SUBACUTE HEPATIC FAILURE-A CLINICAL PROFILE.
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ABSTRACT:
SUBMITTER: Pruthi HS
PROVIDER: S-EPMC5531662 | biostudies-other | 1998 Oct
REPOSITORIES: biostudies-other
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Project description:IntroductionTransverse myelitis is a very rare neurologic syndrome with an incidence per year of 1-5 per million population. We are presenting an interesting case of subacute transverse myelitis with its MRI (magnetic resonance imaging) and CSF (cerebrospinal fluid) findings.CaseA 46-year-old African-American woman presented with decreased sensation in the lower extremities which started three weeks ago when she had a 36-hour episode of sore throat. She reported numbness up to the level just below the breasts. Lyme disease antibodies total IgG (immunoglobulin G) and IgM (immunoglobulin M) in the blood was positive. Antinuclear antibody profile was within normal limits. MRI of the cervical spine showed swelling in the lower cervical cord with contrast enhancement. Cerebrospinal fluid was clear with negative Borrelia Burgdorferi IgG and IgM. Herpes simplex, mycoplasma, coxiella, anaplasma, cryptococcus and hepatitis B were all negative. No oligoclonal bands were detected. Quick improvement ensued after she was given IV Ceftriaxone for 7 days. The patient was discharged on the 8(th) day in stable condition. She continued on doxycycline for 21 days.ConclusionsTransverse myelitis should be included in the differential diagnosis of any patient presenting with acute or subacute myelopathy in association with localized contrast enhancement in the spinal cord especially if flu-like prodromal symptoms were reported. Lyme disease serology is indicated in patients with neurological symptoms keeping in mind that dissociation in Lyme antibody titers between the blood and the CSF is possible.
| S-EPMC2703261 | biostudies-literature
Project description:The present study was aimed at investigating the safety of Lacidipine (LCDP) loaded nanostructured lipid carriers (NLCs) in Wistar rats. NLCs were formulated using ultrasound dispersion technique. Animals were orally treated once daily with NLCs containing 0.140 mg, 0.350 mg, and 0.875 mg of LCDP as low, medium, and high dose per kg body weight, respectively, during 28 days along with blank formulation and pure LCDP. Control rats were fed with water. Animals were observed throughout experiment period and their body weight was recorded once weekly. Overnight fasted rats were sacrificed on the 29th day. Study revealed no signs or symptoms of toxicity or morbidity. No significant changes in the body weight were observed between treated and control group. Significant increase in left testis weight and liver weight was observed in male and female rats, respectively. Haematological estimation revealed significant decrease in haemoglobin count in male rats while female rats showed significant increase in granulocyte count. All the serum clinical parameters were within the normal range and no gross histopathological changes were observed. No delayed effect was noted in satellite group. The results indicate that developed LCDP loaded NLCs are safe when administered orally in rats.
