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Biomedical subjects

H S Debinski

Publications and source records attributed to H S Debinski.

14 recordsLinked to original sources
PubMed2005

Factors influencing uptake of genetic testing for colorectal cancer risk in an Australian Jewish population.

There is a significant excess of colorectal cancer in the Australian Ashkenazi Jewish community. This excess can partially be attributed to inherited factors that are over represented in this population, such as the APC variant I1307K, which is associated with a modest increase in colorectal cancer risk. There is currently only sporadic clinical genetic testing offered for this variant, as neither the exact increase in cancer risk and therefore the appropriate screening strategies for I1307K carriers, nor the acceptability of such testing in Jewish communities have been determined. This study reports a high acceptability of such genetic testing within a community sample of 300 Australian Jewish individuals--94% of participants would have a test for predisposition to colorectal cancer and a majority would make this decision based on the desire for information for their families and to decrease their own cancer risk. Some concerns were noted about genetic testing for cancer predisposition, including insurance discrimination, test accuracy and confidentiality.

Australia↗
PubMed1998

Evaluation of specific herpes DNA viruses in idiopathic megarectum and idiopathic megacolon.

PURPOSE: The aetiology of idiopathic megarectum and idiopathic megacolon is unknown. A previous study in patients with chronic idiopathic intestinal pseudo-obstruction, a condition also associated with a dilated gut, identified the possible involvement of herpes viruses. This study therefore aimed to determine whether these viruses may also be implicated in the pathogenesis of these conditions. METHODS: Resected large bowel from three patients with idiopathic megarectum and three patients with idiopathic megacolon were studied. Histology for viral inclusions and nested polymerase chain reaction (PCR) using specific primers for cytomegalovirus, Epstein-Barr virus, herpes simplex virus type 1 and varicella zoster virus was performed. DNA was extracted from paraffin-embedded blocks by proteinase K and phenol chloroform extraction. RESULTS: Viral inclusions were not seen. PCR failed to identify DNA of the four herpes viruses tested. CONCLUSION: Patients with idiopathic megarectum or idiopathic megacolon may have subtle abnormalities of the enteric innervation, but these do not appear to be attributable to the neurotropic effects of the herpes viruses studied.

Cytomegalovirus↗
PubMed1997

DNA viruses in the pathogenesis of sporadic chronic idiopathic intestinal pseudo-obstruction.

BACKGROUND: Hereditary forms of chronic idiopathic intestinal pseudo-obstruction (CIIP) are well described but the aetiology of most cases of sporadic CIIP is unknown. AIM: To determines whether herpes viruses can persist in the gastrointestinal tract, thereby implicating them in the pathogenesis of CIIP. METHODS: Twenty one specimens of small and large intestine from 13 patients with CIIP (eight visceral myopathy, three visceral neuropathy, two undifferentiated), and 12 patients operated on for colorectal cancer (controls) were examined for evidence of Herpesvirus DNA (cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex virus type 1, and varicella zoster virus) by nested polymerase chain reaction (PCR) and in situ DNA hybridisation (ISH) to localise signal to the muscularis propria or myenteric plexus. RESULTS: Screening with nested PCR produced three patients with positive results. One patient with an inflammatory visceral neuropathy had EBV detected in the small intestine by PCR, and ISH demonstrated localisation to neurones in the myenteric plexus. A patient with a visceral myopathy had EBV DNA in both the small and large intestine; and one patient with a visceral neuropathy had small intestine positive for CMV DNA (both negative by ISH). No control tissue was positive for any virus. CONCLUSIONS: In individual patients there appears to be evidence linking a viral aetiology to sporadic CIIP. The role of neurotropic viruses in acute and chronic motility disturbances needs further study.

Adult↗
PubMed1997

Clinical characteristics of chronic idiopathic intestinal pseudo-obstruction in adults.

