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According to the World Health Organization-led Delphi consensus, long COVID corresponds to the occurrence of symptoms beyond twelve weeks after the onset of acute COVID-19 illness that cannot be explained by alternate diagnosis. This cross-sectional study aimed to analyse the impacts of long COVID on general health and psychosocial well-being. For this study, the participants were interviewed either face to face or via telephone, and their responses were recorded on a questionnaire capturing information on demographics, COVID-19 status, duration of symptoms and long COVID symptoms. The psychosocial impacts of the pandemic were assessed using scales like Short Mood and feeling questionnaire (sMFQ), Warwick-Edinburgh Mental Well-being Scale (WEMWBS), Generalized Anxiety Disorder Assessment (GAD-7) and Perceived Stress Scale (PSS). Regression analysis was conducted to analyse the predictors of long COVID. A total of 300 participants were interviewed, of which 155 (52%) had COVID-19 illness. Of these 54 (35%) had persistent symptoms for a period of more than 12 weeks classified as long COVID. Muscle problems and fatigue were the most frequent (14.7%) symptoms encountered, followed by breathing problems (12.6%) and cognitive issues (12.6%). The symptoms of decrease in appetite and confusion or disorientation during the initial phase of the infection were associated with long COVID. The majority of the participants (83.3%) had moderate level of perceived stress, while moderate to severe levels of stress were observed in 17.3% of the individuals. Moreover, a high level of positive mental well-being was also observed. This study highlights the need for further research into the clinical aspects and implications of long COVID in Pakistan and emphasizes the importance of ongoing support for affected individuals.
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COVID-19 , Humanos , COVID-19/psicología , COVID-19/epidemiología , Estudios Transversales , Femenino , Masculino , Pakistán/epidemiología , Adulto , Persona de Mediana Edad , Síndrome Post Agudo de COVID-19 , Encuestas y Cuestionarios , Adulto Joven , Estrés Psicológico/epidemiología , Salud MentalRESUMEN
The 2',5'- oligoadenylate synthetase (OAS) - ribonuclease L (RNAseL) - phosphodiesterase 12 (PDE12) pathway is an essential interferon-induced effector mechanism against RNA virus infection. Inhibition of PDE12 leads to selective amplification of RNAseL activity in infected cells. We aimed to investigate PDE12 as a potential pan-RNA virus antiviral drug target and develop PDE12 inhibitors that elicit antiviral activity against a range of viruses. A library of 18â000 small molecules was screened for PDE12 inhibitor activity using a fluorescent probe specific for PDE12. The lead compounds (CO-17 or CO-63) were tested in cell-based antiviral assays using encephalomyocarditis virus (EMCV), hepatitis C virus (HCV), dengue virus (DENV), West Nile virus (WNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in vitro. Cross reactivity of PDE12 inhibitors with other PDEs and in vivo toxicity were measured. In EMCV assays, CO-17 potentiated the effect of IFNα by 3 log10. The compounds were selective for PDE12 when tested against a panel of other PDEs and non-toxic at up to 42 mgâ¯kg-1 in rats in vivo. Thus, we have identified PDE12 inhibitors (CO-17 and CO-63), and established the principle that inhibitors of PDE12 have antiviral properties. Early studies suggest these PDE12 inhibitors are well tolerated at the therapeutic range, and reduce viral load in studies of DENV, HCV, WNV and SARS-CoV-2 in human cells and WNV in a mouse model.