| S-EPMC4458540 | biostudies-other
Project description:BackgroundThe risk and course of serum transaminase elevations (TEs) and clinical hepatic serious adverse event (SAE) development in ritonavir-boosted tipranavir (TPV/r) 500/200 mg BID recipients, who also received additional combination antiretroviral treatment agents in clinical trials (TPV/r-based cART), was determined.MethodsAggregated transaminase and hepatic SAE data through 96 weeks of TPV/r-based cART from five Phase IIb/III trials were analyzed. Patients were categorized by the presence or absence of underlying liver disease (+LD or -LD). Kaplan-Meier (K-M) probability estimates for time-to-first US National Institutes of Health, Division of AIDS (DAIDS) Grade 3/4 TE and clinical hepatic SAE were determined and clinical actions/outcomes evaluated. Risk factors for DAIDS Grade 3/4 TE were identified through multivariate Cox regression statistical modeling.ResultsGrade 3/4 TEs occurred in 144/1299 (11.1%) patients; 123/144 (85%) of these were asymptomatic; 84% of these patients only temporarily interrupted treatment or continued, with transaminase levels returning to Grade < or = 2. At 96 weeks of study treatment, the incidence of Grade 3/4 TEs was higher among the +LD (16.8%) than among the -LD (10.1%) patients. K-M analysis revealed an incremental risk for developing DAIDS Grade 3/4 TEs; risk was greatest through 24 weeks (6.1%), and decreasing thereafter (>24-48 weeks: 3.4%, >48 weeks-72 weeks: 2.0%, >72-96 weeks: 2.2%), and higher in +LD than -LD patients at each 24-week interval. Treatment with TPV/r, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline were found to be independent risk factors for development of DAIDS Grade 3/4 TE; the hazard ratios (HR) were 2.8, 2.0, 2.1 and 1.5, respectively. Four of the 144 (2.7%) patients with Grade 3/4 TEs developed hepatic SAEs; overall, 14/1299 (1.1%) patients had hepatic SAEs including six with hepatic failure (0.5%). The K-M risk of developing hepatic SAEs through 96 weeks was 1.4%; highest risk was observed during the first 24 weeks and decreased thereafter; the risk was similar between +LD and -LD patients for the first 24 weeks (0.6% and 0.5%, respectively) and was higher for +LD patients, thereafter.ConclusionThrough 96 weeks of TPV/r-based cART, DAIDS Grade 3/4 TEs and hepatic SAEs occurred in approximately 11% and 1% of TPV/r patients, respectively; most (84%) had no significant clinical implications and were managed without permanent treatment discontinuation. Among the 14 patients with hepatic SAE, 6 experienced hepatic failure (0.5%); these patients had profound immunosuppression and the rate appears higher among hepatitis co-infected patients. The overall probability of experiencing a hepatic SAE in this patient cohort was 1.4% through 96 weeks of treatment. Independent risk factors for DAIDS Grade 3/4 TEs include TPV/r treatment, co-infection with hepatitis B and/or C, DAIDS grade >1 TE and CD4+ > 200 cells/mm3 at baseline.Trial registrationUS-NIH Trial registration number: NCT00144170.
| S-EPMC2803791 | biostudies-literature
Project description:HNF4α is a transcription factor that plays a critical role in terminal hepatocyte failure. HNF4α-based reprogramming therapy can correct terminal liver failure in rats and humans. As liver disease progresses, HNF4α expression decreases in the nuclei of hepatocytes, leading to impaired regulation and hepatic function. Post-translational modifications (PTMs) are a fundamental regulatory mechanism of protein function and localization. In this study, we analyzed HNF4α localization and pathways involved in HNF4α PTMs in human hepatocytes at different stages of decompensated liver function upon Child-Pugh classification. RNA-seq analysis revealed that HNF4α and the PTMs-pathway related to AKT are down-regulation in cirrhotic hepatocytes with terminal failure. These findings were confirmed by protein expression, where the HNF4α nuclear levels are significantly reduced in Child‐Pugh B and C hepatocytes, whereas cytoplasmic expression of HNF4α was increased. Moreover, cMET and phospho-AKT were significantly reduced in Child‐Pugh B and C hepatocytes. The association and statistical contribution of cMET and phospho-AKT to the nuclear localization of HNF4α were confirmed by Spearman’s rank correlation test and pathway analysis. Principal component analysis was used to characterize the protein profiles related to the degree of liver dysfunction. Additionally, HNF4α acetylation was significantly reduced in failing human hepatocytes when compared to normal controls, demonstrating a significant correlation to the degree of hepatic function. Conclusion: These results suggest that the alterations in the cMET-AKT pathway directly correlate to HNF4α localization and the level of hepatic dysfunction. In conclusion, this study has therapeutic implications and suggests that manipulation of these pathways may restore hepatocyte function in terminal liver failure.
