PubMed Health⌕ Search

Biomedical subjects

Guruprasad P Aithal

Publications and source records attributed to Guruprasad P Aithal.

15 recordsLinked to original sources
PubMed2026

Utility of monocyte-derived cells to investigate immune-mediated drug-induced liver injury.

Immune-mediated drug-induced liver injury (DILI) is triggered or exacerbated by the immune system mounting an attack against the drug or its metabolites. The array of in vitro assays for evaluating drug immune liability is limited, highlighting a significant gap in effectively predicting and understanding immune-mediated hepatotoxicity. We aimed to investigate whether monocytes differentiated with the Metaheps (MH) protocol could provide insights into the molecular mechanisms of immune-mediated DILI. MH were generated from monocytes of healthy volunteers (HV) and DILI patients. MH phenotypic characterization was performed by proteomics and qPCR. MH sensitivity to drugs associated with immune-mediated DILI was assessed by lactate dehydrogenase (LDH) assay. Drug-induced LDH release by DILI-derived MH was compared to the upper limit of the 95% CI calculated from HV-derived MH cells treated with the same drug. The 95% CI determined in HV-derived MH was set as the sensitivity threshold for the specific drug. MH cells retain the expression of several immune-related proteins of the parental monocytes and activate a pro-inflammatory response upon exposure to lipopolysaccharide. For all MH (6 out of 6) generated from patients with penicillin-induced DILI, the LDH release upon re-challenge was above the threshold. The sensitivity of MH generated from seven patients with immune checkpoint inhibitor (ICI)-induced hepatotoxicity was ICI-dependent, responding to nivolumab and/or ipilimumab (4 out of 5), but not to pembrolizumab (0 out of 2). Additionally, DILI-derived MH were not sensitive to non-DILI drugs. In conclusion, monocyte-derived cells may serve as an additional tool for drug-specific mechanistic studies of immune-mediated DILI.

Humans↗
PubMed2006

Fracture risk in people with primary biliary cirrhosis: a population-based cohort study.

BACKGROUND & AIMS: Controversy exists as to whether people with primary biliary cirrhosis (PBC) have an increased risk of developing osteoporosis and the extent to which this may translate into an increased risk of fracture. We have performed a cohort study using the General Practice Research Database to quantify the excess fracture risk in people with PBC. METHODS: We identified 930 people with PBC and 9202 age- and sex-matched control subjects. We used Cox regression to estimate the hazard ratios for any fracture, hip fracture, and ulna/radius fracture in the PBC cohort compared with the general population. RESULTS: There were approximately 2-fold relative increases in the risk of any fracture, hip fracture, and ulna/radius fracture for the PBC cohort compared with the general population (hazard ratio [HR], 2.03; 95% confidence interval [CI]: 1.70-2.44; HR 2.14 (95% CI: 1.40-3.28), and HR, 1.96; 95% CI: 1.42-2.71, respectively). The absolute excess in fracture rates were for any fracture, 12.5 per 1000 person-years (95% CI: 8.1-16.9); for hip fracture, 1.9 per 1000 person-years (95% CI: 0.3-3.5); and for ulna/radius fracture, 3.4 per 1000 person-years (95% CI: 1.2-5.7). In those people with more severe disease, the relative risks of fracture were similar (any fracture HR, 2.24; hip fracture HR, 1.25; ulna/radius fracture HR, 1.28). CONCLUSIONS: There are modest increases in both the absolute and relative fracture risks in people with PBC compared with the general population, with the excess risks similar in those with more severe disease.

Adult↗
PubMed2006

Squamous cell carcinoma of the pancreas: report of a case and review of the literature.

CONTEXT: Although, squamous metaplasia of the ductal columnar cells can be observed during periods of inflammation, squamous cell pancreatic carcinoma is an extremely rare tumour. CASE REPORT: We present the case of a 72-year-old man who presented to our hospital with painless obstructive jaundice. After careful and adequate staging investigations that revealed a malignant mass in the head of pancreas he underwent a laparotomy which revealed an inoperable pancreatic cancer. Palliative bypass procedure was done. The biopsy specimens revealed a squamous cell cancer. CONCLUSION: Pure squamous cell carcinoma of the pancreas is a very rare malignancy. In most cases it is not possible to make a pre-operative histological diagnosis and curative resection is unlikely because of dissemination at the time of initial diagnosis or laparotomy.

Aged↗
PubMed2005

EUS-guided Trucut mural biopsies in the investigation of unexplained thickening of the esophagogastric wall.