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COVID-19 , Virus ARN , Humanos , Ratones , Animales , Ratas , Antivirales/farmacología , SARS-CoV-2 , Interferón-alfa , Virus de la Encefalomiocarditis , Hidrolasas Diéster FosfóricasRESUMEN
Pregnancy is associated with progressive hypercholanemia, hypercholesterolemia, and hypertriglyceridemia, which can result in metabolic disease in susceptible women. Gut signals modify hepatic homeostatic pathways, linking intestinal content to metabolic activity. We sought to identify whether enteric endocrine signals contribute to raised serum bile acids observed in human and murine pregnancies, by measuring fibroblast growth factor (FGF) 19/15 protein and mRNA levels, and 7α-hydroxy-4-cholesten-3-one. Terminal ileal farnesoid X receptor (FXR)-mediated gene expression and apical sodium bile acid transporter (ASBT) protein concentration were measured by qPCR and western blotting. Shotgun whole-genome sequencing and ultra-performance liquid chromatography tandem mass spectrometry were used to determine the cecal microbiome and metabonome. Targeted and untargeted pathway analyses were performed to predict the systemic effects of the altered metagenome and metabolite profiles. Dietary CA supplementation was used to determine whether the observed alterations could be overcome by intestinal bile acids functioning as FXR agonists. Human and murine pregnancy were associated with reduced intestinal FXR signaling, with lower FGF19/15 and resultant increased hepatic bile acid synthesis. Terminal ileal ASBT protein was reduced in murine pregnancy. Cecal bile acid conjugation was reduced in pregnancy because of elevated bile salt hydrolase-producing Bacteroidetes. CA supplementation induced intestinal FXR signaling, which was not abrogated by pregnancy, with strikingly similar changes to the microbiota and metabonome as identified in pregnancy. Conclusion: The altered intestinal microbiota of pregnancy enhance bile acid deconjugation, reducing ileal bile acid uptake and lowering FXR induction in enterocytes. This exacerbates the effects mediated by reduced bile acid uptake transporters in pregnancy. Thus, in pregnant women and mice, there is reduced FGF19/15-mediated hepatic repression of hepatic bile acid synthesis, resulting in hypercholanemia.
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Ácidos Cólicos/sangre , Microbioma Gastrointestinal , Reabsorción Intestinal , Embarazo/sangre , Receptores Citoplasmáticos y Nucleares/metabolismo , Amidohidrolasas/genética , Animales , Bacteroides/aislamiento & purificación , Ciego/efectos de los fármacos , Ciego/microbiología , Ácidos Cólicos/farmacología , Enterocitos/efectos de los fármacos , Femenino , Humanos , Ratones Endogámicos C57BL , Receptores Citoplasmáticos y Nucleares/agonistasRESUMEN
BACKGROUND: Thrombin activates hepatic stellate cells via protease-activated receptor-1. The role of Factor Xa (FXa) in hepatic fibrosis has not been elucidated. We aimed to evaluate the impact of FXa and thrombin in vitro on stellate cells and their respective inhibition in vivo using a rodent model of hepatic fibrosis. METHODS: HSC-LX2 cells were incubated with FXa and/or thrombin in cell culture, stained for αSMA and relative gene expression and gel contraction calculated. C57BL/6 J mice were administered thioacetamide (TAA) for 8 weeks with Rivaroxaban (n = 15) or Dabigatran (n = 15). Control animals received TAA alone (n = 15). Fibrosis was scored and quantified using digital image analysis and hepatic tissue hydroxyproline estimated. RESULTS: Stellate cells treated with FXa and thrombin demonstrated upregulation of procollagen, TGF-beta, αSMA and significant cell contraction (43.48%+/- 4.12) compared to culturing with FXa or thrombin alone (26.90%+/- 8.90, p = 0.02; 13.1%+/- 9.84, p < 0.001). Mean fibrosis score, percentage area of fibrosis and hepatic hydroxyproline content (2.46 vs 4.08, p = 0.008; 2.02% vs 3.76%, p = 0.012; 276.0 vs 651.3, p = 0.0001) were significantly reduced in mice treated with the FXa inhibitor compared to control mice. FXa inhibition was significantly more effective than thrombin inhibition in reducing percentage area of fibrosis and hepatic hydroxyproline content (2.02% vs 3.70%,p = 0.031; 276.0 vs 413.1,p = 0.001). CONCLUSIONS: FXa promotes stellate cell contractility and activation. Early inhibition of coagulation using a FXa inhibitor significantly reduces TAA induced murine liver fibrosis and may be a viable treatment for liver fibrosis in patients.
