The utility and safety of paediatric endoscopy in a district general hospital in Southeast England.

This study was done to evaluate the appropriateness, diagnostic yield, and quality of paediatric gastrointestinal endoscopy in a large DGH with tertiary paediatric gastroenterology services. It was a retrospective cohort study of children who had at least one gastrointestinal endoscopy during 31 months (May 2018-Dec 2020) in a district general hospital in Southeast England. The participants were children (2-17 years). Two hundred ninety-three procedures were performed in total, 80% were diagnostic and 20% for surveillance. The median age was 12 years and 52.5% were males. Oesophago-gastro-duodenoscopy (OGD) corresponded to 79.5% of procedures, ileo-colonoscopy (IC) to 7.2% and the remaining had both procedures. The main diagnostic indication was persistent abdominal pain in 33.5% of cases, followed by suspected GORD (14.8%), recurrent vomiting (14.3%), dysphagia (9.1%) and blood loss per rectum (8.6%). A total of 64.7% showed abnormal macroscopic findings, and 69.2% showed histopathological signs of disease. The most common histological diagnosis was gastritis in 23% followed by coeliac disease in 13%, reflux oesophagitis in 12.2% and inflammatory bowel disease in 9.6%. Procedures were performed with utmost safety with two reported cases of complications, which were appropriately managed. The completion rate of diagnostic IC was 87%. A waiting time of 6 weeks was achieved in 50.4% of cases. CONCLUSION: Paediatric endoscopy can be safely performed in a district general hospital with the right setup and can aid in the management of gastrointestinal disease in the paediatric patient. It is important to monitor and regularly audit such practices to improve the quality of specialist services. WHAT IS KNOWN: • Paediatric endoscopy is predominantly performed in large tertiary centres and included in the diagnostic algorithm for many paediatric gastrointestinal conditions. • There are recommendations on clinical indication endorsed by ESPGHAN and key quality indicators published jointly by JAG and BSPGHAN. WHAT IS NEW: • Paediatric endoscopy can be appropriately and safely performed in district general hospital by trained professionals, decreasing the workload in larger tertiary paediatric centres. • Adoption of regular audit practices is essential to ensure and improve quality and appropriateness of this specialist service.

A Plasma α-Tocopherome Can Be Identified from Proteins Associated with Vitamin E Status in School-Aged Children of Nepal.

BACKGROUND: The term vitamin E describes a family of 8 vitamers, 1 of which is α-tocopherol, that is essential for human health. Vitamin E status remains largely unknown in low-income countries because of the complexity and cost of measurement. Quantitative proteomics may offer an approach for identifying plasma proteins for assessing vitamin E status in these populations. OBJECTIVE: To improve options for vitamin E status assessment, we sought to detect and quantify a set of plasma proteins associated with α- and γ-tocopherol concentrations in a cohort of 500 rural Nepalese children aged 6-8 y and, based on nutrient-protein associations, to predict the prevalence of vitamin E deficiency (α-tocopherol <12 µmol/L). METHODS: Study children were born to mothers enrolled in an earlier antenatal micronutrient trial in Sarlahi District, Nepal. Plasma α- and γ-tocopherol concentrations were measured by high-performance liquid chromatography. Plasma aliquots were depleted of 6 high-abundance proteins, digested with trypsin, labeled with isobaric mass tags, and assessed for relative protein abundance by tandem mass spectrometry. Linear mixed-effects models were used to evaluate the association between α-tocopherol status and relative protein abundance and to predict deficiency. RESULTS: We quantified 982 plasma proteins in >10% of all child samples, of which 119 correlated with α-tocopherol (false discovery rate, q < 0.10). Proteins were primarily involved in lipid transport, coagulation, repair, innate host defenses, neural function, and homeostasis. Six proteins [apolipoprotein (apo)C-III; apoB; pyruvate kinase, muscle; forkhead box 04; unc5 homolog C; and regulator of G-protein signaling 8] explained 71% of the variability in plasma α-tocopherol, predicting an in-sample population prevalence of vitamin E deficiency of 51.4% (95% CI: 46.4%, 56.3%) compared with a measured prevalence of 54.8%. Plasma γ-tocopherol was associated with 12 proteins (q < 0.10), 2 of which (apoC-III and Misato 1) explained 20% of its variability. CONCLUSIONS: In this undernourished population of children in South Asia, quantitative proteomics identified a large plasma α-tocopherome from which 6 proteins predicted the prevalence of vitamin E deficiency. The findings illustrate that protein biomarkers, once absolutely quantified, can potentially predict micronutrient deficiencies in populations. The maternal micronutrient supplementation trial from which data were derived as a follow-up activity was registered with clinicaltrials.gov as NCT00115271.

