The critical role of interleukin-6 in protection against neurotropic flavivirus infection.

West Nile virus (WNV) and Japanese encephalitis virus (JEV) are emerging mosquito-borne flaviviruses causing encephalitis globally. No specific drug or therapy exists to treat flavivirus-induced neurological diseases. The lack of specific therapeutics underscores an urgent need to determine the function of important host factors involved in flavivirus replication and disease progression. Interleukin-6 (IL-6) upregulation has been observed during viral infections in both mice and humans, implying that it may influence the disease outcome significantly. Herein, we investigated the function of IL-6 in the pathogenesis of neurotropic flavivirus infections. First, we examined the role of IL-6 in flavivirus-infected human neuroblastoma cells, SK-N-SH, and found that IL-6 neutralization increased the WNV or JEV replication and inhibited the expression of key cytokines. We further evaluated the role of IL-6 by infecting primary mouse cells derived from IL-6 knockout (IL-6-/-) mice and wild-type (WT) mice with WNV or JEV. The results exhibited increased virus yields in the cells lacking the IL-6 gene. Next, our in vivo approach revealed that IL-6-/- mice had significantly higher morbidity and mortality after subcutaneous infection with the pathogenic WNV NY99 or JEV Nakayama strain compared to WT mice. The non-pathogenic WNV Eg101 strain did not cause mortality in WT mice but resulted in 60% mortality in IL-6-/- mice, indicating that IL-6 is required for the survival of mice after the peripheral inoculation of WNV or JEV. We also observed significantly higher viremia and brain viral load in IL-6-/- mice than in WT mice. Subsequently, we explored innate immune responses in WT and IL-6-/- mice after WNV NY99 infection. Our data demonstrated that the IL-6-/- mice had reduced levels of key cytokines in the serum during early infection but elevated levels of proinflammatory cytokines in the brain later, along with suppressed anti-inflammatory cytokines. In addition, mRNA expression of IFN-α and IFN-ß was significantly lower in the infected IL-6-/- mice. In conclusion, these data suggest that the lack of IL-6 exacerbates WNV or JEV infection in vitro and in vivo by causing an increase in virus replication and dysregulating host immune response.

Serum Albumin and C-reactive protein in Hospital Admitted Patients with Chronic Kidney Disease.

Adequate knowledge about the causes of chronic kidney disease and their potential prevention can improve poor clinical outcome in chronic kidney disease (CKD) patients. The study was designed to evaluate the serum albumin and C-reactive protein (CRP) levels in hospitalized patients with Chronic Kidney Disease. This cross-sectional study was carried out in the Department of Biochemistry, Mymensingh Medical College, Mymensingh, Bangladesh with the collaboration of the Department of Nephrology, Mymensingh Medical College Hospital, Mymensingh, from January 2021 to December 2021. The subjects were selected on the basis of inclusion and exclusion criteria by purposive and convenient sampling method. A total of 110 subjects were included in this study. Among them, 55 were diagnosed CKD patients denoted as Group I and 55 were normal healthy individuals denoted as Group II. In this study, serum albumin and CRP levels were measured. All values were expressed as Mean±SD. All statistical analysis was done by using SPSS (statistical package for social science) windows package version 21.0. Statistical significance of difference between Group I and Group II were evaluated by using student's unpaired 't'-test and the significance was defined as p<0.05. Correlation was done by using Pearson's correlation coefficient test. Mean age of Group I was 52.65±4.93 and Group II was 51.15±6.32 (p=0.165). The mean±SD of BMI was 24.46±1.84 for Group I and 24.50±1.05 for Group II (p=0.886). The mean±SD values of serum albumin were 3.62±0.26g/dl and 4.16±0.69g/dl in Group I and Group II respectively. We found highly significant (p<0.001) decrease in serum albumin. The mean±SD values of CRP were 24.00±16.73mg/L and <6.0±0.00mg/L in Group I and Group II respectively. So, we found significant (p<0.05) increase in CRP levels. There was negative correlation between serum albumin and CRP. Analyzing the findings of this study, significant decrease in serum albumin and significant increase in CRP levels were observed in CKD patients.

Glasgow Coma Score Predicting the Poor Outcome of the Patients Presenting Fever with Altered Sensorium.

