MAIN METHODS: The effects of BChE on signaling pathways were determined by immunoblotting in a BChE knockout hepatocyte cell line. DiI-LDL probe was used to explore the effect of BChE expression on LDL internalization. Co-immunoprecipitation and LC-MS were used to explore the interacting proteins with BChE. Finally, a hepatocyte-restricted BChE silencing mouse model was established by AAV8-Tbg-shRNA, and the hypercholesterolemia was induced by 65% kcal% high-fat, high-sucrose diet feeding.
MAIN FINDINGS: Here we demonstrate that butyrylcholinesterase (BChE) governs the LDL receptor levels and LDL uptake capacity through the MEK-ERK signaling cascades to promote Ldlr transcription. BChE interacts and co-localizes with PRMT5, a protein methylation modifier controlling the ERK signaling. PRMT5 regulates LDLR-dependent LDL uptake and is a substrate of chaperone-mediated autophagy (CMA). BChE deficiency induces the PRTM5 degradation dependent on CMA activity, possibly through facilitating the HSC70 (Heat shock cognate 71 kDa) recognition of PRMT5. Remarkably, in vivo hepatocyte-restricted BChE silencing reduces plasma cholesterol levels substantially. In contrast, the BChE knockout mice are predisposed to hypercholesterolemia.
SIGNIFICANCE: Taken together, these findings outline a regulatory role for the BChE-PRMT5-ERK-LDLR axis in hepatocyte cholesterol metabolism, and suggest that targeting liver BChE is an effective therapeutic strategy to treat hypercholesterolemia.
METHODS: The EPIC-Norfolk is a prospective population-based cohort study in Norfolk, UK. In total, 25 637 community dwelling adults aged 40-79 years were recruited. Units of alcohol consumed per week were measured using a validated Food Frequency Questionnaire. The main outcome was the first hospital admission following a fall.
RESULTS: Over a median follow-up period of 11.5 years (299 211 total person years), the cumulative incidence function (95% confidence interval) of hospitalized falls at 121-180 months for non-users, light (>0 to ≤7 units/week), moderate (>7 to ≤28 units/week) and heavy (>28 units/week) were 11.08 (9.94-12.35), 7.53 (7.02-8.08), 5.91 (5.29-6.59) and 8.20 (6.35-10.56), respectively. Moderate alcohol consumption was independently associated with a reduced risk of falls hospitalization after adjustment for most major confounders (hazard ratio = 0.88; 95% confidence interval 0.79-0.99). The relationship between light alcohol consumption and falls hospitalization was attenuated by gender differences. Alcohol intake higher than the recommended threshold of 28 units/week was associated with an increased risk of falls hospitalization (hazard ratio 1.40 [1.14-1.73]).
CONCLUSIONS: Moderate alcohol consumption appears to be associated with a reduced risk of falls hospitalization, and intake above the recommended limit is associated with an increased risk. This provides incentive to limit alcohol consumption within the recommended range and has important implications for public health policies for aging populations. Geriatr Gerontol Int 2021; 21: 657-663.
CASE: A 4-year-old girl was declared dead on arrival to the hospital with a history of chronic constipation since birth. Postmortem examination showed Müllerian remnants attached to abnormal fibrous tissue. The fibrous tissue extended from the descending colon to the rectum and connected to a urinary bladder duplication cyst. The fibrous tissue formed into a constricted band around the rectum. The cause of death was Streptococcus pyogenes sepsis with intestinal obstruction secondary to the rectal fibrotic band and urinary bladder duplication cyst.
SUMMARY AND CONCLUSION: MRKH syndrome is a rare congenital disorder, and the malformations rarely cause death. We describe the features of abnormal fibrous tissue and urinary bladder duplication cyst in a patient with MRKH syndrome.
MATERIAL AND METHODS: A randomized trial was conducted in the University of Malaya Medical Center. A total of 163 term multiparas (no dropouts) with unripe cervixes (Bishop score ≤5) scheduled for labor induction were randomized to outpatient or inpatient Foley catheter. Primary outcomes were delivery during "working hours" 08:00-18:00 h and maternal satisfaction on allocated care (assessed by 11-point visual numerical rating score 0-10, with higher score indicating more satisfied).
CLINICAL TRIAL REGISTRATION: ISRCTN13534944.
RESULTS: Comparing outpatient and inpatient arms, delivery during working hours were 54/82 (65.9%) vs. 48/81 (59.3%) (relative risk 1.1, 95% CI 0.9-1.4, p = 0.421) and median maternal satisfaction visual numerical rating score was 9 (interquartile range 9-9) vs. 9 (interquartile range 8-9, p = 0.134), repectively. Duration of hospital stay and membrane rupture to delivery interval were significantly shorter in the outpatient arm: 35.8 ± 20.2 vs. 45.2 ± 16.2 h (p = 0.001) and 4.1 ± 2.9 vs. 5.3 ± 3.6 h (p = 0.020), respectively. Other maternal and neonatal secondary outcomes were not significantly different.