[Adult Sturge-Weber syndrome without facial hemangioma: report of one case].

Sturge-Weber syndrome (SWS) is characterized by angiomas affecting the ophthalmic division of the trigeminal nerve, epilepsy, intellectual impairment, hemiplegia and glaucoma. We report a patient who developed SWS without facial hemangioma (SWS type III) in his adulthood. The patient presented with repeated episodes of headache since age 37 year. He manifested first attack of seizure at the age 47 year followed by aphasia and right upper limb palsy. Brain CT scan revealed right parietal-occipital calcification, brain CT angiography showed right temporal lobe and occipital lobe vascular malformation, and MRI showed leptomeningeal enhancement in the riht cerebral piamater. The seizure was controlled with antiepileptic drugs and reviewed in routine follow up.

The plasma proteome identifies expected and novel proteins correlated with micronutrient status in undernourished Nepalese children.

Micronutrient deficiencies are common in undernourished societies yet remain inadequately assessed due to the complexity and costs of existing assays. A plasma proteomics-based approach holds promise in quantifying multiple nutrient:protein associations that reflect biological function and nutritional status. To validate this concept, in plasma samples of a cohort of 500 6- to 8-y-old Nepalese children, we estimated cross-sectional correlations between vitamins A (retinol), D (25-hydroxyvitamin D), and E (α-tocopherol), copper, and selenium, measured by conventional assays, and relative abundance of their major plasma-bound proteins, measured by quantitative proteomics using 8-plex iTRAQ mass tags. The prevalence of low-to-deficient status was 8.8% (<0.70 µmol/L) for retinol, 19.2% (<50 nmol/L) for 25-hydroxyvitamin D, 17.6% (<9.3 µmol/L) for α-tocopherol, 0% (<10 µmol/L) for copper, and 13.6% (<0.6 µmol/L) for selenium. We identified 4705 proteins, 982 in >50 children. Employing a linear mixed effects model, we observed the following correlations: retinol:retinol-binding protein 4 (r = 0.88), 25-hydroxyvitamin D:vitamin D-binding protein (r = 0.58), α-tocopherol:apolipoprotein C-III (r = 0.64), copper:ceruloplasmin (r = 0.65), and selenium:selenoprotein P isoform 1 (r = 0.79) (all P < 0.0001), passing a false discovery rate threshold of 1% (based on P value-derived q values). Individual proteins explained 34-77% (R(2)) of variation in their respective nutrient concentration. Adding second proteins to models raised R(2) to 48-79%, demonstrating a potential to explain additional variation in nutrient concentration by this strategy. Plasma proteomics can identify and quantify protein biomarkers of micronutrient status in undernourished children. The maternal micronutrient supplementation trial, from which data were derived as a follow-up activity, was registered at clinicaltrials.gov as NCT00115271.

Genetic ablation or chemical inhibition of phosphatidylcholine transfer protein attenuates diet-induced hepatic glucose production.

UNLABELLED: Phosphatidylcholine transfer protein (PC-TP, synonym StARD2) is a highly specific intracellular lipid binding protein that is enriched in liver. Coding region polymorphisms in both humans and mice appear to confer protection against measures of insulin resistance. The current study was designed to test the hypotheses that Pctp-/- mice are protected against diet-induced increases in hepatic glucose production and that small molecule inhibition of PC-TP recapitulates this phenotype. Pctp-/- and wildtype mice were subjected to high-fat feeding and rates of hepatic glucose production and glucose clearance were quantified by hyperinsulinemic euglycemic clamp studies and pyruvate tolerance tests. These studies revealed that high-fat diet-induced increases in hepatic glucose production were markedly attenuated in Pctp-/- mice. Small molecule inhibitors of PC-TP were synthesized and their potencies, as well as mechanism of inhibition, were characterized in vitro. An optimized inhibitor was administered to high-fat-fed mice and used to explore effects on insulin signaling in cell culture systems. Small molecule inhibitors bound PC-TP, displaced phosphatidylcholines from the lipid binding site, and increased the thermal stability of the protein. Administration of the optimized inhibitor to wildtype mice attenuated hepatic glucose production associated with high-fat feeding, but had no activity in Pctp-/- mice. Indicative of a mechanism for reducing glucose intolerance that is distinct from commonly utilized insulin-sensitizing agents, the inhibitor promoted insulin-independent phosphorylation of key insulin signaling molecules. CONCLUSION: These findings suggest PC-TP inhibition as a novel therapeutic strategy in the management of hepatic insulin resistance.

