Suxamethonium is safe in safe hands; mivacurium should also be considered.
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Humans↗
Biomedical subjects
A Rashid
Publications and source records attributed to A Rashid.
GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas.
Glutathione S-transferases, enzymes that defend cells against damage mediated by oxidant and electrophilic carcinogens, may be critical determinants of cancer pathogenesis. We report here that the pathogenesis of hepatocellular carcinoma (HCC), one of the most common cancers in the world, frequently involves an accumulation of somatic DNA methylation changes at GSTP1, the gene encoding the pi-class glutathione S-transferase. For our study, Hep3B HCC cells and a cohort of 20 HCC tissue specimens were subjected to analysis for GSTP1 expression and for somatic GSTP1 alterations. GSTP1 DNA hypermethylation in HCC DNA was assessed by Southern blot analysis, via a polymerase chain reaction (PCR) assay, and by using a genomic sequencing approach. Hep3B HCC cells failed to express GSTP1 mRNA or GSTP1 polypeptides. Similarly, HCC cells in 19 of 20 HCC cases were devoid of GSTP1 polypeptides. By Southern blot analysis, DNA from Hep3B HCC cells displayed abnormal GSTP1 hypermethylation. Treatment of Hep3B HCC cells in vitro with the DNA methyltransferase inhibitor 5-aza-deoxycytidine both reversed GSTP1 DNA hypermethylation and restored GSTP1 expression. Using a PCR assay, somatic GSTP1 DNA hypermethylation was also detected in HCC DNA from 17 of 20 HCC cases. Genomic sequencing analyses, undertaken to map 5-methyldeoxycytidine nucleotides located at the GSTP1 transcriptional regulatory region, frequently detected somatic DNA hypermethylation near the gene promoter in HCC DNA. The data indicate that GSTP1 DNA hypermethylation changes appear frequently in human HCC. In addition, the data raise the possibility that somatic GSTP1 inactivation, via hypermethylation, may contribute to the pathogenesis of HCC.
Adult↗
Effects of temperature strategy during cardiopulmonary bypass on cerebral oxygen balance.
BACKGROUND: Cerebral injury is the most serious complication of cardiopulmonary perfusion (CPB). With the advent of warm heart surgery, the effect of temperature strategy during perfusion and its effect on cerebral oxygen balance needs further study. METHODS: Three groups of patients (n=8, each) undergoing coronary artery bypass graft (CABG) surgery were studied. Group H, M and N underwent CPB at 28 degrees C, 32 degrees C and normothermia (>36 degrees C), respectively. The extracorporeal circuit was primed with Hartmann's solution 2.5 l and flow of 1.8 l min(-1) m(-2) at 28 degrees C, and 2.4 1 min-1 m(-2) at 32 degrees C and normothermia. All patients had a 4F oximetry catheter (Opticath, Oximetrix, Abbott Laboratories) inserted in the right jugular bulb for continuous measurement of jugular venous oxygen saturation (sjvO2). Data was collected at six specific times: T1- within 5 min before initiation of CPB, T2 - within the first minute after CPB, T3 - during stable temperature on CPB (28 degrees C, 32 degrees C, >36 degrees C), T4 - during rewarming at 34 degrees C in groups H and M, 15 min before coming off CPB in group N, T5 - 15 min after CPB, T6 - skin closure. At each time mean arterial pressure (MAP) and sjvO2 were recorded. Arterial blood and jugular venous blood were sampled for measurement of arterial oxygen saturation (saO2) and jugular venous lactate (sjv(lactate)), respectively. RESULTS: SjvO2 values decreased at times T2, T3 and T4 when compared to baseline (p<0.05) but there were no significant group differences at any time. Cerebral arteriovenous oxygen saturation (a-jvO2) differences mirrored sjvO2 changes. Sjv(lactate) values increased from baseline following CPB but fell consistently with time - there were no significant group differences at each time point. SjvO2 and a-jvO2 values were not significantly correlated with sjv(lactate). CONCLUSION: During pump flows employed in this study, cerebral oxygen balance and perfusion appear unaffected by temperature.
Aged↗
Distribution of blood pressure in a national sample of Malaysian adults.
We describe the distribution of blood pressure (BP) by age, sex and ethnicity in Malaysian adults. A national sample of 21,391 individuals aged 30 or older had usable data. They were selected by stratified 2-stage cluster sampling. BP was measured using an automated oscillometric device, Visomat. Percentile tables and curves by age, sex and ethnicity are presented. The systolic and diastolic BP distribution was right skewed and showed the expected increase with age. This was markedly so in Malay and other indigenous women; as a result they had most severe hypertension.