CONCLUSIONS: The trial failed to demonstrate the anticipated increase in births during working hours with outpatient compared with inpatient induction of labor with Foley catheter in parous women with an unripe cervix. Hospital stay and membrane rupture to delivery interval were significantly shortened in the outpatient group. The rate of maternal satisfaction was high in both groups and no significant differences were found.
MAIN METHODS: A pull-down assay was performed to identify the binding partner of the L-SP40 peptide. Co-immunoprecipitation and co-localization assays with the L-SP40 peptide were employed to confirm the receptor partner in RD cells. The outcomes were validated using receptor knockdown and antibody blocking assays. The L-SP40 peptide was further evaluated for the protection of neonatal mice against lethal challenge by mouse-adapted EV-A71.
KEY FINDINGS: The L-SP40 peptide was found to interact and co-localize with nucleolin, the key attachment receptor of Enteroviruses A species, as demonstrated in the pull-down, co-immunoprecipitation and co-localization assays. Knockdown of nucleolin from RD cells led to a significant reduction of 3.5 logs of viral titer of EV-A71. The L-SP40 peptide demonstrated 80% protection of neonatal mice against lethal challenge by the mouse-adapted virus with a drastic reduction in the viral loads in the blood (~4.5 logs), skeletal muscles (1.5 logs) and brain stem (1.5 logs).
SIGNIFICANCE: L-SP40 peptide prevented severe hind limb paralysis and death in suckling mice and could serve as a potential broad-spectrum antiviral candidate to be further evaluated for safety and potency in future clinical trials against EV-A71.
METHODS: In the present cross-sectional study conducted at a tertiary teaching hospital, we aimed to investigate the prevalence and associated risk factors of undiagnosed depression in patients with epilepsy. We recruited patients with epilepsy aged 18-65 years after excluding those with background illnesses that may have contributed to the depressive symptoms. In total, 129 participants were recruited. We collected their demographic and clinical details before interviewing them using two questionnaires-the Neurological Disorders Depression Inventory for Epilepsy and Beck's Depression Inventory-II. Subsequently, if a participant screened positive for depression, the diagnosis was confirmed using the Diagnostic and Statistical Manual of Mental Disorders questionnaire, and a psychiatric clinic referral was offered.
RESULTS: Among the 129 participants, 9.3 % had undiagnosed major depressive disorder, and there was a female preponderance (66.7 %). The risk factors for undiagnosed depression among patients with epilepsy included low socioeconomic background (p = 0.026), generalized epilepsy (p = 0.036), and temporal lobe epilepsy (p = 0.010). Other variables such as being underweight and unmarried were more common among patients diagnosed with depression than without but no statistically significant relationship was found.
CONCLUSION: The prevalence of undiagnosed depression among patients with epilepsy was higher than that in population-based studies conducted in Western countries. Although questionnaires to screen for depression are widely available, some clinicians rarely use them and, therefore, fail to identify patients who may benefit from psychosocial support and treatment that would improve their disease outcomes and quality of life. The present study indicated that clinicians should use screening questionnaires to identify undiagnosed depression in people with epilepsy.
METHODS: This is a retrospective case control study in Hospital Seri Manjung and Hospital Teluk Intan, Perak, Malaysia. P. aeruginosa bacteraemia cases that occurred between 1st January 2015 to 31st December 2019 were included, whilst E. coli bacteraemia cases that occurred within the same period were recruited successively until 1:2 case control ratio was achieved. Subjects below 12-year-old and those with polymicrobial bacteraemia were excluded. Demographic, clinical and treatment data were collected using pre-tested data collection forms by trained investigators.
RESULTS: A total of 61 patients with P. aeruginosa bacteraemia and 122 patients with E. coli bacteraemia were included. Recent admission in the earlier three months, regular haemodialysis, immunosuppressive therapy in the past 30 days, chronic wound/pressure sore at presentation and indwelling urinary catheter at presentation were identified as independent predictors of CO pseudomonal bacteraemia. Whilst older age was identified as a negative predictor of CO Pseudomonal bacteraemia (all p<0.05). The 30-day mortality rate was 34.4% in subjects with P. aeruginosa bacteraemia and 27.0% in those with E. coli bacteraemia (p=0.302). Predictors of 30-day mortality for community onset gram negative bacteraemia were as follow: older age, underlying solid tumours, neutropaenia at presentation, in-patient mechanical ventilation, and inpatient nasogastric tube insertion. Unexpectedly, receipt of inappropriate empirical antibiotics which was switched later (delayed and non-delayed switching) was identified as the negative predictors of mortality (all p<0.05).
CONCLUSION: It is prudent to restrict the usage of empirical anti-pseudomonal antibiotics among individuals at risk as liberal usage of broad-spectrum antibiotics engenders emergence of drug resistant organism, particularly in district setting where community onset pseudomonal bacteraemia remains scarce. Subjects with elevated risk of mortality should receive early escalation of care as per sepsis management guidelines.