An audit of patients admitted to hospital in Nepal for COPD exacerbation.

Objectives: Chronic obstructive pulmonary disease is a large and increasing problem in low- and middle-income countries; Nepal is no exception. We aimed to obtain information on patient characteristics and the level of care provided to patients admitted for acute exacerbation of chronic obstructive pulmonary disease in two Nepalese hospitals and to compare the given care with the Global Initiative for Chronic Obstructive Lung Disease guidelines. Methods: This was a cross-sectional, observational, descriptive study. All patients admitted to two Nepalese hospitals due to acute exacerbation of chronic obstructive pulmonary disease between 18 February and 5 April 2019 were asked to participate. Results: In total, 108 patients with a median age of 70 years participated. Fifty-three (42.7%) were male, 80 (74.8%) were former smokers, and 46 (45.1%) were farmers. Using the Global Initiative for Chronic Obstructive Lung Disease A-D classification, 97 (90.6%) of the patients were classified in group D. All the patients received supplementary oxygen treatment and 103 (95.4%) were treated with short-acting beta2 agonists. A total of 105 (97.2%) patients received antibiotics, and 80 (74.5%) received systemic corticosteroids. The majority was discharged with triple therapy including long-acting muscarinic antagonist, long-acting beta2 agonist, and inhaled corticosteroids, and 72 (75.8%) were discharged with long-term oxygen treatment. Conclusion: All elements of the Global Initiative for Chronic Obstructive Lung Disease guidelines were applied. However, due to a lack of information, it cannot be concluded whether the treatment was provided on the correct indications. The average patient received almost all the treatment alternatives available. This might indicate a very sick population or over-treatment.

Risk factors for wasting among hospitalised children in Nepal.

BACKGROUND: Malnutrition has various adverse effects in children. This study aimed to determine risk factors for malnutrition among hospitalised children, changes in nutritional status at admission and discharge and effects of use of systematic anthropometric measurement in identification of malnutrition. METHODS: We enrolled 426 children, aged between 6 months and 15 years, admitted to Siddhi Memorial Hospital, Bhaktapur, Nepal, from November 2016 to June 2017. Anthropometric measurements were performed at the time of admission and discharge. Risk factors were assessed by multivariable logistic regression models. RESULTS: Median age of children was 26 months (IQR: 13-49), and males were 58.7%. The prevalence of wasting was 9.2% (39/426) at admission and 8.5% (36/426) at discharge. Risk factors associated with wasting at admission were ethnic minority (aOR: 3.6, 95% CI 1.2-10.8), diarrhoeal diseases (aOR = 4.0; 95% CI 1.3-11.8), respiratory diseases (aOR: 3.4, 95% CI 1.4-8.1) and earthquake damage to house (aOR = 2.6; 95% CI 1.1-6.3). Clinical observation by care providers identified only 2 out of 112 malnutrition cases at admission and 4 out of 119 cases at discharge that were detected by the systematic anthropometric measurement. CONCLUSIONS: Ethnic minority, diarrhoeal diseases, respiratory infections and house damage due to the earthquake were risk factors associated with wasting. Systematic anthropometric examination can identify significantly more malnourished children than simple observation of care providers.

Predictors of Mortality in COVID-19-Positive Patients On and Off CPAP: A Review From a Tertiary Care Setting in the NHS.

