively correlated with the markers of mesenchymal phenotype and stemness, and conversely, negatively correlated with hepatic differentiation markers. HDAC9 was transcriptionally upregulated in epithelial-mesenchymal transition (EMT)-induced HCC cells treated with TGF-ß. Genetic and pharmacological inhibition of HDAC9 in undifferentiated HCC cells showed decreased sphere-forming activity, which indicates an ability of anchorage-independent cell growth and self-renewal. We also showed that aldehyde dehydrogenase 1A3 (ALDH1A3) was downregulated in HDAC9-suppressing cells, and ALDH inhibitor disulfiram significantly decreased the sphere formation of undifferentiated HCC cells. Together, our data provide useful information for the development of HDAC9-specific inhibitors for the treatment of HCC progression.

Short-term inhibition of autophagy benefits pancreatic ß-cells by augmenting ether lipids and peroxisomal function, and by countering depletion of n-3 polyunsaturated fatty acids after fat-feeding.

OBJECTIVE: Investigations of autophagy in ß-cells have usually focused on its homeostatic function. More dynamic roles in inhibiting glucose-stimulated insulin secretion (GSIS), potentially involving remodelling of cellular lipids, have been suggested from in vitro studies but not evaluated in vivo. METHODS: We employed temporally-regulated deletion of the essential autophagy gene, Atg7, in ß-cells. Mice were fed chow or high-fat diets (HFD), in conjunction with deletion of Atg7 for the last 3 weeks (short-term model) or 9 weeks (long-term model). Standard in vivo metabolic phenotyping was undertaken, and 450 lipid species in islets quantified ex vivo using mass spectroscopy (MS). MIN6 cells were also employed for lipidomics and secretory interventions. RESULTS: ß-cell function was impaired by inhibiting autophagy in the longer-term, but conversely improved by 3-week deletion of Atg7, specifically under HFD conditions. This was accompanied by augmented GSIS ex vivo. Surprisingly, the HFD had minimal effect on sphingolipid and neutral lipid species, but modulated >100 phospholipids and ether lipids, and markedly shifted the profile of polyunsaturated fatty acid (PUFA) sidechains from n3 to n6 forms. These changes were partially countered by Atg7 deletion, consistent with an accompanying upregulation of the PUFA elongase enzyme, Elovl5. Loss of Atg7 separately augmented plasmalogens and alkyl lipids, in association with increased expression of Lonp2, a peroxisomal chaperone/protease that facilitates maturation of ether lipid synthetic enzymes. Depletion of PUFAs and ether lipids was also observed in MIN6 cells chronically exposed to oleate (more so than palmitate). GSIS was inhibited by knocking down Dhrs7b, which encodes an enzyme of peroxisomal ether lipid synthesis. Conversely, impaired GSIS due to oleate pre-treatment was selectively reverted by Dhrs7b overexpression. CONCLUSIONS: A detrimental increase in n6:n3 PUFA ratios in ether lipids and phospholipids is revealed as a major response of ß-cells to high-fat feeding. This is partially reversed by short-term inhibition of autophagy, which results in compensatory changes in peroxisomal lipid metabolism. The short-term phenotype is linked to improved GSIS, in contrast to the impairment seen with the longer-term inhibition of autophagy. The balance between these positive and negative inputs could help determine whether ß-cells adapt or fail in response to obesity.

Effect of nitazoxanide on diarrhea: A systematic review and network meta-analysis of randomized controlled trials.

