Genomic analysis of tyrosine hydroxylase gene sequence variations and its association with D-9- tetrahydrocannabinol dependence in addicts

Purpose: To elucidate the genetic basis of drug addiction by conducting a genetic analysis of TH (tyrosine hydroxylase) gene and the novel polymorphisms that might help in understanding addiction and its molecular basis. Methods: Forty-two subjects were recruited into three groups for this study. DNA was isolated from the individuals. PCR amplification of TH gene was carried out and amplicons were sequenced. Genomic characterization of TH gene provided five polymorphic loci – TH 1, TH 2, TH 3, TH 4 and TH 5 which were found among all the groups. Results: According to Shannon’s diversity index, the studied population was between 0.0762 and 0.6032. Heterozygosity index depicted that TH 1 locus was less heterozygous (0.3288), followed by TH 5 (0.3152). TH 1 (0.1462) was the least heterozygous. Genotypic analysis predicted that among these five loci, TH 4 (p = 0.039898) and TH 2 (p = 0.851716) were non-significant (p > 0.05) and obeyed Hardy Weinberg Equilibrium (HWE) law. There are few genetic changes in the studied population that can statistically be associated with drug addiction. Still, their genotypic distribution in the gene pool was very low. Conclusion: On the basis of these findings, drug addiction in the studied population is more likely a social issue rather than a genetic one. Keywords: Tyrosine hydroxylase, SNP, Drug dependenc

Occipital Encephalocele and Review of Literature

Encephalocele is a rare congenital malformation of the central nervous system. It is defined as a congenital herniation of the intracranial compartments through a long defect and contains various rudimentary cerebral tissue components or sometimes only cerebrospinal fluid. They are located at midline of parietal or occipital region when the defect is small. Usually only the meninges herniate and the anomaly is cranial Meningocele or cranium bifidum with Meningocele. We present 47 cases of encephalocele, mostly occipital encephalocele, operated during last 5 years in our hospital at the department of Neurosurgery SZH, RYK. This is a retrospective study.Material and Methods: Between January 2008 and December 2013. Forty seven cases of encephalocele have been treated at our department. They were diagnosed on the basis of clinical findings and CT scan was done in all patients. All patients were operated and diagnosis was confirmed at peroperatively. Demographic, clinical, radiological and operative data were reviewed from hospital charts.Results: The total number of patients was 47, out of which 23 were male and 24 were female. Neurosurgical data of patients with encephalocele over the five years and three months from January 2008 to April 2014 were retrospectively studied. The average age of the patients at the time presentation was 10 months and seven days.Conclusion: Encephalocele is a relatively uncommon neurosurgical entity largely seen in the pediatric population. Treatment of this condition can be rewarding if properly managed early. Occipital, parietal, frontal, and frontonasal types may be approached without opening the cranium, while sincipital and basal encephalocele usually require craniotomy. In this series we present our experience in the operative management of encepha-locele with good outcome and also share our recommendation in technical consideration for surgical approaches

A Novel Hybrid GWO-LS Estimator for Harmonic Estimation Problem in Time Varying Noisy Environment

The power quality of the Electrical Power System (EPS) is greatly affected by electrical harmonics. Hence, accurate and proper estimation of electrical harmonics is essential to design appropriate filters for mitigation of harmonics and their associated effects on the power quality of EPS. This paper presents a novel statistical (Least Square) and meta-heuristic (Grey wolf optimizer) based hybrid technique for accurate detection and estimation of electrical harmonics with minimum computational time. The non-linear part (phase and frequency) of harmonics is estimated using GWO, while the linear part (amplitude) is estimated using the LS method. Furthermore, harmonics having transients are also estimated using proposed harmonic estimators. The effectiveness of the proposed harmonic estimator is evaluated using various case studies. Comparing the proposed approach with other harmonic estimation techniques demonstrates that it has a minimum mean square error with less complexity and better computational efficiency

Enhancing the Expression and Purification of IL-29: A study of autoinduction and one-step Purification Methods