To assess the role of the Glasgow Comma Score (GCS) for predicting the outcome of the patient with fever and altered sensorium was the objective of the study. This prospective observational study was conducted for six months following ethical approval. Informed consent was obtained prior enrollment. A total of 50 patients with complaints of fever for <2 weeks duration with altered sensorium with or without seizure were included in the study. GCS was calculated for all patients just after admission and before starting interventions. All patients were investigated and managed according to the hospital protocol. The outcome of the patients (living or dead within the hospital) was evaluated against the admission GCS score. The study was performed in accordance with the current Declaration of Helsinki. Of all, 42.0% (n=21) of the patients had bacterial meningitis, followed by viral encephalitis, cerebral malaria and coma vigil. Complete recovery occurred in 60.0% of cases, while recovery with disability occurred in 28.0% of cases. Death occurred in 12.0% of cases (n=6) due to cerebral malaria, viral encephalitis and bacterial meningitis (n=2 each cause). A higher number of deaths occurred in the lower GCS group (n=5 in GCS group 3-5) and this difference was statistically significant (p<0.05). Moreover, considering death as an outcome, multivariate logistic regression showed that GCS (OR 70.598, 95% CI-1.243-4009.41; p=0.039) was an independent predictor of the outcome. GCS seemed to be a predictor of the short-term outcome of the patient presenting with fever and altered sensorium in our setting. However, further exploration in larger setting with appropriate study design is recommended.

Fagonia cretica: Identification of compounds in bioactive gradient high performance liquid chromatography fractions against multidrug resistant human gut pathogens.

Plants are alternative source of natural medicines due to secondary active metabolites. Fagonia cretica extracts and Gradient High-Pressure Liquid Chromatography fractionations were checked against multidrug-resistant gastrointestinal pathogens including, Salmonella typhi, Escherichia coli and Shigella flexneri. ESI-MS/MS analysis of bioactive HPLC fractions was performed to elucidate antibacterial compounds. F. cretica extracts exhibited potential antibacterial activity. Twenty-four (24) HPLC fractions were obtained from methanol, ethanol and aqueous extracts of F. cretica. Eighteen (18) fractions showed antibacterial activity, while no activity was observed by the remaining six (6) fractions. HPLC fractions, F1 (25g ± 0.20 mm) and F2 (15f ± 0.12 mm) of aqueous extract exhibited activity against multidrug resistant GI pathogens. Gallic acid, quinic acid, cyclo-l-leu-l-pro, vidalenolone, liquirtigenin, rosmarinic acid and cerebronic acid were identified in F1 fraction of aqueous extract, while succinic acid, cyclo (l-Leul-Pro) and liquirtigenin were identified in F2 fraction of aqueous extract through ESI-MS/MS analysis. F. cretica extracts and HPLC fractions showed potential activity against MDR GI pathogens. Vidalenolone, Cyclo-1-leu-1-pro and Cerebronic acid are first time reported in F. cretica. Further characterization of bioactive compounds from F. cretica may be helpful to elucidate antibacterial therapeutic molecules.

SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways.

Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice.

Feasibility and Efficacy of Virtual Reality Interventions to Improve Psychosocial Functioning in Psychosis: Systematic Review.

BACKGROUND: Functional recovery in psychosis remains a challenge despite current evidence-based treatment approaches. To address this problem, innovative interventions using virtual reality (VR) have recently been developed. VR technologies have enabled the development of realistic environments in which individuals with psychosis can receive psychosocial treatment interventions in more ecological settings than traditional clinics. These interventions may therefore increase the transfer of learned psychosocial skills to real-world environments, thereby promoting long-term functional recovery. However, the overall feasibility and efficacy of such interventions within the psychosis population remain unclear. OBJECTIVE: This systematic review aims to investigate whether VR-based psychosocial interventions are feasible and enjoyable for individuals with psychosis, synthesize current evidence on the efficacy of VR-based psychosocial interventions for psychosis, and identify the limitations in the current literature to guide future research. METHODS: This research followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Literature searches were conducted in PubMed and PsycINFO in May 2021. We searched for peer-reviewed English articles that used a psychosocial intervention with a VR component. Participants in the included studies were diagnosed with schizophrenia, schizoaffective disorder, or another psychotic disorder. The included studies were divided into four categories as follows: cognitive remediation interventions, social skills interventions, vocational skills interventions, and auditory verbal hallucinations and paranoia interventions. The risk of bias assessment was performed for each study. RESULTS: A total of 18 studies were included in this systematic review. Of these 18 studies, 4 (22%) studies used a cognitive remediation intervention, 4 (22%) studies used a social skills intervention, 3 (17%) studies used a vocational skills intervention, and 7 (39%) studies implemented an intervention aimed at improving auditory verbal hallucinations or paranoia. A total of 745 individuals with psychosis were included in the study. All the studies that evaluated feasibility showed that VR-based psychosocial interventions were feasible and enjoyable for individuals with psychosis. The preliminary evidence on efficacy included in this review suggests that VR-based psychosocial interventions can improve cognitive, social, and vocational skills in individuals with psychosis. VR-based interventions may also improve the symptoms of auditory verbal hallucinations and paranoia. The skills that participants learned through these interventions were durable, transferred into real-world environments, and led to improved functional outcomes, such as autonomy, managing housework, and work performance. CONCLUSIONS: VR-based interventions may represent a novel and efficacious approach for improving psychosocial functioning in psychosis. Therefore, VR-based psychosocial interventions represent a promising adjunctive therapy for the treatment of psychosis, which may be used to improve psychosocial skills, community functioning, and quality of life.