We aimed to systematically review evidence pertaining to the safety and efficacy of nitazoxanide in treating infectious diarrhea. On September 21, 2017, we identified relevant studies using 12 databases. The estimates of the included studies were pooled as a risk ratio (RR). We conducted a network and pairwise random-effects meta-analysis for both direct and indirect comparisons of different organisms that are known to cause diarrhea. The primary and secondary analysis outcomes were clinical response until cessation of illness, parasitological response and adverse events. We included 18 studies in our analysis. In cryptosporidiosis, the overall estimate favored nitazoxanide in its clinical response in comparison with placebo RR 1.46 [95% CI 1.22-1.74; P-value <0.0001]. Network meta-analysis among patients with Giardia intestinalis showed an increase in the probability of diarrheal cessation and parasitological responses in comparison with placebo, RR 1.69 [95% CI 1.08-2.64, P-score 0.27] and RR 2.91 [95% CI 1.72-4.91, P-score 0.55] respectively. In Clostridium difficile infection, the network meta-analysis revealed a non-significantly superior clinical response effect of nitazoxanide to metronidazole 31 days after treatment RR 1.21 [95% CI 0.87-1.69, P-score 0.26]. In Entamoeba histolytica, the overall estimate significantly favored nitazoxanide in parasitological response with placebo RR 1.80 [95% CI 1.35-2.40, P-value < 0.001]. We highlighted the effectiveness of nitazoxanide in the cessation of diarrhea caused by Cryptosporidium, Giardia intestinalis and Entamoeba histolytica infection. We also found significant superiority of NTZ to metronidazole in improving the clinical response to G. intestinalis, thus it may be a suitable candidate for treating infection-induced diarrhea. To prove the superiority of NTZ during a C. difficile infection may warrant a larger-scale clinical trial since its superiority was deemed insignificant. We recommend nitazoxanide as an appropriate option for treating infectious diarrhea.

Development of polyoxymethylene passive sampler for assessing air concentrations of PCBs at a confined disposal facility (CDF).

In this study, 76 µm polyoxymethylene (POM) strips were evaluated as a passive air sampler (PAS) for monitoring the volatile emissions from dredged material placed in confined disposal facilities (CDF). Laboratory evaluations were used to assess the uptake kinetics, average equilibrium time, and estimate the POM-air partition coefficients (KPOM-A) of 16 PCB congeners. The uptake kinetics defined the effective averaging time for air sampling and ranged from about a week for dichlorobiphenyls to 2 weeks or more for tetra- and pentachlorobiphenyls at ∼20 °C under internal mass transfer resistance control which was applicable for Log KPOM-A < 8. The measured Log KPOM-A for PCBs ranged from 5.65 to 9.34 and exhibited an average deviation of 0.19 log unit from the theoretical value of KPOM-W/KAW. The PAS approach was then tested with a preliminary field application (n = 17) at a CDF allowing equilibration over 42 days. The field application focused on lower congener PCBs as a result of the estimated increase in KPOM-A and longer uptake times expected at the low ambient temperatures during the field study (average of 3.5 °C). Total PCB air concentrations around the CDF averaged 0.32 ng/m3 and varied according to proximity to placement of the dredged materials and predominant wind directions. Average PAS concentration of low congener number PCBs (15, 18, 20/28, 31) were compared to available high volume air sampler (HVAS) measurements. The PAS concentrations were within 20% of HVAS in the dominant north and south directions and showed similar trends as east and west HVAS samplers although PAS concentrations were as much as an order of magnitude below the west HVAS.

Torasemide versus furosemide in treatment of heart failure: A systematic review and meta-analysis of randomized controlled trials.

AIM: Diuretics are a cornerstone in treatment of heart failure (HF). Torasemide is a loop diuretic with a potential advantage over other diuretics. We aim to meta-analyse and compare the effect of torasemide with furosemide in HF patients. METHODS: A comprehensive literature search using 12 databases including PubMed, Scopus, and Web of Science was performed. All randomized controlled trials (RCTs) comparing furosemide and torasemide in HF patients were included and meta-analysed. We assessed the risk of bias using Cochrane Collaboration's tool. The protocol was registered in PROSPERO (CRD42016046112). RESULTS: Eighteen RCTs with 1598 patients were included. There was a significant difference between torasemide 20 mg and furosemide 40 mg in increasing the urine volume (standard difference of the mean (SDM) [95% confidence interval] = -0.78 [-1.52 to -0.053], P = .036). Torasemide 10 mg and 10 to 20 mg have a significant effect on potassium excretion in comparison with furosemide 25 to 40 mg (P = .018 and .023, respectively). In general, torasemide and furosemide have no significant difference in mortality, edema improvement, weight loss, heart rate, and reducing systolic/diastolic blood pressure. However, oral torasemide has a significant lower hospital stay P < .001 and superior effect in improving ejection fraction P = .029. CONCLUSION: Although not all results are statistically significant, torasemide has potential advantages on multiple aspects of HF management when compared with furosemide. More studies are needed to clarify these effects.