BACKGROUND: Chronic idiopathic intestinal pseudo-obstruction, a syndrome of ineffectual motility due to a primary disorder of enteric nerve or muscle, is rare. AIMS: To determine the clinical spectrum, underlying pathologies, response to treatments, and prognosis in a consecutive unselected group of patients. METHODS: Cross sectional study of all patients with clinical and radiological features of intestinal obstruction in the absence of organic obstruction, associated with dilated small intestine (with or without dilated large intestine), being actively managed in one tertiary referral centre at one time. RESULTS: Twenty patients (11 men and nine women, median age 43 years, range 22-67) fulfilled the diagnostic criteria. Median age at onset of symptoms was 17 years (range two weeks to 59 years). Two patients had an autosomally dominant inherited visceral myopathy. Major presenting symptoms were pain (80%), vomiting (75%), constipation (40%), and diarrhoea (20%). Eighteen patients required abdominal surgery, and a further patient had a full thickness rectal biopsy. The mean time interval from symptom onset to first operation was 5.8 years. Histology showed visceral myopathy in 13, visceral neuropathy in three, and was indeterminate in three. In the one other patient small bowel motility studies were suggestive of neuropathy. Two patients died within two years of symptom onset, one from generalised thrombosis and the other from an inflammatory myopathy. Of the remaining 18 patients, eight were nutritionally independent of supplements, two had gastrostomy or jejunostomy feeds, and eight were receiving home parenteral nutrition. Five patients were opiate dependent, only one patient had benefited from prokinetic drug therapy, and five patients required formal psychological intervention and support. CONCLUSIONS: In a referral setting visceral myopathy is the most common diagnosis in this heterogeneous syndrome, the course of the illness is usually prolonged, and prokinetic drug therapies are not usually helpful. Ongoing management problems include pain relief and nutritional support.

Abdominal Pain↗
PubMed1997

p53 and K-ras status in duodenal adenomas in familial adenomatous polyposis.

BACKGROUND: The genetic alterations in patients with familial adenomatous polyposis (FAP) and duodenal adenomas are poorly characterized when compared with data relating to colorectal tumorigenesis in the same patients. METHODS: Point mutation of the K-ras oncogene and point mutation and overexpression of the TP53 tumour suppressor gene were investigated in 32 duodenal polyps (seven without mucosal pathology, 23 with mildly dysplastic adenomas and two with moderately dysplastic adenomas) from 21 patients with FAP. RESULTS: K-ras mutation, TP53 mutation or positive p53 staining were not found in duodenal polyps without histological abnormality. Of 25 duodenal adenomas, K-ras mutation was found in three (two mildly dysplastic, one moderately dysplastic), 20 showed positive p53 immunostaining, and mutation of the TP53 gene was found in one moderately dysplastic adenoma. p53 protein overexpression in duodenal adenomas was significantly more frequent than mutation of either K-ras or TP53 (P < 0.01). CONCLUSION: p53 dysfunction is a hallmark of duodenal adenomas in patients with FAP. Overexpression may indicate DNA damage and thus an early step in tumorigenesis.

Adenoma↗
PubMed1996

Electrogastrography in chronic intestinal pseudoobstruction.

This study aimed to characterize the disturbance of gastric electrical control activity in chronic intestinal pseudoobstruction (CIP) and to determine whether surface electrogastrography (EGG) could be used to diagnose the presence and type of CIP. Gastric electrical control activity was recorded for 30 min in each of the fasting and fed states by EGG in 14 adults with CIP proven on clinical, radiological, and histological grounds, and in 14 age- and sex-matched controls. Electrical activity was recorded from four pairs of Ag-AgCl bipolar skin electrodes, the captured signal amplified and digitalized, and running spectral analysis performed. The dominant frequency and power of spectrum were calculated using a sequence of computerized algorithms. Results were correlated with the known pathological diagnoses [visceral myopathy (M), N = 7; visceral neuropathy (N), N = 4; undifferentiated (U), N = 3]. Dysrhythmias were present in 13 of 14 patients. Tachygastria (electrical control activity frequency >5 cycles/minute) and a normal amplitude response to food, was seen in five patients (N = 4, U = 1). Irregular continuous activity without a dominant frequency or bradyarrhythmia, together with a diminished electrical response activity (ERA) to food, were found in six patients (M = 5, U = 1). Mixed abnormalities were seen in two patients (M = 1, U = 1), and normal activity with a clear dominant frequency of 3 cycles/minute was present in only one patient (M = 1). This noninvasive technique is both sensitive and specific in providing evidence of a dysrhythmia in patients with CIP and discriminates between primary pathologies. EGG may prove diagnostically useful in these disorders and may provide insight into the disturbance of electrical control activity.