Background: Cytokines have long been viewed as a sign of hope due to their immunomodulatory and therapeutic characteristics. Developing simple, economical and readily scaled technologies to simplify their manufacturing is a critical challenge.Method: In this study we have used a customized medium to automatically induce the expression of the IL-29 in E. coli expression system from the T7 promoter, allowing for higher yields as compared to the traditional technique of IPTG induction. Similarly, one-step purification method is employed to make the fermentation process cost-effective, along with enhancing its efficiency.Results: From 1 L batches of IPTG-induced and autoinduced media, the harvested biomass was 11.8 g and 13.4 g, respectively and their corresponding IBs were 3.8 g and 4.8 g. Total protein purified from 1 L batch was 132  mg, at a concentration of 13 mg/mL, with an indicated high purity of 97%. IL-29 significantly decrease the metabolic activity of HepG2 cells. Specifically, 50% of the cells died at a concentration of 0.156 μg/mL, while 80% of the cells died at a concentration of 5 μg/mL.Conclusion: This study presents an economical solution for producing and purifying IL-29 in E. coli, resulting in higher yields of biomass and IBs than expensive traditional method. The purified protein was highly pure and had immunomodulatory effects on HepG2 cells. These findings have important implications for developing simplified and scalable technologies for cytokine production with therapeutic potential.Keywords: Escherichia coli; Cytokines; Interleukins; Interferons; Protein purification    

Efficacy of Five Days Nitrofurantoin Therapy versus Fosfomycin Stat Dose in Clinical Resolution of Uncomplicated Urinary Tract Infections

Objective: To compare the efficacy of 5-days Nitrofurantoin therapy versus Fosfomycin stat dose in clinical resolution of uncomplicated urinary tract infections in females of reproductive age group. Study Design: Comparative prospective study. Place and Duration of Study: Department of Medicine, Pak Emirates Military Hospital, Rawalpindi Pakistan, from Apr 2019 to Mar 2020. Methodology: A total of 498 females of reproductive age (18 years to 40 years) with lower urinary tract infection symptoms(increased urinary hesitancy, frequent micturition, tenderness at suprapubic region) and positive urine dipstick test for nitrates/leukocyte esterase test were incorporated in the study. Patients were randomly assigned to Group-A and Group-B,comprising 249 patients. Group-A was given tablet Nitrofurantoin 100mg every six hourly. Group-B was given Fosfomycin 3gstat dose. Patients were advised to follow up on days 14 and 28 of treatment to observe the clinical resolution of urinary tractinfection symptoms and bacteriologic response. Results: Clinical resolution of urinary tract infection on the 28th day of treatment was attained in 172(69.1%) patients of the Nitrofurantoin-Group versus 140(56.2%) patients receiving Fosfomycin (p-value 0.003). Baseline urine cultures were positive in 286(57.4%) patients. Microbiologic resolution was achieved in 109 of 140(77.9%) and 100 of 146(68.4%) (p- value=0.026). Conclusion: Among the females of reproductive age, five days of Nitrofurantoin therapy is superior to stat dose Fosfomycin in the clinical and microbiologic resolution of uncomplicated urinary tract infections