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Coagulación Sanguínea/fisiología , Factor Xa/fisiología , Células Estrelladas Hepáticas/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/fisiopatología , Trombina/fisiología , Actinas/genética , Actinas/metabolismo , Animales , Antitrombinas/uso terapéutico , Línea Celular , Forma de la Célula , Dabigatrán/uso terapéutico , Modelos Animales de Enfermedad , Inhibidores del Factor Xa/uso terapéutico , Expresión Génica , Células Estrelladas Hepáticas/patología , Humanos , Hidroxiprolina/metabolismo , Cirrosis Hepática/prevención & control , Masculino , Ratones Endogámicos C57BL , Procolágeno/metabolismo , Receptor PAR-1/metabolismo , Rivaroxabán/uso terapéutico , Trombina/antagonistas & inhibidores , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
OBJECTIVE: In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection. DESIGN: Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon-γ (IFN-γ) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy. RESULTS: MOB, production of superoxide and bacterial killing in response to Escherichia coli were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90â days. Expression of the gp91 phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN-γ stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7â days in vivo prednisolone therapy. CONCLUSIONS: Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.
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Infecciones Bacterianas/inmunología , Hepatitis Alcohólica/fisiopatología , Monocitos/fisiología , NADPH Oxidasas/metabolismo , Fagocitosis , Estallido Respiratorio , Adulto , Antiinflamatorios/uso terapéutico , Estudios de Casos y Controles , Células Cultivadas , Técnicas de Cocultivo , Recuento de Colonia Microbiana , Escherichia coli/inmunología , Femenino , Hepatitis Alcohólica/tratamiento farmacológico , Hepatitis Alcohólica/enzimología , Humanos , Interferón gamma/farmacología , Masculino , Glicoproteínas de Membrana/metabolismo , Persona de Mediana Edad , NADPH Oxidasa 2 , Valor Predictivo de las Pruebas , Prednisolona/uso terapéutico , Estallido Respiratorio/efectos de los fármacos , Transducción de Señal , Proteína 1 Supresora de la Señalización de Citocinas/metabolismoRESUMEN
BACKGROUND & AIMS: Characteristics of decompensated cirrhosis and acute-on-chronic liver failure (ACLF) include susceptibility to infection, immuneparesis, and monocyte dysfunction. MER receptor tyrosine kinase (MERTK) is expressed by monocytes and macrophages and contributes to down-regulation of innate immune responses. We investigated whether MERTK expression is altered on monocytes from patients with liver failure. METHODS: We analyzed blood and liver samples collected from patients admitted to the liver intensive therapy unit at King's College Hospital in London from December 2012 through July 2014. Patients had either ACLF (n = 41), acute decompensation of cirrhosis without ACLF (n = 9), cirrhosis without decompensation (n = 17), or acute liver failure (n = 23). We also analyzed samples from healthy individuals (controls, n = 29). We used flow cytometry to determine the level of innate immune function, and associated the findings with disease severity. We developed an assay to measure recruitment and migration of immune cells from the tissue parenchyma. Immunohistochemistry and confocal microscopy were used to determine levels of MERTK in bone marrow, liver, and lymph node tissues. We performed immunophenotype analyses and measured the production of tumor necrosis factor and interleukin 6 and intracellular killing of Escherichia coli by monocytes and peritoneal macrophages incubated with lipopolysaccharide, with or without an inhibitor of MERTK (UNC569). RESULTS: The number of monocytes and macrophages that expressed MERTK was greatly increased in the circulation, livers, and lymph nodes of patients with ACLF, compared with patients with stable cirrhosis and controls. MERTK expression (mean fluorescence intensity) correlated with the severity of hepatic and extrahepatic disease and systemic inflammatory responses. Based on immunophenotype, migration, and functional analyses, MERTK-expressing monocytes migrate across the endothelia to localize into tissue sites and regional lymph nodes. Expression of MERTK reduced the response of cultured monocytes to lipopolysaccharide; the addition of UNC569 restored production of inflammatory cytokines in response to lipopolysaccharide. CONCLUSIONS: Patients with ACLF have increased numbers of immunoregulatory monocytes and macrophages that express MERTK and suppress the innate immune response to microbes. The number of these cells correlates with disease severity and the inflammatory response. MERTK inhibitors restore production of inflammatory cytokines by immune cells from patients with ACLF, and might be developed to increase the innate immune response in these patients.