BACKGROUND: In patients with thickened esophagogastric wall on CT but without evidence of malignancy on endoscopic mucosal biopsies, obtaining adequate histology from the gut wall is difficult. We examined whether it is feasible to obtain diagnostic tissue core from the gut wall by using EUS-guided Trucut biopsy technique in this group of patients. METHODS: Ten patients were included in this study. Under EUS guidance, mucosa was penetrated by using a 19-gauge Trucut needle, and a 18-mm tissue tray was advanced obliquely through the wall layers to avoid penetration of the serosa. Then, the cutting sheath was fired over the tray. OBSERVATIONS: Biopsies were performed without complications. Diagnoses of carcinoma were made in 5 patients. Four other patients had benign histology, and, during follow-up, all these diagnoses have been proven to be true negatives. One Trucut biopsy specimen was considered false negative. CONCLUSIONS: The EUS-guided Trucut mural biopsy technique could yield diagnostic tissue cores in patients with unexplained thickening of the esophagogastric wall.

Adult↗
PubMed2005

When is a herb a drug?

With the growing popularity and use of herbal remedies in the industrial countries there has been an increasing recognition and reporting of adverse reactions. Drug development represents discovery and characterization of naturally occurring plant metabolites or their synthetic analogues. Therefore, a herbal remedy should be considered a drug for all clinical purposes. The liver, being central to the metabolism of virtually all xenobiotics, is inevitably exposed to reactive metabolites and liver injury is a potential complication of nearly every medication, including herbal remedies. Recognition of herb induced hepatotoxicity depends on clinical awareness of the problem, a suspicion that a herbal preparation is involved, and detailed enquiry regarding the use of all supplements and remedies. Herbal medicines should be regulated more systematically and monitoring for adverse reaction should improve.

Chemical and Drug Induced Liver Injury↗
PubMed2005

Monitoring liver function during methotrexate therapy for psoriasis: are routine biopsies really necessary?

Methotrexate is a widely used and efficacious treatment for psoriasis. Current recommendations advise liver biopsy after each cumulative 1-1.5g dosage of methotrexate. Although studies of methotrexate hepatotoxicity in psoriasis are of variable quality, the evidence indicates that in patients with no risk factors for liver disease on long-term, low-dosage (<20mg), once-weekly methotrexate, liver biopsy is justified after an initial cumulative dosage of 4g. Advances in the non-invasive assessment of liver fibrogenesis may eventually further reduce the need for biopsy.

Biopsy↗
PubMed2004

Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity.

Diclofenac is a nonsteroidal anti-inflammatory drug that causes rare but serious hepatotoxicity, the mechanism of which is unclear. The purpose of the present study was to explore the potential role played by the immune processes. Antibodies to diclofenac metabolite-modified liver protein adducts were detected in the sera of seven out of seven patients with diclofenac-induced hepatotoxicity, 12 of 20 subjects on diclofenac without hepatotoxicity, and none of four healthy controls. The antibodies recognized adducts expressed in livers from rats treated with multiple doses of diclofenac, but not in those given single doses. In addition, several potential diclofenac adducts were identified in the liver of a patient with diclofenac-induced hepatic failure, but not from a normal human donor liver, by immunoblotting with an adduct-selective rabbit antiserum. To determine whether or not polymorphisms in genes encoding cytokine-related proteins influence susceptibility to hepatotoxicity, genotyping for the polymorphisms -627 in the interleukin (IL)-10 gene, -590 in the IL-4 gene, and codon 551 in the IL-4 receptor (IL-4R) were performed on DNA from 24 patients on diclofenac with hepatotoxicity, 48 subjects on diclofenac without hepatotoxicity, and healthy controls. The frequencies of the variant alleles for IL-10 and IL-4 were higher in patients (OR [odds ratio]: 2.8 for IL-10; 2.6 for IL-4; 5.3 for IL-10 + IL-4) compared with healthy controls and subjects on diclofenac without hepatotoxicity (OR: 2.8 for IL-10; 1.2 for IL-4; 5.0 for IL-10 + IL-4). In conclusion, the observed polymorphisms, resulting in low IL-10 and high IL-4 gene transcription, could favor a T helper (Th)-2 mediated antibody response to neoantigenic stimulation associated with disease susceptibility.

Adult↗
PubMed2004

Upstream and coding region CYP2C9 polymorphisms: correlation with warfarin dose and metabolism.

OBJECTIVES: To assess whether CYP2C9 alleles other than CYP2C9*2 and *3 are associated with a low-warfarin dose requirement and the relevance of upstream CYP2C9 polymorphisms to dose requirement and metabolism. METHODS: CYP2C9 exons, intron-exon boundaries and 3 kb of upstream sequence in 20 patients requiring or= 0.01, was obtained. In individuals negative for coding region polymorphisms, neither individual genotypes for T-1188C or DeltaG-2664DeltaT-2665 or particular combinations of haplotype pairs were predictive of dose requirement or S-warfarin total clearance, suggesting neither upstream polymorphism was functionally significant. Dose requirements in CYP2C9*11 heterozygotes were not statistically significantly different from homozygous wild-type individuals. CONCLUSIONS: The coding region non-synonymous polymorphisms associated with the CYP2C9*2 and CYP2C9*3 alleles are the major CYP2C9-related factor affecting warfarin dose in UK Caucasians. Upstream CYP2C9 polymorphisms do not appear to be important independent determinants of dose requirement.