Effect of Nanoparticles on the Bulk Shear Viscosity of a Lung Surfactant Fluid.

Inhaled nanoparticles (<100 nm) reaching the deep lung region first interact with the pulmonary surfactant, a thin lipid film lining the alveolar epithelium. To date, most biophysical studies have focused on particle-induced modifications of the film interfacial properties. In comparison, there is less work on the surfactant bulk properties and on their changes upon particle exposure. Here we study the viscoelastic properties of a biomimetic pulmonary surfactant in the presence of various engineered nanoparticles. The microrheology technique used is based on the remote actuation of micron-sized wires via the application of a rotating magnetic field and on time-lapse optical microscopy. It is found that particles strongly interacting with lipid vesicles, such as cationic silica (SiO2, 42 nm) and alumina (Al2O3, 40 nm) induce profound modifications of the surfactant flow properties, even at low concentrations. In particular, we find that silica causes fluidification, while alumina induces a liquid-to-soft solid transition. Both phenomena are described quantitatively and accounted for in the context of colloidal physics models. It is finally suggested that the structure and viscosity changes could impair the fluid reorganization and recirculation occurring during breathing.

Synthesis of ß-d-galactopyranoside-Presenting Glycoclusters, Investigation of Their Interactions with Pseudomonas aeruginosa Lectin A (PA-IL) and Evaluation of Their Anti-Adhesion Potential.

Pseudomonas aeruginosa is an opportunistic human pathogen associated with cystic fibrosis. This bacterium produces, among other virulence factors, a soluble d-galactose-specific lectin PA-IL (LecA). PA-IL plays an important role in the adhesion to the host cells and is also cytotoxic. Therefore, this protein is an interesting therapeutic target, suitable for inhibition by carbohydrate-based compounds. In the current study, ß-d-galactopyranoside-containing tri- and tetravalent glycoclusters were synthesized. Methyl gallate and pentaerythritol equipped with propargyl groups were chosen as multivalent scaffolds and the galactoclusters were built from the above-mentioned cores by coupling ethylene or tetraethylene glycol-bridges and peracetylated propargyl ß-d-galactosides using 1,3-dipolar azide-alkyne cycloaddition. The interaction between galactoside derivatives and PA-IL was investigated by several biophysical methods, including hemagglutination inhibition assay, isothermal titration calorimetry, analytical ultracentrifugation, and surface plasmon resonance. Their ability to inhibit the adhesion of P. aeruginosa to bronchial cells was determined by ex vivo assay. The newly synthesized multivalent galactoclusters proved to be significantly better ligands than simple d-galactose for lectin PA-IL and as a result, two representatives of the dendrimers were able to decrease adhesion of P. aeruginosa to bronchial cells to approximately 32% and 42%, respectively. The results may provide an opportunity to develop anti-adhesion therapy for the treatment of P. aeruginosa infection.

Treatment of type 2 diabetes with the designer cytokine IC7Fc.

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.

Investigation of the Binding Affinity of a Broad Array of l-Fucosides with Six Fucose-Specific Lectins of Bacterial and Fungal Origin.