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Insuficiencia Hepática Crónica Agudizada/metabolismo , Enfermedad Hepática en Estado Terminal/metabolismo , Inmunidad Innata/inmunología , Cirrosis Hepática/metabolismo , Fallo Hepático Agudo/metabolismo , Hígado/metabolismo , Ganglios Linfáticos/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Insuficiencia Hepática Crónica Agudizada/inmunología , Adulto , Anciano , Enfermedad Hepática en Estado Terminal/inmunología , Femenino , Humanos , Inmunidad Innata/efectos de los fármacos , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Hígado/efectos de los fármacos , Hígado/inmunología , Cirrosis Hepática/inmunología , Fallo Hepático Agudo/inmunología , Ganglios Linfáticos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/inmunología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/inmunología , Pirazoles/farmacología , Pirimidinas/farmacología , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/inmunología , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Tirosina Quinasa c-MerRESUMEN
BACKGROUND & AIMS: Hirmi Valley liver disease was first reported in 2001 in Tigray, Ethiopia. 591 cases, including 228 deaths, were reported up to December 2009. The pyrrolizidine alkaloid acetyllycopsamine was detected in stored grain and residents reported adding the pesticide DDT (dichlorodiphenyldichloroethylene) directly to their food stores. We aimed to characterise the clinical features of the disease, and explore the role of these chemicals in its aetiology. METHODS: 32 cases were examined and full clinical histories taken. Nine cases underwent liver biopsy in hospitals. Serum and urine samples were collected from cases and controls. Urine was analysed for acetyllycopsamine by UPLC-MS. Total DDT in serum was measured by ELISA. Hepatotoxicity of DDT and acetyllycopsamine alone or in combination was explored in C57BL/6J mice. RESULTS: Clinical presentation included epigastric pain, abdominal swelling, bloody diarrhoea, hepatomegaly, splenomegaly, and ascites. Histology revealed acute injury characterised by centrilobular necrosis or chronic injury with bile ductular reaction, cytomegaly and fibrosis but no hepatic vein occlusion. Acetyllycopsamine was detected in urine samples taken in the affected area with significantly greater concentrations in 45 cases than in 43 controls (p=0.02). High levels of DDT (>125 ppb) were detected in 78% of serum samples. In mice, DDT (3 × 75 mg/kg) significantly increased the hepatotoxicity (plasma ALT, p=0.0065) of acetyllycopsamine (750 mg/kg), and in combination induced liver pathology similar to Hirmi Valley liver disease including centrilobular necrosis and cytomegaly. CONCLUSIONS: This novel form of disease appears to be caused by co-exposure to acetyllycopsamine and DDT.
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Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , DDT/toxicidad , Alcaloides de Pirrolicidina/toxicidad , Adolescente , Adulto , Fosfatasa Alcalina/análisis , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Niño , Preescolar , DDT/sangre , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana EdadRESUMEN
Introduction: Hypertriglyceridemia (HTG) is a complex disorder caused by genetic and environmental factors that frequently results from loss-of-function variants in the gene encoding lipoprotein lipase (LPL). Heterozygous patients have a range of symptoms, while homozygous LPL deficiency presents with severe symptoms including acute pancreatitis, xanthomas, and lipemia retinalis. Methods: We described the clinical characteristics of three Slovenian patients (an 8-year-old female, an 18-year-old man, and a 57-year-old female) and one Pakistani patient (a 59-year-old male) with LPL deficiency. We performed next-generation sequencing (NGS) targeting all coding exons and intron-exon boundaries of the LPL gene, and Sanger sequencing for variant confirmation. In addition, we performed a systematic literature review of all cases with three identified variants and described their clinical characteristics. Results: Two Slovenian patients with a heterozygous pathogenic variant NM_000237.3:c.984G>T (p.Met328Ile) were diagnosed within the first three years of life and had triglyceride (TG) values of 16 and 20 mmol/L. An asymptomatic Pakistani patient with TG values of 36.8 mmol/L until the age of 44 years, was identified as heterozygous for a pathogenic variant NM_000237.3:c.724G>A (p.Asp242Asn). His TG levels dropped to 12.7 mmol/L on dietary modifications and by using fibrates. A Slovenian patient who first suffered from pancreatitis at the age of 18 years with a TG value of 34 mmol/L was found to be homozygous for NM_000237.3:c.337T>C (p.Trp113Arg). Conclusions: Patients with LPL deficiency had high TG levels at diagnosis. Homozygous patients had worse outcomes. Good diet and medication compliance can reduce severity.