2020-03-19 | GSE134422 | GEO
Project description:Epidemiological studies prove that type II diabetes, characterized by insulin resistance (IR), may be caused by fine particulate matter 2.5 (PM2.5). However, underlying mechanisms whereby PM2.5, particularly during short-term exposure, induces liver dysfunction leading to IR remains poorly understood. In the present study, HepG2 cells and the BALB/c mouse model were used to explore how PM2.5 affects insulin sensitivity. The effects of subacute PM2.5 exposure on glucose metabolism were examined using commercial kits. Oxidative stress and inflammation were detected by fluorescent staining and RT-qPCR. The phosphorylation of PI3K/AKT was examined by Western blot. Subacute PM2.5 exposure induced IR, as reflected by increased glucose levels in cell supernatants, elevated insulin levels, and the impaired intraperitoneal glucose tolerance test in mice. PM2.5 induced oxidative stress, as evidenced by increased reactive oxygen species, cytochrome P450 2E1, and malondialdehyde, along with reduced superoxide dismutase 1/2 and silent information regulator 1. IL-6 and TNF-α were found to be upregulated using RT-qPCR. Western blot showed that PM2.5 inhibited the PI3K-AKT signaling pathway, indicated by the decreased phosphorylation of PI3K/AKT in HepG2 cells. Additionally, H&E staining showed only mild hepatic injury in mice liver. These results firmly suggest that subacute PM2.5 exposure induces insulin resistance through oxidative stress, inflammation, and the inhibition of the PI3K-AKT signaling pathway.
| S-EPMC11766349 | biostudies-literature
Project description:AimsWe documented the midterm prognosis of left ventricular thrombus (LVT) in heart failure (HF) patients with dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM). We aimed to characterize patients with LVT in the context of HF with reduced (≤40%) left ventricular ejection fraction and evaluate their risk for death and/or embolic events, overall, and specifically in patients with ischaemic or non-ischaemic aetiology. We also intended to identify risk factors for LVT in patients with DCM.Methods and resultsWe included all HF patients (N = 105, age 56 ± 13) admitted from 2005 to 2018 in our institution for LVT without significant valve disease/prosthesis, heart transplant/left ventricular assist device, congenital heart disease, or acute myocardial infarction. Our primary endpoint was the 1 year risk of the composite of all-cause mortality (ACM) and symptomatic embolic events. Mean left ventricular ejection fraction was 23 ± 9%, and median BNP was 1795 pg/mL. Most (97%) patients were treated with vitamin K anticoagulants, and 64% had ICM. Symptomatic embolic events and/or ACM occurred in 20% of the population [embolic events (all within 30 days of LVT diagnosis) 15% and ACM 6%] and was similarly frequent in DCM or ICM (P > 0.05). Suspected/transient embolic events were more frequent in DCM (overall 13%; 29% in DCM vs. 5% in ICM, P < 0.01). Major bleeding occurred in 5% of patients. Left ventricular reverse remodelling occurred in 65% of patients, more frequently in DCM (86% in DCM vs. 65% in ICM, P = 0.02). In a case-control analysis matching DCM patients, BNP level was the only factor significantly associated with LVT (2447 pg/mL in LVT vs. 347 pg/mL, P < 0.001).ConclusionsPatients with LVT have markedly high natriuretic peptides and experience a 20% 1 year risk for embolic events and/or death following diagnosis despite anticoagulant treatment. Most patients have favourable remodelling/recovery. As all symptomatic embolic events occurred within 30 days of LVT diagnosis, a very careful initial management is warranted.
