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Biomedical subjects

A S Arora

Publications and source records attributed to A S Arora.

11 recordsLinked to original sources
PubMed2005

Spontaneous perforation in the ringed esophagus.

A 54-year-old man presented to the ER with chest pain. He underwent an upper endoscopy revealing a large linear esophageal tear and a CT chest showed free air in the mediastinum. He was managed conservatively and was discharged 2 days later. An UGI series revealed a distal esophageal stricture. He was commenced on esomeprazole for gastroesophageal reflux symptoms and his dysphagia improved significantly. Upper endoscopy revealed multiple rings throughout the esophagus. Biopsies from the distal and mid-esophagus were normal. The underlying pathophysiology, in patients with dysphagia and a ringed esophagus has evoked debate in the literature. Opinions range from underlying gastroesophageal reflux disease (GERD) to eosinophilic esophagitis (EE). Our patient's symptoms of GERD and dysphagia resolved with proton pump inhibitor therapy. Normal histology excluded underlying EE. There have been a few case reports of esophageal perforation in patients with a ringed esophagus, and underlying EE, but none with spontaneous perforation occurring in a 'ringed esophagus'. Perforations in the upper and mid-esophagus can usually be managed conservatively, while those in the distal esophagus often need surgery due to the high risk of developing mediastinitis. However, our patient, despite sustaining a large tear in the distal esophagus, did well with conservative management. This case demonstrates that spontaneous perforation in the ringed esophagus, with normal underlying histology can occur in the distal esophagus and may not require surgery.

Esophageal Perforation↗
PubMed2001

Practical approaches to dysphagia caused by esophageal motor disorders.

Dysphagia is a common symptom with which patients present. This review focuses primarily on the esophageal motor disorders that result in dysphagia. Following a brief description of the normal swallowing mechanisms and the messengers involved, more specific motor abnormalities are discussed. The importance of achalasia, as the only pathophysiologically defined esophageal motor disorder, is discussed in some detail, including recent developments in pathogenesis and treatment options. Other esophageal spastic disorders are described, with relevant manometric tracings included. In recent years, the importance of gastroesophageal reflux as a primary cause of esophageal dysmotility has been recognized, and this is also discussed. In addition, the motility disturbances that develop after surgical fundoplication are reviewed.

Deglutition Disorders↗
PubMed2001

Medical therapy for gastroesophageal reflux disease.

Gastroesophageal reflux disease (GERD) is a chronic condition that ranges from mild, intermittent symptoms to more severe cases of esophageal strictures and possibly adenocarcinoma of the esophagus. The etiology of GERD is multifactorial, although transient lower esophageal sphincter relaxations are thought to play an important role in addition to poor esophageal clearance and weak lower esophageal sphincter pressures. Lifestyle modifications and over-the-counter medications may be used to treat GERD. After these methods are tried, therapy with histamine receptor type 2 antagonists is the best treatment, although increasingly, proton pump inhibitors are being used. Long-term therapy needs to be maintained in patients with GERD, in contrast to those patients with peptic ulcer disease. The role of lifestyle modifications is described, and the costs of the various regimens are compared.

Antacids↗
PubMed2001

Infliximab-associated reversible cholestatic liver disease.

Infliximab, a novel therapy for Crohn disease, has been shown to be both safe and effective. We describe a 44-year-old woman with Crohn disease who developed jaundice after an infusion of infliximab. Multiple investigations were undertaken, cholestatic liver disease was diagnosed, and her condition improved with supportive therapy. Although likely a rare adverse event, cholestatic liver injury should be considered in patients presenting with jaundice who have received infliximab therapy.

Adult↗
PubMed2000

Iatrogenic esophagitis.

A variety of medications have been reported to cause esophageal injury. Nearly 1000 cases have probably been described in the past 30 years, and this is a vast under-representation. Pill-induced esophageal injury is also associated with many underlying esophageal diseases. This review addresses the etiology, diagnosis, and clinical features of pill-induced esophageal injury as well as the specific medications that have been reported to cause it. Ways to prevent esophageal injury, including better instructions to patients who are prescribed such medications, are also discussed.

Capsules↗
PubMed1997

Ceramide induces hepatocyte cell death through disruption of mitochondrial function in the rat.

Although ceramide signaling pathways have been implicated in cell death, neither their role in hepatocellular death nor the cellular mechanisms mediating ceramide-induced cell death are known. The mitochondrial membrane permeability transition (MMPT) has been proposed as a common final pathway in cell death. Thus the aims of our study were to determine if ceramides cause hepatocellular death by necrosis and not apoptosis as confirmed by morphology and the absence of internucleosomal DNA cleavage. Ceramide-mediated hepatocyte necrosis was acyl chain-length, concentration, and time-dependent. Ceramides induced cell necrosis was associated with adenosine triphosphate (ATP) depletion and mitochondrial depolarization suggesting that ceramides caused mitochondrial dysfunction. In isolated mitochondria, ceramides induced the cyclosporine A-sensitive MMPT in an acyl chain-length and concentration dependent manner. Ceramide toxicity was specific as the less potent dihydro form did not induce cell necrosis, significant ATP depletion, mitochondrial depolarization nor the MMPT. In conclusion, ceramide induced cell death is acyl-chain length dependent and mediated by the MMPT. These data show for the first time that ceramide acts as a mediator of hepatocyte necrosis by causing mitochondrial failure.

Adenosine Triphosphate↗
PubMed1996

Hepatocellular carcinoma cells resist necrosis during anoxia by preventing phospholipase-mediated calpain activation.