Bleeding disorders in the tribe: result of consanguineous in breeding

<p>Abstract</p> <p>Objective</p> <p>To determine the frequency and clinical features of bleeding disorders in the tribe as a result of consanguineous marriages.</p> <p>Design</p> <p>Cross Sectional Study</p> <p>Introduction</p> <p>Countries in which consanguinity is a normal practice, these rare autosomal recessive disorders run in close families and tribes. Here we describe a family, living in village Ali Murad Chandio, District Badin, labeled as haemophilia.</p> <p>Patients & Methods</p> <p>Our team visited the village & developed the pedigree of the whole extended family, up to seven generations. Performa was filled by incorporating patients, family history of bleeding, signs & symptoms, and bleeding from any site. From them 144 individuals were screened with CBC, bleeding time, platelet aggregation studies & RiCoF. While for PT, APTT, VWF assay and Factor VIII assay, samples were kept frozen at -70 degrees C until tested.</p> <p>Results</p> <p>The family tree of the seven generations comprises of 533 individuals, 63 subjects died over a period of 20 years and 470 were alive. Out of all those 144 subjects were selected on the basis of the bleeding history. Among them 98(68.1%) were diagnosed to have a bleeding disorder; 44.9% patients were male and 55.1% patients were female. Median age of all the patients was 20.81, range (4 months- 80 yrs). The results of bleeding have shown that majority had gum bleeding, epistaxis and menorrhagia. Most common bleeding disorder was Von Willebrand disease and Platelet functional disorders.</p> <p>Conclusion</p> <p>Consanguineous marriages keep all the beneficial and adversely affecting recessive genes within the family; in homozygous states. These genes express themselves and result in life threatening diseases. Awareness, education & genetic counseling will be needed to prevent the spread of such common occurrence of these bleeding disorders in the community.</p

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children &lt;18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p&lt;0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p&lt;0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p&lt;0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin

Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity

A major goal of biomedicine is to understand the function of every gene in the human genome. Loss-of-function mutations can disrupt both copies of a given gene in humans and phenotypic analysis of such 'human knockouts' can provide insight into gene function. Consanguineous unions are more likely to result in offspring carrying homozygous loss-of-function mutations. In Pakistan, consanguinity rates are notably high. Here we sequence the protein-coding regions of 10,503 adult participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS), designed to understand the determinants of cardiometabolic diseases in individuals from South Asia. We identified individuals carrying homozygous predicted loss-of-function (pLoF) mutations, and performed phenotypic analysis involving more than 200 biochemical and disease traits. We enumerated 49,138 rare (<1% minor allele frequency) pLoF mutations. These pLoF mutations are estimated to knock out 1,317 genes, each in at least one participant. Homozygosity for pLoF mutations at PLA2G7 was associated with absent enzymatic activity of soluble lipoprotein-associated phospholipase A2; at CYP2F1, with higher plasma interleukin-8 concentrations; at TREH, with lower concentrations of apoB-containing lipoprotein subfractions; at either A3GALT2 or NRG4, with markedly reduced plasma insulin C-peptide concentrations; and at SLC9A3R1, with mediators of calcium and phosphate signalling. Heterozygous deficiency of APOC3 has been shown to protect against coronary heart disease; we identified APOC3 homozygous pLoF carriers in our cohort. We recruited these human knockouts and challenged them with an oral fat load. Compared with family members lacking the mutation, individuals with APOC3 knocked out displayed marked blunting of the usual post-prandial rise in plasma triglycerides. Overall, these observations provide a roadmap for a 'human knockout project', a systematic effort to understand the phenotypic consequences of complete disruption of genes in humans.D.S. is supported by grants from the National Institutes of Health, the Fogarty International, the Wellcome Trust, the British Heart Foundation, and Pfizer. P.N. is supported by the John S. LaDue Memorial Fellowship in Cardiology from Harvard Medical School. H.-H.W. is supported by a grant from the Samsung Medical Center, Korea (SMO116163). S.K. is supported by the Ofer and Shelly Nemirovsky MGH Research Scholar Award and by grants from the National Institutes of Health (R01HL107816), the Donovan Family Foundation, and Fondation Leducq. Exome sequencing was supported by a grant from the NHGRI (5U54HG003067-11) to S.G. and E.S.L. D.G.M. is supported by a grant from the National Institutes of Health (R01GM104371). J.D. holds a British Heart Foundation Chair, European Research Council Senior Investigator Award, and NIHR Senior Investigator Award. The Cardiovascular Epidemiology Unit at the University of Cambridge, which supported the field work and genotyping of PROMIS, is funded by the UK Medical Research Council, British Heart Foundation, and NIHR Cambridge Biomedical Research Centre ... Fieldwork in the PROMIS study has been supported through funds available to investigators at the Center for Non-Communicable Diseases, Pakistan and the University of Cambridge, UK