| S-EPMC8006720 | biostudies-literature
Project description:BackgroundThe prognosis for patients with chronic hepatitis B virus (HBV)-related subacute liver failure is poor. Thus, accurate prognostication would facilitate management and optimize liver allocation. This study aimed to explore the risk factors for HBV-related subacute liver failure and establish a risk model.MethodsA total of 192 patients with HBV-related subacute liver failure treated at the First Affiliated Hospital of Xi'an Jiaotong University during January 2018 to January 2019 were selected and divided into the survival group (n=113) and the death group (n=79) based on their status within 6 months. Patient information were collected, including age, sex, body mass index, complications, hepatitis B e antigen (HBeAg), hepatic encephalopathy, hepatorenal syndrome, infections, ascites, HBV-DNA, Model for End-Stage Liver Disease (MELD), liver function tests, international normalized ratio (INR), serum creatinine and total cholesterol. Binary logistic regression was employed to identify risk factors for risk model establishment. The predictive value of the risk model was assessed with a receiver operating characteristic (ROC) curve.ResultsCompared with the survival group, the patient age, incidence of hepatic encephalopathy and hepatorenal syndrome, infection and ascites rate, MELD score, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), INR, and serum creatinine levels were significantly elevated, whereas the total cholesterol level was significantly decreased in the death group (all P<0.05). Patient age [odds ratio (OR) =1.11, P=0.03], hepatic encephalopathy (OR =8.31, P=0.02), infection (OR =4.27, P=0.005), ascites (OR =4.54, P=0.006), MELD score (OR =1.39, P<0.001), INR (OR =5.89, P=0.001), and total cholesterol (OR =0.31, P=0.002) were identified as prognostic factors affecting patient mortality. Although both the MELD score and the risk model established in the present study could differentiate patient outcomes, the area under the curve (AUC) (0.94 vs. 0.82, P<0.001) and sensitivity (91.1% vs. 58.2%, P<0.001) of the established risk model were significantly higher than those of the MELD score.ConclusionsPatient age, hepatic encephalopathy, infection, ascites, MELD score, INR, and total cholesterol level were independent prognostic factors. The prognostic model established based on these risk factors may have favorable predictive value.
| S-EPMC9073775 | biostudies-literature
Project description:Traumatic brain injury (TBI) in general has varied neuropathological consequences depending upon the intensity and biomechanics of the injury. Furthermore, in pediatric TBI, intrinsic developmental changes add further complexity, necessitating a biochemical dimension for improved TBI characterization. In our earlier study investigating the subacute stage TBI metabolome (72 h post-injury) in a developmental rat model, significant ipsilateral brain biochemical changes occurred across 25 metabolite sets as determined by metabolite set enrichment analysis (MSEA). The broad metabolic perturbation was accompanied by behavioral deficits and neuronal loss across the ipsilateral hemisphere containing the injury epicenter. In order to obtain a consolidated biochemical profile of the TBI assessment, a subgrouping of the 190 identified brain metabolites was performed. Metabolites were divided into seven major subgroups: oxidative energy/mitochondrial, glycolysis/pentose phosphate pathway, fatty acid, amino acid, neurotransmitters/neuromodulators, one-carbon/folate and other metabolites. Subgroups were based on the chemical nature and association with critically altered biochemical pathways after TBI as obtained from our earlier untargeted analysis. Each metabolite subgroup extracted from the ipsilateral sham and TBI brains were modeled using multivariate partial least square discriminant analysis (PLS-DA) with the model accuracy used as a measurable index of TBI neurochemical impact. Volcano plots of each subgroup, corrected for multiple comparisons, determined the TBI neurochemical specificity. The results provide a ranked biochemical profile along with specificity of changes after developmental TBI, enabling a consolidated biochemical template for future classification of different TBI intensities and injury types in animal models.