Although hepatocellular carcinoma (HCC) cells are more resistant to anoxic injury than normal hepatocytes, the mechanisms responsible for this differential sensitivity remain obscure. Because enhanced calpain protease activity contributes to hepatocyte necrosis, we tested the hypothesis that HCC cells resist anoxia by preventing calpain activation. Cell viability in two rat HCC cell lines (N1S1 and McA-RH7777 cells) was fourfold greater compared to rat hepatocytes after 4 h of anoxia. Although calpain activity increased twofold in rat hepatocytes during anoxia, no increase in calpain activity occurred in HCC cells. Western and Northern blot analysis revealed greater or equivalent expression of calpains and calpastatin in HCC cells compared to hepatocytes. Because increases in cytosolic free Ca++ (Cai++) and phospholipid degradation products regulate calpains in vitro, we measured Cai++ and phospholipid degradation. Ca++i did not change in any cell types during 60 min of anoxia. In contrast, phospholipid degradation was fourfold greater in hepatocytes compared to HCC cells. Melittin, a phospholipase A2 activator, increased calpain activity and cell necrosis in all cell types; melittin-induced cell necrosis was ameliorated by a calpain protease inhibitor. In summary, these data demonstrate for the first time 1) calpain activation without a measureable increase in Ca++i, 2) phospholipase-mediated calpain activation in hepatocytes and HCC cells, and 3) the adaptive mechanism responsible for the resistance of HCC cells to anoxia-an inhibition of phospholipid-mediated calpain activation. Interruption of phospholipase-mediated calpain activation may be a therapeutic strategy for preventing anoxic cell injury.

Adenosine Triphosphate↗
PubMed1996

Induction of the mitochondrial permeability transition by protease activity in rats: a mechanism of hepatocyte necrosis.

BACKGROUND & AIMS: The mitochondrial membrane permeability transition (MMPT) has been proposed as a mechanism of cell necrosis. In contrast, it has been suggested that enhanced activity of calpain-like proteases causes cell necrosis. To integrate these concepts, the hypothesis that stimulation of mitochondrial calpain-like protease activity induces the MMPT was developed. METHODS: Calpain-like protease activity and the MMPT were measured in rat liver mitochondria. The mitochondrial membrane potential and cell necrosis were measured in rat hepatocytes. RESULTS: The protease inhibitor Cbz-Leu-Leu-Tyr-CHN2 inhibited both calpain-like protease activity and induction of the MMPT by Ca2+ and tert-butyl hydroperoxide. This effect of Cbz-Leu-Leu-Tyr-CHN2 was specific because serine, aspartate, and metalloprotease inhibitors did not inhibit the MMPT. The protease inhibitor Cbz-Leu-Leu-Tyr-CHN2 also delayed the onset of mitochondrial depolarization and cell necrosis during treatment of rat hepatocytes with tert-butyl hydroperoxide, a model of oxidative stress relevant to human disease. CONCLUSIONS: These data suggest a unifying hypothesis linking calpain-like protease activity to the MMPT in cell necrosis. We propose for the first time that activation of mitochondrial calpain-like protease activity can function as a cytolytic trigger initiating the MMPT in cell necrosis.

Animals↗
PubMed1996

The role of metals in ischemia/reperfusion injury of the liver.

Based on current information, we have described the role that metals play in potentiating and ameliorating liver I/R injury. To date, most of the data have focused on the deleterious effects of free iron in mediating I/R injury. Several therapeutic strategies have proven useful in animal models to counteract the effect of iron as a potentiator of I/R injury. These approaches have predominantly centered on the role of iron chelation using DFO and DFO conjugates. The data suggest that chelation of iron may prove useful in preventing I/R injury such as occurs in liver transplantation. Indeed, enough data are now available to initiate and support clinical trials (e.g., addition of DFO conjugates to explant storage solutions). The role of copper, however, is less well defined. Copper is important for the function of copper-zinc SOD. However, free copper may be as injurious as free iron. Further studies are needed to clarify the role of copper in I/R-induced hepatocellular necrosis. Selenium has a well-defined antioxidant role as part of GSH peroxidase (GSH antioxidant pathway). More recent data suggest that selenium may also act as an antioxidant through selenoprotein P, but the role of selenoprotein P in I/R injury remains to be defined. Finally, zinc appears to function as an antioxidant in less well-defined pathways. Further studies are needed to identify the fundamental mechanisms by which zinc may ameliorate oxidative damage during I/R injury. These data demonstrate that metals play a critical role in I/R injury of the liver and remain a fruitful area for investigation and development of therapeutic strategies.

Animals↗
PubMed1996

A cascade of degradative hydrolase activity contributes to hepatocyte necrosis during anoxia.

Calpain proteases contribute to hepatocyte necrosis during anoxia. Our aim was to ascertain the mechanism causing calpain activation during anoxia. In rat hepatocytes, a twofold increase in calpain activity occurred despite the lack of an increase in cytosolic Ca2+ concentration ([Ca2+]i). The increase in calpain activity was not associated with an increase in calpain mRNA or a decrease in calpastatin mRNA expression. Because phospholipid degradation products generated by phospholipases can activate calpains at physiological [Ca2+]i, we determined the effect of phospholipase inhibitors and activators on calpain activity. Pretreatment of hepatocytes with fluphenazine, a phospholipase inhibitor, decreased calpain activation and improved cell survival. Melittin, a phospholipase A2 activator, increased calpain activity and potentiated cell killing. Finally, phospholipid degradation preceded the increase in calpain activity. Thus the enhanced calpain activity occurring in hepatocytes during anoxia 1) is regulated at the posttranslational level and 2) appears to be dependent on phospholipase activity. These data suggest a novel cascade for degradative hydrolase activity during hepatocyte necrosis by anoxia with phospholipase-mediated activation of calpains.

Animals↗