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Lipoproteína Lipasa , Humanos , Masculino , Femenino , Eslovenia/epidemiología , Adolescente , Persona de Mediana Edad , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/deficiencia , Niño , Pakistán/epidemiología , Hiperlipoproteinemia Tipo I/genética , MutaciónRESUMEN
BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. METHODS: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. FINDINGS: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). INTERPRETATION: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.
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Eliminación de Componentes Sanguíneos , Enfermedades Cardiovasculares , Hiperlipoproteinemia Tipo II , Sistema de Registros , Humanos , Femenino , Masculino , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/complicaciones , Niño , Eliminación de Componentes Sanguíneos/métodos , Adolescente , Preescolar , Estudios de Seguimiento , Enfermedades Cardiovasculares/prevención & control , Lactante , LDL-Colesterol/sangre , Lipoproteínas/sangre , Estudios de Cohortes , Resultado del Tratamiento , HomocigotoRESUMEN
Coronary artery calcium (CAC) scoring improves traditional risk factor-based coronary heart disease (CHD) risk stratification. Here, the contribution of CAC scoring to a traditional 10-year CHD risk prediction scores and new artificial intelligence methods used to automate CAC scoring were reviewed. Research shows that traditional risk factors tend to overestimate or underestimate the actual risk of CHD, meaning that including CAC score in the risk stratification has potential to reduce over- and undertreatment. The automated CAC scoring methods are shown to be accurate and significantly more time-effective than the commonly used semi-automated method.
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Background: Familial hypercholesterolemia (FH) is an autosomal inherited disorder characterised by elevated low-density lipoprotein cholesterol and premature cardiovascular events. Despite being declared as a public health priority, FH remains highly underdiagnosed, generally due to the lack of awareness and shortcomings in the available infrastructure, particularly in lower income countries. Methods: To map the existing infrastructure for the management of FH, a survey was conducted among 128 physicians (cardiologists, paediatricians, endocrinologists, and internal medicine specialists) from different regions of Pakistan. Findings: The respondents encountered a limited number of adults or children with diagnosed FH. A very small proportion of the population had access to free cholesterol and genetic testing even when indicated by a physician. In general, cascade screening of the relatives was not performed. Uniform diagnostic criteria for FH had not been established even within the same institution or province. The use of statins and ezetimibe in addition to lifestyle changes were the most common recommended treatment option for FH patients. The respondents considered lack of financial resources as a major barrier for the management of FH and stressed on taking relevant measures for a uniform FH screening programs around the country. Interpretation: National FH screening programmes are not in place worldwide hence FH is commonly undiagnosed, and many individuals are at a high risk for cardiovascular diseases. Timely screening of population for FH requires knowledge about FH among the clinicians and the availability of fundamental infrastructure coupled with sufficient financial resources. Funding: The authors confirm independence from the sponsor. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. FS received funding from Higher Education Commission, Pakistan (Grant 20-15760) and UG received grants from Slovenian Research Agency (J3-2536, P3-0343).