Introduction Since the first description of a coronavirus-related pneumonia outbreak in December 2019, the virus SARS-CoV-2 that causes the infection/disease coronavirus disease 2019 (COVID-19) has evolved into a pandemic, and as of today, millions have been affected. Objectives Our aim was to identify the predictors of mortality in COVID-19-positive patients on or off continuous positive airway pressure (CPAP). Methodology This was an observational study. Data were collected from February 2020 to April 2020 with patients admitted to the COVID-19 ward at The James Cook University Hospital, Middlesbrough, England. The inclusion criteria were COVID-19-positive patients confirmed through PCR tests on or off CPAP. Patients who had negative RT-PCR for COVID-19 and those who were intubated were excluded. Results A total of 56 patients diagnosed with COVID-19 (through RT-PCR) were included in the final analysis, among which 27 were on CPAP, while 29 did not require CPAP (NCPAP). The overall mean age of the patients was 66 ± 14 (range: 26-94) years. The mean age of CPAP and NCPAP patients was 63 ± 15 (range: 26-85) years and 68 ± 13 (range: 40-94) years, respectively. The ethnicity of 54 (96.4%) patients was White-Caucasian, while 2 (3.6%) were British-Asian. In the study sample, 16 (28.6%) patients expired, of which 11 (40.7%) were on CPAP, while 5 (16.7%) did not require CPAP during the disease course. Correlation analysis showed that overall higher age, Medical Research Council Dyspnoea (MRCD) score, performance status (PS), and consolidation affecting more than one quadrant of the lungs were significantly correlated with increased mortality. Among patients receiving CPAP, higher age, MRCD score, and PS were significant predictors of mortality. Among the NCPAP group, advancing age, respiratory rate, MRCD score, PS, increased creatinine levels, and consolidation affecting more than one quadrant of the lungs were the predictors of mortality. Conclusion Even with a small sample size, we can see that there are definitive predictors that are directly proportional to increased mortality in COVID-19 patients on CPAP, such as higher age, performance status, MRCD score, and increased lung involvement of consolidation in more than one quadrant, which can help us rationalize management.

Screening for early onset neonatal sepsis: NICE guidance-based practice versus projected application of the Kaiser Permanente sepsis risk calculator in the UK population.

OBJECTIVE: To compare management recommendations of the National Institute for Health and Care Excellence (NICE) guidelines with the Kaiser Permanente sepsis risk calculator (SRC) for risk of early onset neonatal sepsis (EONS). DESIGN: Multicentre prospective observational projection study. SETTING: Eight maternity hospitals in Wales, UK. PATIENTS: All live births ≥34 weeks gestation over a 3-month period (February-April 2018). METHODS: Demographics, maternal and infant risk factors, infant's clinical status, antibiotic usage and blood culture results from first 72 hours of birth were collected. Infants were managed using NICE recommendations and decisions compared with that projected by SRC. MAIN OUTCOME MEASURE: Proportion of infants recommended for antibiotics on either tool. RESULTS: Of 4992 eligible infants, complete data were available for 3593 (71.9%). Of these, 576 (16%) were started on antibiotics as per NICE recommendations compared with 156 (4.3%) projected by the SRC, a relative reduction of 74%. Of the 426 infants avoiding antibiotics, SRC assigned 314 (54.6%) to normal care only. There were seven positive blood cultures-three infants were recommended antibiotics by both, three were not identified in the asymptomatic stage by either; one was a contaminant. No EONS-related readmission was reported. CONCLUSION: The judicious adoption of SRC in UK clinical practice for screening and management of EONS could potentially reduce interventions and antibiotic usage in three out of four term or near-term infants and promote earlier discharge from hospital in >50%. We did not identify any EONS case missed by SRC when compared with NICE. These results have significant implications for healthcare resources.

Dietary green tea extract lowers plasma and hepatic triglycerides and decreases the expression of sterol regulatory element-binding protein-1c mRNA and its responsive genes in fructose-fed, ovariectomized rats.

The objective of this study was to determine whether green tea (GT) inhibits the expression of genes regulating hepatic lipogenesis and intestinal lipid transport in fructose-fed ovariectomized (OX) rats. OX rats were assigned to: 1) a control group (S) fed the AIN-93G diet with corn starch as the major carbohydrate source; 2) another control group (F) fed the same diet but containing fructose at 60% as the major carbohydrate source; 3) a group fed the F diet but containing 0.5% GT; and 4) a group fed the F diet containing 1% GT. At 6 wk, plasma and liver triglyceride (TG) and cholesterol and expression of liver sterol regulatory element-binding protein-1c (SREBP-1c) and selected genes involved in lipogenesis and lipid transport were measured. Fructose elevated plasma TG and cholesterol compared with the S group. GT at 0.5 and 1.0% markedly lowered plasma and liver TG. Fructose increased the expression of SREBP-1c, fatty acid synthase, and stearoyl-CoA desaturase 1 mRNA in the liver, whereas GT decreased the expression of these lipogenic genes. Similarly, fructose increased the abundance of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase mRNA, whereas GT significantly decreased its expression. GT did not alter the expression of scavenger receptor class B, type 1, microsomal TG transfer protein, and apobec 1 in the liver and intestine. The results suggest that the lipid-lowering effect of GT is mediated partly by its inhibition of hepatic lipogenesis involving SREBP-1c and its responsive genes without affecting lipoprotein assembly.