Action Potentials↗
PubMed1996

Colorectal polyp counts and cancer risk in familial adenomatous polyposis.

BACKGROUND & AIMS: In familial adenomatous polyposis, colorectal cancer prevention is by prophylactic colectomy, but dietary or chemopreventative strategies have been recently proposed in low-risk individuals. The aim of this study was to define predictive risk factors for colorectal cancer in familial adenomatous polyposis. METHODS: Between 1918 and 1993, 317 patients underwent colectomy. A multivariate analysis was performed to assess the relationship between colorectal cancer risk and polyp count, sex, and age at colectomy. RESULTS: The median polyp count was 842 (range, 78-7500), and cancer was found in 22% of patients. Polyp count and age, but not sex, predicted cancer risk. Patients with >1000 polyps had 2.3 times greater risk of cancer than those with <1000 polyps (P=0.006). Synchronous cancers increased with poly count (P<0.05). Each 10-year age group had a 2.4-fold difference in cancer risk (95% confidence interval, 1.9-3.2; P<0.001). Four cases of cancer occurred in patients at low risk (younger than 30 years of age, <1000 polyps; 3.3%). CONCLUSIONS: More adenomas and older age are associated with a higher risk of colorectal cancer. However, cancer does occur in low-risk individuals and may be missed by surveillance, making alternatives to prophylactic surgery inadvisable.

Adenomatous Polyposis Coli↗
PubMed1996

UDP-glucuronosyltransferase in Gilbert's syndrome.

The diagnosis of Gilbert's syndrome, a condition characterised by mild jaundice related to chronic unconjugated hyperbilirubinemia, is often presumptive and the pathogenesis is incompletely understood. It would be of interest to develop an immunohistochemical staining method to confirm a diagnosis of Gilbert's syndrome. To this end liver tissues from ten patients with a presumed diagnosis of Gilbert's syndrome and six normal controls were examined by immunohistochemistry with polyclonal antibodies raised to UDP-glucuronosyltransferase (UGT). All subjects had normal liver biopsies by hemotoxylin and eosin staining. In normal human liver specific staining for UGT was seen diffusely in all hepatocytes of the hepatic lobule with zone 3 accentuation. There was a reduction of immunostaining throughout the hepatic lobule in all specimens from patients with Gilbert's syndrome and faint residual staining was seen in zone 3. This thus proved a useful method to confirm a clinical diagnosis of Gilbert's syndrome. Raising monospecific antibodies to UGT may give an insight into polypmorphisms of phase II drug metabolism. Bosma et al.* have recently provided evidence from in vitro studies that subjects with Gilbert's syndrome have a putative defect in the promoter region of the gene encoding UDP-glucuronosyltransferase 1, resulting in reduced transcription. These studies have yet to be confirmed from human biopsy specimens and the possibility of second mutations in intronic sequences affecting the stability of UDP-glucuronosyltransferase 1 m RNA are being explored. *Bosma PJ, Chowdhury JR, Bakker C et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med 1995; 333: 1171-5.

Adult↗
PubMed1996

UDP glucuronosyltransferase in the cirrhotic rat liver.