Series of multivalent α-l-fucoside containing glycoclusters and variously decorated l-fucosides were synthesized to find potential inhibitors of fucose-specific lectins and study the structure-binding affinity relationships. Tri- and tetravalent fucoclusters were built using copper-mediated azide-alkyne click chemistry. Series of fucoside monomers and dimers were synthesized using various methods, namely glycosylation, an azide-alkyne click reaction, photoinduced thiol-en addition, and sulfation. The interactions between compounds with six fucolectins of bacterial or fungal origin were tested using a hemagglutination inhibition assay. As a result, a tetravalent, α-l-fucose presenting glycocluster showed to be a ligand that was orders of magnitude better than a simple monosaccharide for tested lectins in most cases, which can nominate it as a universal ligand for studied lectins. This compound was also able to inhibit the adhesion of Pseudomonas aeruginosa cells to human epithelial bronchial cells. A trivalent fucocluster with a protected amine functional group also seems to be a promising candidate for designing glycoconjugates and chimeras.

Therapeutic efficacy and safety of chamomile for state anxiety, generalized anxiety disorder, insomnia, and sleep quality: A systematic review and meta-analysis of randomized trials and quasi-randomized trials.

This systematic review and meta-analysis aimed to study the efficacy and safety of chamomile for the treatment of state anxiety, generalized anxiety disorders (GADs), sleep quality, and insomnia in human. Eleven databases including PubMed, Science Direct, Cochrane Central, and Scopus were searched to retrieve relevant randomized control trials (RCTs), and 12 RCTs were included. Random effect meta-analysis was performed by meta package of R statistical software version 3.4.3 and RevMan version 5.3. Our meta-analysis of three RCTs did not show any difference in case of anxiety (standardized mean difference = -0.15, 95% CI [-0.46, 0.16], P = 0.4214). Moreover, there is only one RCT that evaluated the effect of chamomile on insomnia and it found no significant change in insomnia severity index (P > 0.05). By using HAM-A scale, there was a significant improvement in GAD after 2 and 4 weeks of treatment (mean difference = -1.43, 95% CI [-2.47, -0.39], P = 0.007), (MD = -1.79, 95% CI [-3.14, -0.43], P = 0.0097), respectively. Noteworthy, our meta-analysis showed a significant improvement in sleep quality after chamomile administration (standardized mean difference = -0.73, 95% CI [-1.23, -0.23], P < 0.005). Mild adverse events were only reported by three RCTs. Chamomile appears to be efficacious and safe for sleep quality and GAD. Little evidence is there to show its effect on anxiety and insomnia. Larger RCTs are needed to ascertain these findings.

Systematic review of spontaneous splenic rupture in dengue-infected patients.

Dengue infection varies from a mild febrile form to more severe disease with plasma leakage, shock, and multiorgan failure. Several serious complications such as cardiomyopathy, encephalopathy, encephalitis, hepatic damage, and neural manifestations cause organ damage in dengue infection. Splenic rupture, a less well known but life-threatening complication, can occur in dengue. The mechanism of splenic rupture in dengue is still unclear. Optimal therapeutic management is required to save the lives of patients with this complication. The objective of this study was to conduct a systematic review of studies documenting the development of spontaneous nontraumatic splenic rupture in patients with dengue infection. In March 2018, a search was conducted systematically in nine electronic databases, in addition to hand- searching. A total of 127 references were exported to Endnote; 47 references remained after removing duplicates. Finally, 16 reports met the inclusion criteria and represented 17 cases. All articles were evaluated and data extracted according to predefined criteria: number of cases, age, sex, severity of dengue disease, days of illness before admission, methods of definitive diagnosis, timing of the event, and management and outcome. A total of 17 individual patients including 13 males and four females were found. Most of the patients were young adults (ranging from 20 to 52 years) and diagnosed with computed tomography scan and managed with splenectomy. Four cases were fatal. Pathological splenic rupture in dengue is a rare, life-threatening condition where timely management can achieve a favorable outcome.

Disruption of beta cell acetyl-CoA carboxylase-1 in mice impairs insulin secretion and beta cell mass.