Aged↗
PubMed2004

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity.

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.

Animals↗
PubMed2003

Genetic regulation of warfarin metabolism and response.

Genetic factors make an important contribution to the wide interindividual variation in warfarin dose requirement. Several cytochromes P450, each of which shows genetic polymorphism leading to interindividual variation in levels of activity, contribute to oxidative metabolism of warfarin. The most important of these is CYP2C9, which 7-hydroxylates S-warfarin. In clinical studies, possession of the CYP2C9*2 or CYP2C9*3 variant alleles, which result in decreased enzyme activity, has been associated with a significant decrease in mean warfarin dose requirement in at least eight studies. Several studies also suggest that possession of a variant allele is associated with an increased risk of adverse events. Other genetic factors such as polymorphisms affecting CYP3A4 or CYP1A2 may also be relevant to warfarin dose requirement. The molecular basis of warfarin resistance remains unclear but could be due to unusually high CYP2C9 activity (pharmacokinetic resistance) or to abnormal vitamin K epoxide reductase (pharmacodynamic resistance). There is less information available on genetic factors affecting other anticoagulants, but the CYP2C9 genotype is also relevant to acenocoumarol dose.

Anticoagulants↗
PubMed2002

Helical CT versus EUS with fine needle aspiration for celiac nodal assessment in patients with esophageal cancer.

BACKGROUND: Conventional CT is insensitive for detection of metastatic involvement of celiac lymph nodes in esophageal cancer. Helical CT has theoretical advantages over "slice" CT in this regard, but its performance has not yet been prospectively studied. METHODS: Consecutive patients with untreated esophageal cancer were recruited after obtaining informed consent. Helical CT was performed on all patients and TNM staging was performed by a single radiologist. Subsequently, all patients underwent esophageal radial and, as needed, curvilinear array EUS with fine needle aspiration (FNA), for evaluation of celiac lymph nodes and TNM staging. Test performance characteristics with 95% confidence intervals were calculated, assuming EUS with FNA as the reference standard. RESULTS: Forty-eight patients were recruited, of whom 37 (77%) were men. The mean (SD) age was 63.6 (10) years. Excluding 5 patients in whom a confirmatory FNA was not available (n = 43), helical CT identified celiac lymph nodes in 12 (28%) patients. The reference standard of EUS with FNA identified 15 (35%) patients with metastatic celiac lymph nodes, giving a sensitivity, specificity, and positive and negative predictive values for helical CT of 53% (95% CI [28%, 79%]), 86% (95% CI [73%, 99%]), 67% (95% CI [40%, 93%]), and 77% (95% CI [63%, 92%]), respectively, for assessing celiac lymph nodal involvement. The sensitivity and specificity of helical CT in detecting T4 disease were 25% (95% CI [3.8%, 46%]) and 94% (95% CI [85%, 100%]), respectively. There were 12 patients (25%; 95% CI [13%, 37%]) who were felt to have resectable disease by helical CT but had either metastatic involvement of celiac lymph nodes or T4 disease by EUS/FNA. CONCLUSIONS: Despite technological advances, helical CT still appears unreliable, mainly because of insensitivity, for the identification of inoperable T4 or metastatic involvement of celiac lymph node disease in esophageal cancer.

Adenocarcinoma↗
PubMed2002

Accuracy of EUS for detection of intraductal papillary mucinous tumor of the pancreas.

BACKGROUND: Patients with intraductal papillary mucinous tumors of the pancreas (IPMT) present with symptoms similar to those of chronic pancreatitis. This study assessed the accuracy of EUS for detection of IPMT and identified features that discriminate IPMT from chronic pancreatitis. METHODS: EUS accuracy for detecting IPMT was determined with characteristic findings by endoscopic retrograde pancreatography as the reference standard. To determine EUS features characteristic of IPMT, EUS images from patients with IPMT were compared with those from patients (similar age, gender) with chronic pancreatitis. RESULTS: Thirty-eight patients (23 men, 15 women; age range 40-90 years) with IPMT were identified between 1994 and 2001. For EUS, the sensitivity was 86%, specificity 99%, positive predictive value 78%, and negative predictive value 99% for detection of IPMT. When compared with patients with chronic pancreatitis, the EUS features of dilation of pancreatic duct (89% vs. 42%, p < 0.0001), cysts (45% vs. 11%, p = 0.002), and pancreatic atrophy (32% vs. 3%, p = 0.002) were more common, whereas parenchymal features of chronic pancreatitis were less common with IPMT (21% vs. 97%, p < 0.0001). By multivariate analysis, the presence of no more than one parenchymal feature of chronic pancreatitis suggested the diagnosis of IPMT (odds ratio 43.84; 95% CI [4.13, 465.74]). CONCLUSIONS: EUS may be useful in the initial evaluation of patients suspected to have IPMT. Paucity of parenchymal features of chronic pancreatitis is important in differentiating IPMT from other causes of chronic pancreatitis.

Adenocarcinoma, Mucinous↗