Raisins and additional walking have distinct effects on plasma lipids and inflammatory cytokines.

BACKGROUND: Raisins are a significant source of dietary fiber and polyphenols, which may reduce cardiovascular disease (CVD) risk by affecting lipoprotein metabolism and inflammation. Walking represents a low intensity exercise intervention that may also reduce CVD risk. The purpose of this study was to determine the effects of consuming raisins, increasing steps walked, or a combination of these interventions on blood pressure, plasma lipids, glucose, insulin and inflammatory cytokines. RESULTS: Thirty-four men and postmenopausal women were matched for weight and gender and randomly assigned to consume 1 cup raisins/d (RAISIN), increase the amount of steps walked/d (WALK) or a combination of both interventions (RAISINS + WALK). The subjects completed a 2 wk run-in period, followed by a 6 wk intervention. Systolic blood pressure was reduced for all subjects (P = 0.008). Plasma total cholesterol was decreased by 9.4% for all subjects (P < 0.005), which was explained by a 13.7% reduction in plasma LDL cholesterol (LDL-C) (P < 0.001). Plasma triglycerides (TG) concentrations were decreased by 19.5% for WALK (P < 0.05 for group effect). Plasma TNF-alpha was decreased from 3.5 ng/L to 2.1 ng/L for RAISIN (P < 0.025 for time and group x time effect). All subjects had a reduction in plasma sICAM-1 (P < 0.01). CONCLUSION: This research shows that simple lifestyle modifications such as adding raisins to the diet or increasing steps walked have distinct beneficial effects on CVD risk.

Open label comparative trial of mono versus dual antibiotic therapy for Typhoid Fever in adults.

BACKGROUND: Emerging resistance to antibiotics renders therapy of Typhoid Fever (TF) increasingly challenging. The current single-drug regimens exhibit prolonged fever clearance time (FCT), imposing a great burden on both patients and health systems, and potentially contributing to the development of antibiotic resistance and the chronic carriage of the pathogens. The aim of our study was to assess the efficacy of combining third-generation cephalosporin therapy with azithromycin on the outcomes of TF in patients living in an endemic region. METHODS: An open-label, comparative trial was conducted at Dhulikhel Hospital, Nepal, between October 2012 and October 2014. Only culture-confirmed TF cases were eligible. Patients were alternately allocated to one of four study arms: hospitalized patients received either intravenous ceftriaxone or a combination of ceftriaxone and oral azithromycin, while outpatients received either oral azithromycin or a combination of oral azithromycin and cefexime. The primary outcome evaluated was FCT and the secondary outcomes included duration of bacteremia. RESULTS: 105 blood culture-confirmed patients, of whom 51 were treated as outpatients, were eligible for the study. Of the 88 patients who met the inclusion criteria for FCT analysis 41 patients received a single-agent regimen, while 47 patients received a combined regimen. Results showed that FCT was significantly shorter for the latter (95 versus 88 hours, respectively, p = 0·004), and this effect was exhibited in both the hospitalized and the outpatient sub-groups. Repeat blood cultures, drawn on day 3, were positive for 8/47 (17%) patients after monotherapy, versus 2/51 (4%) after combination therapy (p = 0·045). No severe complications or fatalities occurred in any of the groups. CONCLUSIONS: Combined therapy of third-generation cephalosporins and azithromycin for TF may surpass monotherapy in terms of FCT and time to elimination of bacteremia. TRIAL REGISTRATION: Trial registration number: NCT02224040.

Pre-earthquake national patterns of preschool child undernutrition and household food insecurity in Nepal in 2013 and 2014.