Fagonia cretica: Identification of compounds in bioactive gradient high performance liquid chromatography fractions against multidrug resistant human gut pathogens

@#Plants are alternative source of natural medicines due to secondary active metabolites. Fagonia cretica extracts and Gradient High-Pressure Liquid Chromatography fractionations were checked against multidrug-resistant gastrointestinal pathogens including, Salmonella typhi, Escherichia coli and Shigella flexneri. ESI-MS/MS analysis of bioactive HPLC fractions was performed to elucidate antibacterial compounds. F. cretica extracts exhibited potential antibacterial activity. Twenty-four (24) HPLC fractions were obtained from methanol, ethanol and aqueous extracts of F. cretica. Eighteen (18) fractions showed antibacterial activity, while no activity was observed by the remaining six (6) fractions. HPLC fractions, F1 (25g ± 0.20 mm) and F2 (15f ± 0.12 mm) of aqueous extract exhibited activity against multidrug resistant GI pathogens. Gallic acid, quinic acid, cyclo-l-leu-l-pro, vidalenolone, liquirtigenin, rosmarinic acid and cerebronic acid were identified in F1 fraction of aqueous extract, while succinic acid, cyclo (l-Leul-Pro) and liquirtigenin were identified in F2 fraction of aqueous extract through ESI-MS/MS analysis. F. cretica extracts and HPLC fractions showed potential activity against MDR GI pathogens. Vidalenolone, Cyclo-1-leu-1-pro and Cerebronic acid are first time reported in F. cretica. Further characterization of bioactive compounds from F. cretica may be helpful to elucidate antibacterial therapeutic molecules.

SARS-CoV-2 variants of concern infect the respiratory tract and induce inflammatory response in wild-type laboratory mice

The emergence of new severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) variants of concern poses a major threat to the public health due to possible enhanced virulence, transmissibility and immune escape. These variants may also adapt to new hosts in part through mutations in the spike protein. In this study, we evaluated the infectivity and pathogenicity of SARS-CoV-2 variants of concern in wild-type C57BL/6 mice. Six-week-old mice were inoculated intranasally with a representative virus from the original B.1 lineage or emerging B.1.1.7 and B.1.351 lineages. We also infected a group of mice with a mouse-adapted SARS-CoV-2 (MA10). Viral load and mRNA levels of multiple cytokines and chemokines were analyzed in the lung tissues on day 3 after infection. Our data show that unlike the B.1 virus, the B.1.1.7 and B.1.351 viruses are capable of infecting C57BL/6 mice and replicating at high concentrations in the lungs. The B.1.351 virus replicated to higher titers in the lungs compared to the B.1.1.7 and MA10 viruses. The levels of cytokines (IL-6, TNF-, IL-1{beta}) and chemokine (CCL2) were upregulated in response to the B.1.1.7 and B.1.351 infection in the lungs. Overall, these data indicate a greater potential for infectivity and adaptation to new hosts by emerging SARS-CoV-2 variants.

Pattern of Neonatal Danger Signs and its Related Factors in a Tertiary Level Hospital.

Considering very limited information in the pattern of neonatal danger signs with associated risk factors in our perspective, the aim of the study was to understand the country-context pattern of neonatal danger signs and its related factors in a tertiary level hospital. This cross-sectional study was conducted among 259 mothers and their neonates in Dhaka Medical College Hospital, Dhaka, Bangladesh from 01 January 2015 to 31 December 2015. Data were collected by face to face interview from mother by pre-tested semi structure questionnaire which was adopted from WHO-UNICEF list of newborn danger signs. Measurement of weight was taken from hospital record. Observation of danger signs were done by following check list. Data analysis was done by SPSS 20.0. Of all, majority (41.6%) was in the age group of 20-24 years & was educated up to secondary level (42.47%). More than half of the participants (54.1%) had family income >10,000 BDT. Sixty percentage of mother took ANC visit <3 times during their pregnancy period. About 42.1% had ≥1 co-morbidities. Hospital was the predominate place of birth with 48.3% caesarean delivery. At least one neonatal danger sign was present in 20.1% while 39.4% had at least 2 danger signs. Rest of the child had ≥2 danger signs at a time. The distribution of danger signs were not feeding since birth or stop feeding 206(79.5%), severe chest in drawing 145(56.1%) respiratory rates 60 or more 126(48.6%), convulsion 72(27.8%), yellow soles 68(26.3%). Factors like 'fail to identify with an expert health assistant', trial of delivery at home, delivery at home, older neonatal age (8-28 days), presence of injury at birth, and cutting of umbilical cord by blade during delivery were associated with higher number of danger signs (p<0.05 in all cases). About 80% neonate in our setting had ≥1 sign and had association with fail to identify with an expert health assistant', trial of delivery at home, delivery at home, older neonatal age, presence of injury at birth, and cutting of umbilical cord by blade during delivery.