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Objectives: This study aimed to determine the prevalence of blood transfusion-transmitted infections (TTIs), among blood donors in Pakistan, specifically HIV, hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis, and malaria. Methods: Data records of all registered blood donors (n = 120â 968) during 2008-2019, at a blood transfusion center in a tertiary care hospital were assessed. Frequency of the seropositive donors for HIV, HCV, HBV, syphilis, and malaria was analyzed. Results: The overall age range of the donors was 25-65 years. Nearly all were male (99.0%). HCV, syphilis, and malaria were more prevalent among those aged 26-35 years. Most donors (81.1%) were residents of Islamabad city. The infection with the highest prevalence among the screened blood donors was HCV (1.5%; 95% CI: 0.423-0.661) followed by syphilis (0.8%; 95% CI: 1.149-1.432). HCV and syphilis were most frequently observed in blood group B positive (B+) donors while HIV was more common in those who were O+. The frequency of co-infection of syphilis with HCV and HIV was 0.02% and 0.01%, respectively. Conclusions: Among male blood donors, the most prevalent TTI infection was HCV followed by HIV; the latter is on the rise. HCV and syphilis are the most frequent co-infections.
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BACKGROUND: Owing to the atherogenic properties, low density lipoprotein cholesterol (LDL-C) is the primary target for treatment and diagnosis of cardiovascular diseases (CVDs), hence accurate measurement of LDL-C is critical. Despite the availability of direct measurement assays for LDL-C, it is routinely calculated by Friedewald equation in clinical settings in Pakistan mostly due to financial constraints. However, the validity of this equation is impacted by several factors, therefore several other equations have been developed for the calculation of LDL-C. MATERIALS AND METHODS: LDL-C of 39,385 individuals measured directly by homogenous assays (dLDL) was compared with LDL-C calculated by thirteen equations (cLDL-C). Stratifications based on different lipids i.e., triglycerides (TG), total cholesterol (TC), high-density lipoprotein (HDL) were made to check the validity of these equations across all ranges of lipid profile. The correlation and median difference between dLDL and cLDL-C was statistically analyzed. RESULTS: Overall Teerakanchana equation displayed a strong positive correlation (ρ = 0.967) and least median difference (-8.81) with dLDL, followed by Martin equation (ρ = 0.967). For higher TG ranges (>500 mg/dL), Teerakanchana equation had the least median difference (1.31) and a strong correlation (ρ = 0.800). CONCLUSION: Our data suggest that Teerakanchana equation may be employed as an alternative to Friedewald equation for Pakistani population.
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Hipertrigliceridemia , LDL-Colesterol , Humanos , Lipoproteínas HDL , Pakistán , TriglicéridosRESUMEN
INTRODUCTION: Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus (HIV) affect a significant proportion of the populace in developing countries. Pregnant women and deprived segments of the population are disproportionately affected. The aim of our study was to assess the awareness regarding the three blood-borne infections amongst pregnant Pakistani women belonging to low socioeconomic classes. METHODOLOGY: A cross-sectional survey was conducted among 297 pregnant women at two antenatal healthcare facilities in Islamabad, Pakistan between September and November 2019. A pretested structured questionnaire was employed for data collection and knowledge levels were classified into three categories i.e. "Good", "Average", and "Poor" according to pre-set criteria. Data were analyzed using Microsoft Excel 2016 and SPSS Version 21. RESULTS: None of the study participants had "Good" knowledge regarding the three blood-borne infections. Around 52% of the women had "Poor" while 47% had "Average" knowledge. None of the study participants were aware that HIV can be transmitted during delivery. Women aged 30-35 years had significantly higher knowledge as compared to other age groups (p < 0.001). The difference in knowledge amongst women in association with education, income status, and previous pregnancies was not significant. CONCLUSIONS: Awareness regarding Hepatitis B, Hepatitis C, and HIV amongst pregnant Pakistani women of low socioeconomic status is insufficient which can lead to an increased risk of acquiring these infections, especially during childbirth. It is vital to impart health education regarding these diseases and monitor hygiene standards in health care facilities.