BACKGROUND AND OBJECTIVES: Preschool undernutrition remains a burden in Nepal. This paper reports results of surveys in 2013 and 2014, examining patterns of child nutritional status across the country, associations with household food insecurity and antecedent comparative national data for subsequent evaluations of nutritional status following the earthquake in Nepal in 2015. METHODS AND STUDY DESIGN: A multi-stage sample was drawn comprising 21 sites in 75 districts of the country, representing the mountains, hills and Terai zones, providing proportionate to zonal samples of 4286 and 4947 households and 5401 and 5474 preschool children in each year, respectively. Children 6 to 59 months of age were measured for weight and height, expressed as standardized z-scores for height-for-age (HAZ), weight-for-height (WHZ), and stunting and wasting (<-2 z for each). The household food insecurity access scale (HFIAS) was used to measure food security. RESULTS: Between 2013 and 2014, HAZ decreased from a mean (SD) of -1.46 (1.39) to -1.54 (1.33) z-scores, while the prevalence of stunting increased from 35.5% to 37.4% (p<0.05 for both), evident in the mountains and Terai but not hills. In both years, wasting was highest (~22%) in the Terai versus mountains or hills (~8%). More households were classified food secure in 2014 (73%) than 2013 (59%), evident in all zones. CONCLUSIONS: Two midyear surveys in Nepal revealed a stable nutritional situation among preschool children, reflecting a pause in the long-term decline in stunting noted in previous years. The same period saw a slight reduction in wasting and improved household food security.

Effects of a carbohydrate-restricted diet with and without supplemental soluble fiber on plasma low-density lipoprotein cholesterol and other clinical markers of cardiovascular risk.

Carbohydrate-restricted diets (CRDs) promote weight loss, reductions in plasma triacylglycerol (TAG) levels, and increases in high-density lipoprotein cholesterol (HDL-C) levels but may cause undesirable low-density lipoprotein cholesterol (LDL-C) responses in some people. The objective of the present study was to determine the effect of adding soluble fiber to a CRD on plasma LDL-C and other traditionally measured markers of cardiovascular disease. Using a parallel-arm, double-blind, placebo-controlled design, 30 overweight and obese men (body mass index, 25-35 kg/m(2)) were randomly assigned to supplement a CRD with soluble fiber (Konjac-mannan, 3g/d) (n = 15) or placebo (n = 15). Plasma lipids, anthropometrics, body composition, blood pressure, and nutrient intake were evaluated at baseline and at 6 and 12 weeks. Compliance was excellent as assessed by 7-day weighed dietary records and ketonuria. Both groups experienced decreases in (P < .01) body weight, percent body fat, systolic blood pressure, waist circumference, and plasma glucose levels. After 12 weeks, HDL-C and TAG improved significantly in the fiber (10% and -34%) and placebo (14%, -43%) groups. LDL-C decreased by 17.6% (P < .01) at week 6 and 14.1% (P < .01) at week 12 in the fiber group. Conversely, LDL-C reductions were significant in the placebo group only after 12 weeks (-6.0%, P < .05). We conclude that although clearly effective at lowering LDL-C, adding soluble fiber to a CRD during active and significant weight loss provides no additional benefits to the diet alone. Furthermore, a CRD led to clinically important positive alterations in cardiovascular disease risk factors.

Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation.

The NLRP3 inflammasome is activated in the early period following subarachnoid hemorrhage(SAH), resulting in inflammatory responses. Recent studies have shown that activation of NLRP3 inflammasome is suppressed by autophagy, but the potential mechanism is unclear. In this study, we examined whether mitophagy was involved in the beneficial effect of melatonin and its relationship with NLRP3 inflammasome activation after SAH. In total, 130 adult-male SD rats were randomly divided into four groups: sham group, SAH + vehicle group, SAH + melatonin group, and SAH + 3-methyladenine (3-MA) + melatonin group. Brain samples were used for brain water content analysis, ROS assay, Western blot, immunohistochemistry and transmission electron microscopy. The results showed that melatonin treatment markedly increased the expression of both autophagy markers(LC3-II/LC3-I and Atg 5), and mitophagy markers(Parkin and PINK-1) following SAH induction. Additionally, melatonin treatment attenuated pathological changes in mitochondria and reduced ROS generation, which are closely related to NLRP3 inflammasome activation. Consequently, melatonin-mediated upregulation of proteins associated with mitophagy inhibited NLRP3 inflammasome activation and significantly reduced pro-inflammatory cytokine levels after SAH. Conversely, 3-MA, an autophagy inhibitor, reversed these beneficial effects of melatonin on mitophagy and the NLRP3 inflammasome. These results suggest that mitophagy-associated NLRP3 inflammasome inhibition by melatonin is neuroprotective against early brain injury post-SAH in rats.