| S-EPMC6509949 | biostudies-literature
Project description:AimsLimited data on the uptake of guideline-directed medical therapies (GDMTs) and the mortality of acute decompensated HF (ADHF) patients are available from India. The National Heart Failure Registry (NHFR) aimed to assess clinical presentation, practice patterns, and the mortality of ADHF patients in India.Methods and resultsThe NHFR is a facility-based, multi-centre clinical registry of consecutive ADHF patients with prospective follow-up. Fifty three tertiary care hospitals in 21 states in India participated in the NHFR. All consecutive ADHF patients who satisfied the European Society of Cardiology criteria were enrolled in the registry. All-cause mortality at 90 days was the main outcome measure. In total, 10 851 consecutive patients were recruited (mean age: 59.9 years, 31% women). Ischaemic heart disease was the predominant aetiology for HF (72%), followed by dilated cardiomyopathy (18%). Isolated right HF was noted in 62 (0.6%) participants. In eligible HF patients, 47.5% received GDMT. The 90 day mortality was 14.2% (14.9% and 13.9% in women and men, respectively) with a re-admission rate of 8.4%. An inverse relationship between educational class based on years of education and 90 day mortality (high mortality in the lowest educational class) was observed in the study population. Patients with HF with reduced ejection fraction and HF with mildly reduced ejection fraction who did not receive GDMT experienced higher mortality (log-rank P < 0.001) than those who received GDMT. Baseline educational class, body mass index, New York Heart Association functional class, ejection fraction, dependent oedema, serum creatinine, QRS > 120 ms, atrial fibrillation, mitral regurgitation, haemoglobin levels, serum sodium, and GDMT independently predicted 90 day mortality.ConclusionOne of seven ADHF patients in the NHFR died during the first 90 days of follow-up. One of two patients received GDMT. Adherence to GDMT improved survival in HF patients with reduced and mildly reduced ejection fractions. Our findings call for innovative quality improvement initiatives to improve the uptake of GDMT among HF patients in India.
| S-EPMC9773752 | biostudies-literature
Project description:BackgroundThe regenerative capacity of the heart after myocardial infarction is limited. Our previous study showed that ectopic introduction of 4 cell cycle factors (4F; CDK1 [cyclin-dependent kinase 1], CDK4 [cyclin-dependent kinase 4], CCNB [cyclin B1], and CCND [cyclin D1]) promotes cardiomyocyte proliferation in 15% to 20% of infected cardiomyocytes in vitro and in vivo and improves cardiac function after myocardial infarction in mice.MethodsUsing temporal single-cell RNA sequencing, we aimed to identify the necessary reprogramming stages during the forced cardiomyocyte proliferation with 4F on a single cell basis. Using rat and pig models of ischemic heart failure, we aimed to start the first preclinical testing to introduce 4F gene therapy as a candidate for the treatment of ischemia-induced heart failure.ResultsTemporal bulk and single-cell RNA sequencing and further biochemical validations of mature human induced pluripotent stem cell-derived cardiomyocytes treated with either LacZ or 4F adenoviruses revealed full cell cycle reprogramming in 15% of the cardiomyocyte population at 48 hours after infection with 4F, which was associated mainly with sarcomere disassembly and metabolic reprogramming (n=3/time point/group). Transient overexpression of 4F, specifically in cardiomyocytes, was achieved using a polycistronic nonintegrating lentivirus (NIL) encoding 4F; each is driven by a TNNT2 (cardiac troponin T isoform 2) promoter (TNNT2-4Fpolycistronic-NIL). TNNT2-4Fpolycistronic-NIL or control virus was injected intramyocardially 1 week after myocardial infarction in rats (n=10/group) or pigs (n=6-7/group). Four weeks after injection, TNNT2-4Fpolycistronic-NIL-treated animals showed significant improvement in left ventricular ejection fraction and scar size compared with the control virus-treated animals. At 4 months after treatment, rats that received TNNT2-4Fpolycistronic-NIL still showed a sustained improvement in cardiac function and no obvious development of cardiac arrhythmias or systemic tumorigenesis (n=10/group).ConclusionsThis study provides mechanistic insights into the process of forced cardiomyocyte proliferation and advances the clinical feasibility of this approach by minimizing the oncogenic potential of the cell cycle factors owing to the use of a novel transient and cardiomyocyte-specific viral construct.
| S-EPMC9038650 | biostudies-literature