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Infecciones por VIH , Hepatitis B , Hepatitis C , Complicaciones Infecciosas del Embarazo , Infecciones de Transmisión Sanguínea , Estudios Transversales , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/epidemiología , Hepacivirus , Hepatitis B/complicaciones , Hepatitis B/epidemiología , Hepatitis C/complicaciones , Hepatitis C/epidemiología , Humanos , Pakistán/epidemiología , Embarazo , Complicaciones Infecciosas del Embarazo/epidemiología , Mujeres EmbarazadasRESUMEN
Background: Due to nonspecific symptoms, rare dyslipidaemias are frequently misdiagnosed, overlooked, and undertreated, leading to increased risk for severe cardiovascular disease, pancreatitis and/or multiple organ failures before diagnosis. Better guidelines for the recognition and early diagnosis of rare dyslipidaemias are urgently required. Methods: Genomic DNA was isolated from blood samples of a Pakistani paediatric patient with hypertriglyceridemia, and from his parents and siblings. Next-generation sequencing (NGS) was performed, and an expanded dyslipidaemia panel was employed for genetic analysis. Results: The NGS revealed the presence of a homozygous missense pathogenic variant c.230G>A (NM_178172.6) in exon 3 of the GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1) gene resulting in amino acid change p.Cys77Tyr (NP_835466.2). The patient was 5.5 years old at the time of genetic diagnosis. The maximal total cholesterol and triglyceride levels were measured at the age of 10 months (850.7 mg/dl, 22.0 mmol/L and 5,137 mg/dl, 58.0 mmol/L, respectively). The patient had cholesterol deposits at the hard palate, eruptive xanthomas, lethargy, poor appetite, and mild splenomegaly. Both parents and sister were heterozygous for the familial variant in the GPIHBP1 gene. Moreover, in the systematic review, we present 62 patients with pathogenic variants in the GPIHBP1 gene and clinical findings, associated with hyperlipoproteinemia. Conclusion: In a child with severe hypertriglyceridemia, we identified a pathogenic variant in the GPIHBP1 gene causing hyperlipoproteinemia (type 1D). In cases of severe elevations of plasma cholesterol and/or triglycerides genetic testing for rare dyslipidaemias should be performed as soon as possible for optimal therapy and patient management.
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Homozygous familial hypercholesterolemia (HoFH) and compound heterozygous familial hypercholesterolemia (cHeFH) are rare disorders generated by disease-causing variants in both alleles of the LDLR or other familial hypercholesterolemia (FH)-related genes. HoFH and cHeFH are characterized by severely elevated low-density lipoprotein-cholesterol (LDL-C), frequently leading to early cardiovascular disease. We investigated the genetic and clinical characteristics of HoFH and cHeFH patients from the Slovenian FH registry and/or those who were previously diagnosed or managed at our institution (Slovenian, Pakhtun and Albanian ethnicity), where genetic testing is not available. Our study includes seven patients. Their median age at the time of clinical diagnosis was 6.3 years (2.9-12.9 years); 2/7 were females. Two patients were diagnosed through the universal FH screening and five patients were diagnosed due to the presence of xanthomas. All the mutations are present in LDLR gene: 7 different genotypes for HoFH (p.Cys167Leu, p.Asp178Asn, p.Cys243Tyr, p.Gly549Asp, p.Cys27Trp, p.Ile585Thr and p.Val797Met) and p.Gly549Asp/p.Gln384Pro genotype for cHeFH patient. The median initial level of LDL-C was 17.0 mmol/L [655 mg/dL] (range 7.6-21.6 mmol/L). The HoFH/cHeFH patients are clinically and genetically very diverse. The clinical criteria (as Simon Broome criteria) might be applicable already in children to raise suspicion of FH but in some cases fail to distinguish heterozygous FH and HoFH/cHeFH patients. However, genetic testing is helpful in confirming the diagnosis, also for a prompt awareness, better compliance to treatment and family screening.