A predicted model for postoperative seizure outcomes after the surgical resection of supratentorial cavernous malformations.

To explore a predicted model for postoperative seizure outcomes after the surgical resection of supratentorial cavernous malformations.This study was a retrospective review of consecutive patients with cerebral supratentorial cavernous malformations presenting with seizures. All patients underwent surgical resection of CCMs. Univariate and multivariate analyses were performed to determine the predictive value of the preoperative seizure frequency, seizure type, seizure duration, lesion location, lesion size, and the presence of residual hemosiderin.A total of 43 patients met the inclusion criteria. After a mean follow-up period of 40.95 months, 34 patients who were free from postoperative seizures were classified into Engel class I, and the remaining 9 patients were classified into Engel classes II-IV. A univariate analysis showed that the seizure frequency (χ = 13.440, P = 0.004) and seizure duration (χ = 5.145, P = 0.023) prior to surgery were associated with a worse postoperative seizure prognosis. Other covariates including age at onset, gender, a history of the medications taken, smoking status, family history, lesion characteristics, and the role of hemosiderin were not related to seizure outcomes. Logistic regression results demonstrated that the preoperative seizure frequency was an effective predictor (P = 0.004). The receiver operating characteristic curve indicated that area under the curve for the preoperative seizure frequency test was 0.833 (95% confidence interval 0.709-0.957, P = 0.002).The preoperative seizure frequency was a prognostic factor for postoperative seizure outcomes after surgical resection of supratentorial cavernous malformations. To obtain a favorable prognosis for CCM patients with preoperative seizures, early intervention might be a better choice.

JTT-130, a microsomal triglyceride transfer protein (MTP) inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs.

BACKGROUND: Microsomal transfer protein inhibitors (MTPi) have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG). However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. METHODS: Male guinea pigs (n = 10 per group) were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control), 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. RESULTS: Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P < 0.05). Atorvastatin had the most pronounced hypolipidemic effects with a 35% reduction in LDL cholesterol and 40% reduction in TG. JTT-130 did not induce hepatic lipid accumulation compared to controls. Cholesteryl ester transfer protein (CETP) activity was reduced in a dose dependent manner by increasing doses of MTPi and guinea pigs treated with atorvastatin had the lowest CETP activity (P < 0.01). In addition the number of molecules of cholesteryl ester in LDL and LDL diameter were lower in guinea pigs treated with atorvastatin. In contrast, hepatic enzymes involved in maintaining cholesterol homeostasis were not affected by drug treatment. CONCLUSION: These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.

The Role of Hemosiderin Excision in Seizure Outcome in Cerebral Cavernous Malformation Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Whether the excision of hemosiderin surrounding cerebral cavernous malformations (CCMs) is necessary to achieve a seizure-free result has been the subject of debate. Here, we report a systematic review of related literature up to Jan 1, 2015 including 594 patients to assess the effect of hemosiderin excision on seizure outcome in patients with CCMs by meta-analysis. METHODS: Ten studies comparing extended hemosiderin excision with only lesion resection were identified by searching the English-language literature. Meta-analyses, subgroup analyses and sensitivity analysis were conducted to determine the association between hemosiderin excision and seizure outcome after surgery. RESULTS: Seizure outcome was significantly improved in the patients who underwent an extended excision of the surrounding hemosiderin (OR, 0.62; 95% CI: 0.42-0.91; P = 0.01). In subgroup analysis, studies from Asia (OR, 0.42; 95% CI: 0.25-0.71; P = 0.001), male-majority (female ratio < 50%) studies (OR, 0.56; 95% CI: 0.33-0.96; P = 0.04), low occurrence rate of multiple CCMs (OR, 0.37; 95% CI: 0.20-0.71; P = 0.003), cohort studies (OR, 0.44; 95% CI: 0.28-0.68; P = 0.78), longer duration of seizure symptoms (> 1 year) before surgery (OR, 0.43; 95% CI: 0.22-0.84; P = 0.01), lesion diameter > 2 cm (OR, 0.41; 95% CI: 0.19-0.87; P = 0.02) and short-term (< 3 years) follow-up (OR, 0.48; 95% CI: 0.29-0.80; P = 0.005) tended to correlate with a significantly favorable outcome. CONCLUSION: Patients who underwent extended surrounding hemosiderin excision could exhibit significantly improved seizure outcomes compared to patients without hemosiderin excision. However, further well-designed prospective multiple-center RCT studies are still needed.