In patients with cirrhosis, the elimination of drugs metabolized by glucuronidation is relatively preserved, in comparison with the metabolism of drugs by oxidation. This study explores this phenomenon at a molecular level. In cirrhotic rat livers the content of UDP-glucuronosyltransferase (UGT) was examined by immunohistochemistry and immunoblotting using three antibodies: (i) a polyclonal antibody directed against a broad number of UGT isoforms from both family 1 and family 2; (ii) a family 2-specific antibody; and a (iii) family 1-specific antibody. The steady state mRNA level of UGT of a family 2 isoform was also detected by northern blot analysis. The results demonstrate normal or increased UGT protein by immunohistochemistry and immunoblot in cirrhotic livers compared with controls. This was accompanied by increased steady state mRNA encoding the UGT isoform UGT2B1. In contrast, an isoform of cytochrome P450 (CYP2C11) was reduced markedly in both immunohistochemical staining and immunoblot analysis. These results suggest that in cirrhosis there is a comparative increase or at least a maintenance of UGT enzyme content and that this most likely occurs at a pretranslational level.

Animals↗
PubMed1995

Localization of uridine 5'-diphosphate-glucuronosyltransferase in human liver injury.

BACKGROUND/AIMS: Pharmacokinetic studies in patients with cirrhosis have shown a decreased clearance of drugs metabolized by cytochrome P450, whereas drugs metabolized by glucuronidation frequently have a normal elimination. The mechanism for the apparent preservation of glucuronidation has not been elucidated. The aim of this study was to examine the expression of uridine 5'-diphosphate-glucuronosyltransferase (UGT) in human liver injuries. METHODS: UGT was measured by immunohistochemistry using a UGT polyclonal antibody, which was then compared with a representative isoform of cytochrome P450. Normal liver biopsy specimens (n = 8) and a spectrum of liver injury biopsy specimens (n = 47) were examined. RESULTS: Compared with normal liver, increased staining for UGT in remaining hepatocytes was seen in liver damaged by chronic alcohol abuse, but the most intense immunoreactivity was observed in remaining and regenerative hepatocytes in specimens with cirrhosis. Primary biliary cirrhosis showed diffusely increased immunoreactivity. Other nonmalignant groups showed an increased staining relative to chronicity of liver disease. In contrast, in all liver injuries, cytochrome P450 staining was reduced as compared with controls. CONCLUSIONS: Chronic liver damage results in increased UGT in remaining viable hepatocytes. Mechanisms may operate in liver injury to preserve expression of UGT in functional hepatocytes, and this may explain the preservation of glucuronidation in cirrhosis.

Aryl Hydrocarbon Hydroxylases↗
PubMed1995

Novel drug therapies in inflammatory bowel disease.

This paper reviews the published data on novel drug treatments for inflammatory bowel disease. Steroids that are topically active or rapidly metabolized have a definite therapeutic role and have fewer long-term side-effects than other steroids. Methotrexate can promote remission in approximately 50% of patients, but is less effective in maintaining remission. Cyclosporin is valuable for treating patients with severe ulcerative colitis but is less valuable for patients with Crohn's disease. None of the drugs that modify specific inflammatory mediators have proven efficacy but tumour necrosing factor and CD4 antibodies may be promising. In patients with distal colitis, lignocaine appears to be effective.

Humans↗
PubMedDate not supplied

Upper intestinal surveillance in familial adenomatous polyposis.

Our understanding of the natural history of upper gastrointestinal (GI) involvement in familial adenomatous polyposis (FAP) is still evolving, although we know that the main cause of death after colectomy in FAP is upper GI malignancy, affecting 5% of patients. The aim of duodenal surveillance is to target high risk individuals and identify cancers early. We have screened 200 patients prospectively and have observed that duodenal polyposis progresses slowly, but there are some young people who have severe disease who merit close observation. We pay particular attention to endoscopic technique and histological detail, and use a duodenal staging system. Patients are offered randomisation to studies of chemopreventive agents, and those with advanced disease are considered for surgery. Successful management is inhibited by our deficient knowledge of the natural history of upper gastrointestinal polyposis, and by our inability to identify high risk individuals with histological markers rather than because of any technological deficiencies in endoscopic equipment.

Adenomatous Polyposis Coli↗