RESUMEN
In ruminants and other large animals, expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) is confined to the perinatal period when it plays a key role in nonshivering thermogenesis. This study determined whether loss of expression of the BAT phenotype was due to reduced response to a beta-agonist, isoprenaline, and expression of the peroxisome proliferator-activated receptor (PPAR) family [PPARalpha, PPARgamma, PPAR coactivator 1alpha (PGC-1alpha)], which regulates UCP1 gene expression. Perirenal adipose tissue (PAT) was sampled from ovine fetuses, newborn lambs, and lambs on d 1, 5, 7, and 21 of life. UCP1 mRNA and protein in PAT increased from d 123 of fetal life to reach a maximum at birth followed by a rapid decrease over the first 5 d of life. Expression of the coactivator, PGC-1alpha and PPAR alpha, peaked between fetal day 123 and birth, and then declined to undetectable levels in the first days of life. In vivo administration of isoprenaline was able to induce expression of UCP1, PGC-1alpha, and PPARalpha in BAT up to 5 d of age but thereafter was ineffective. In vitro addition of beta-receptor, PPARalpha, and PPARgamma agonists were unable to overcome the suppression of UCP1, PPARalpha, and PPARgamma expression observed in differentiated adipocytes prepared from 30-d-old compared with 1-d-old lambs. These data are consistent with a model in which postnatal loss of UCP1 expression and beta-adrenergic induction of the brown adipocyte phenotype is due to loss of expression of PGC-1alpha and PPARalpha.
Asunto(s)
Tejido Adiposo Pardo , Agonistas Adrenérgicos beta/farmacología , Animales Recién Nacidos/fisiología , Isoproterenol/farmacología , Adipocitos/fisiología , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/crecimiento & desarrollo , Tejido Adiposo Pardo/fisiología , Animales , Regulación de la Temperatura Corporal/fisiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Núcleo Celular/metabolismo , Células Cultivadas , Femenino , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/fisiología , Canales Iónicos/genética , Masculino , Proteínas Mitocondriales/genética , PPAR alfa/agonistas , PPAR alfa/genética , PPAR gamma/agonistas , PPAR gamma/genética , Embarazo , ARN Mensajero/metabolismo , Receptores Adrenérgicos beta/metabolismo , Ovinos , Transactivadores/genética , Transactivadores/metabolismo , Proteína Desacopladora 1RESUMEN
BACKGROUND: The ubiquitin-proteasome system is the predominant pathway for myofibrillar proteolysis but a previous study in C2C12 myotubes only observed alterations in lysosome-dependent proteolysis in response to complete starvation of amino acids or leucine from the media. Here, we determined the interaction between insulin and amino acids in the regulation of myotube proteolysis RESULTS: Incubation of C2C12 myotubes with 0.2 x physiological amino acids concentration (0.2 x PC AA), relative to 1.0 x PC AA, significantly increased total proteolysis and the expression of 14-kDa E2 ubiquitin conjugating enzyme (p < 0.05). The proteasome inhibitor MG132 blocked the rise in proteolysis observed in the 0.2 x PC AA media. Addition of insulin to the medium inhibited proteolysis at both 0.2 and 1.0 x PC AA and the expression of 14-kDa E2 proteins and C2 sub unit of 20 S proteasome (p < 0.05). Incubation of myotubes with increasing concentrations of leucine in the 0.2 x PC AA media inhibited proteolysis but only in the presence of insulin. Incubation of rapamycin (inhibitor of mTOR) inhibited amino acid or insulin-dependent p70 S6 kinase phosphorylation, blocked (P < 0.05) the inhibitory effects of 1.0 x PC AA on protein degradation, but did not alter the inhibitory effects of insulin or leucine CONCLUSION: In a C2C12 myotube model of myofibrillar protein turnover, amino acid limitation increases proteolysis in a ubiquitin-proteasome-dependent manner. Increasing amino acids or leucine alone, act additively with insulin to down regulate proteolysis and expression of components of ubiquitin-proteasome pathway. The effects of amino acids on proteolysis but not insulin and leucine, are blocked by inhibition of the mTOR signalling pathway.