A combination of psyllium and plant sterols alters lipoprotein metabolism in hypercholesterolemic subjects by modifying the intravascular processing of lipoproteins and increasing LDL uptake.

We previously demonstrated that a diet therapy involving consumption of 7.28 g psyllium (PSY) and 2 g of plant sterols (PS) per day reduced LDL cholesterol from 3.6 +/- 0.7 to 3.1 +/- 0.8 mmol/L (P < 0.01) and decreased the number of intermediate density lipoprotein particles and the smaller LDL and HDL subfractions in hypercholesterolemic individuals (n = 33). The study design was a randomized double blind crossover. Subjects consumed either 2 test cookies containing PSY+PS or 2 placebo cookies for 1 mo with a 3-wk wash out between treatments. To explore mechanisms of the lipid-lowering effects of combined PSY+PS, we present data related to intravascular and molecular regulation. Intake of PSY+PS decreased the cholesterol concentration in LDL-1 from 2.46 +/- 0.66 to 2.26 +/- 0.46 mmol/L and in LDL-2 from 0.63 +/- 0.24 to 0.54 +/- 0.27 mmol/L (P < 0.05) in the test compared with the placebo period. An increase in LDL peak size from 27.3 +/- 0.8 to 27.5 +/- 0.6 nm (P < 0.05) and a decrease in the prevalence of LDL pattern B from 27 to 18% (P < 0.05) also occurred during the PSY+PS period. Cholesteryl ester transfer protein activity was 11% lower (P < 0.05) during the test period. Notably, the abundance of the LDL receptor in circulating mononuclear cells as measured by real time PCR was 26% higher during the test compared with the placebo period (P < 0.03). These results indicate that the hypocholesterolemic action of PSY and PS can be explained in part by modifications in the intravascular processing of lipoproteins and by increases in LDL receptor-mediated uptake.

Carbohydrate restriction alters hepatic cholesterol metabolism in guinea pigs fed a hypercholesterolemic diet.

The current study was undertaken to evaluate the effect of carbohydrate restriction on hepatic cholesterol metabolism in guinea pigs fed a hypercholesterolemic diet. Hartley male guinea pigs (n = 10 per group) were fed 1 of 3 diets: a diet with a percent energy distribution of 42:23:35 carbohydrate:protein:fat and 0.04% cholesterol (control), a diet with the same macronutrient distribution but with 0.25% cholesterol (HChol), or a carbohydrate-restricted (CR) diet with a percent energy distribution of 11:30:59 carbohydrate:protein:fat and 0.25% cholesterol for 12 wk. There was more accumulation of hepatic cholesterol and triglycerides as well as lower 3-hydroxy-3-methyl glutaryl-CoA reductase messenger RNA abundance in guinea pigs fed the high-cholesterol diets (HChol and CR) (P < 0.01). Guinea pigs fed the CR diet had lower concentrations of hepatic total cholesterol and cholesteryl ester than those fed the HChol diet (P < 0.05). There was no diet effect on hepatic LDL receptor expression. Hepatic acyl CoA cholesteryl acyltransferase (ACAT) activity was lowest in guinea pigs fed the low-cholesterol diet (9.7 +/- 4.8 pmol.min(-1).mg(-1)), intermediate in those fed the CR diet (37.3 +/- 12.4 pmol.min(-1).mg protein(-1)), and highest in guinea pigs fed the HChol diet (55.9 +/- 11.2 pmol.min(-1).mg(-1)). ACAT activity was significantly correlated with hepatic cholesterol (r = 0.715; P < 0.01) and LDL cholesterol (r = 0.59; P < 0.01) for all dietary groups, suggesting a major role of this enzyme in hepatic cholesterol homeostasis and in lipoprotein concentrations. These results indicate that dietary cholesterol increases hepatic lipid accumulation and affects hepatic cholesterol homeostasis. Carbohydrate restriction in the presence of high cholesterol is associated with lower hepatic ACAT activity and an attenuation of hepatic cholesterol accumulation.