AIMS/HYPOTHESIS: Pancreatic beta cells secrete insulin to maintain glucose homeostasis, and beta cell failure is a hallmark of type 2 diabetes. Glucose triggers insulin secretion in beta cells via oxidative mitochondrial pathways. However, it also feeds mitochondrial anaplerotic pathways, driving citrate export and cytosolic malonyl-CoA production by the acetyl-CoA carboxylase 1 (ACC1) enzyme. This pathway has been proposed as an alternative glucose-sensing mechanism, supported mainly by in vitro data. Here, we sought to address the role of the beta cell ACC1-coupled pathway in insulin secretion and glucose homeostasis in vivo. METHODS: Acaca, encoding ACC1 (the principal ACC isoform in islets), was deleted in beta cells of mice using the Cre/loxP system. Acaca floxed mice were crossed with Ins2cre mice (ßACC1KO; life-long beta cell gene deletion) or Pdx1creER mice (tmx-ßACC1KO; inducible gene deletion in adult beta cells). Beta cell function was assessed using in vivo metabolic physiology and ex vivo islet experiments. Beta cell mass was analysed using histological techniques. RESULTS: ßACC1KO and tmx-ßACC1KO mice were glucose intolerant and had defective insulin secretion in vivo. Isolated islet studies identified impaired insulin secretion from beta cells, independent of changes in the abundance of neutral lipids previously implicated as amplification signals. Pancreatic morphometry unexpectedly revealed reduced beta cell size in ßACC1KO mice but not in tmx-ßACC1KO mice, with decreased levels of proteins involved in the mechanistic target of rapamycin kinase (mTOR)-dependent protein translation pathway underpinning this effect. CONCLUSIONS/INTERPRETATION: Our study demonstrates that the beta cell ACC1-coupled pathway is critical for insulin secretion in vivo and ex vivo and that it is indispensable for glucose homeostasis. We further reveal a role for ACC1 in controlling beta cell growth prior to adulthood.

Programmatic Evaluation of an Algorithm for Intensified Tuberculosis Case Finding and Isoniazid Preventive Therapy for People Living With HIV in Thailand and Vietnam.

BACKGROUND: Tuberculosis (TB) screening affords clinicians the opportunity to diagnose or exclude TB disease and initiate isoniazid preventive therapy (IPT) for people living with HIV (PLHIV). METHODS: We implemented an algorithm to diagnose or rule out TB among PLHIV in 11 HIV clinics in Thailand and Vietnam. We assessed algorithm yield and uptake of IPT and factors associated with TB disease among PLHIV. RESULTS: A total of 1448 PLHIV not yet on antiretroviral therapy (ART) were enrolled and screened for TB. Overall, 634 (44%) screened positive and 119 (8%) were diagnosed with TB; of these, 40% (48/119) were diagnosed by a positive culture following a negative sputum smear microscopy. In total, 55% of those eligible (263/477) started on IPT and of those, 75% (196/263) completed therapy. The prevalence of TB disease we observed in this study was 8.2% (8218 per 100,000 persons): 46 and 25 times the prevalence of TB in the general population in Thailand and Vietnam, respectively. Several factors were independently associated with TB disease including being underweight [aOR (95% CI): 2.3 (1.2 to 2.6)] and using injection drugs [aOR (95% CI): 2.9 (1.3 to 6.3)]. CONCLUSIONS: The high yield of TB disease diagnosed among PLHIV screened with the algorithm, and higher burden among PLHIV who inject drugs, underscores the need for innovative, tailored approaches to TB screening and prevention. As countries adopt test-and-start for antiretroviral therapy, TB screening, sensitive TB diagnostics, and IPT should be included in differentiated-care models for HIV to improve diagnosis and prevention of TB among PLHIV.

Angiostrongylus cantonensis Is an Important Cause of Eosinophilic Meningitis in Southern Vietnam.

We utilized polymerase chain reaction (PCR) to demonstrate that Angiostrongylus cantonensis was responsible for 67.3% of 55 cases of eosinophilic meningitis from a cohort of 1,690 adult patients with CNS infection at a tertiary hospital in southern Vietnam. Longer duration of illness, depressed consciousness, and peripheral blood eosinophilia were associated with PCR positivity.