Adult↗
Alterations in liver ATP homeostasis in human nonalcoholic steatohepatitis: a pilot study.
CONTEXT: The mechanisms that drive progression from fatty liver to steatohepatitis and cirrhosis are unknown. In animal models, obese mice with fatty livers are vulnerable to liver adenosine triphosphate (ATP) depletion and necrosis, suggesting that altered hepatic energy homeostasis may be involved. OBJECTIVE: To determine if patients with fatty liver disease exhibit impaired recovery from hepatic ATP depletion. DESIGN: Laboratory analysis of liver ATP stores monitored by nuclear magnetic resonance spectroscopy before and after transient hepatic ATP depletion was induced by fructose injection. The study was conducted between July 15 and August 30, 1998. SETTING: University hospital. PATIENTS: Eight consecutive adults with biopsy-proven nonalcoholic steatohepatitis and 7 healthy age- and sex-matched controls. MAIN OUTCOME MEASURE: Level of ATP 1 hour after fructose infusion in patients vs controls. RESULTS: In patients, serum aminotransferase levels were increased (P = .02 vs controls); albumin and bilirubin values were normal and clinical evidence of portal hypertension was absent in both groups. However, 2 patients had moderate fibrosis and 1 had cirrhosis on liver biopsy. Mean serum glucose, cholesterol, and triglyceride levels were similar between groups but patients weighed significantly more than controls (P = .02). Liver ATP levels were similar in the 2 groups before fructose infusion and decreased similarly in both after fructose infusion (P = .01 vs initial ATP levels). However, controls replenished their hepatic ATP stores during the 1-hour follow-up period (P<.02 vs minimum ATP) but patients did not. Hence, patients' hepatic ATP levels were lower than those of controls at the end of the study (P = .04). Body mass index (BMI) correlated inversely with ATP recovery, even in controls (R = -0.768; P = .07). Although BMI was greater in patients than controls (P = .02) and correlated strongly with fatty liver and serum aminotransferase elevations, neither of the latter 2 parameters nor the histologic severity of fibrosis strongly predicted hepatic ATP recovery. CONCLUSIONS: These data suggest that recovery from hepatic ATP depletion becomes progressively less efficient as body mass increases in healthy controls and is severely impaired in patients with obesity-related nonalcoholic steatohepatitis.
Adenosine Triphosphate↗
Chromosome 9p21 loss and p16 inactivation in primary sclerosing cholangitis-associated cholangiocarcinoma.
BACKGROUND: Cholangiocarcinoma is a frequent complication of primary sclerosing cholangitis and is a leading cause of mortality in patients with this disease. The tumor suppressor gene p16 is commonly inactivated in many neoplasms; however, the role of p16 in the pathogenesis of cholangiocarcinoma is unclear. Therefore, we examined the role of p16 inactivation in the pathogenesis of cholangiocarcinoma associated with primary sclerosing cholangitis. MATERIALS AND METHODS: Paraffin-embedded sections from 10 patients who developed cholangiocarcinoma in the setting of primary sclerosing cholangitis were examined. Chromosomal loss at 9p21 was determined using microsatellite analysis. Methylation of a CpG island in the promoter region of the p16 gene was determined using methylation-specific polymerase chain reaction. p16 inactivation was also determined using immunohistochemistry. RESULTS: Allelic loss at chromosome 9p21 was present in 9 of 10 tumors (90%). Methylation of the p16 promoter was present in 2 of the 8 tumors examined (25%). Four of seven tumors (57%) analyzed by immunohistochemistry demonstrated an absence of p16 nuclear staining. CONCLUSIONS: Loss of chromosome 9p21 and inactivation of the p16 tumor suppressor gene are common events in primary sclerosing cholangitis-associated cholangiocarcinoma and may play a role in the high incidence of cholangiocarcinoma in patients with primary sclerosing cholangitis.
Adult↗
Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion.
Uncoupling protein 2 (UCP2) uncouples respiration from oxidative phosphorylation and may contribute to obesity through effects on energy metabolism. Because basal metabolic rate is decreased in obesity, UCP2 expression is predicted to be reduced. Paradoxically, hepatic expression of UCP2 mRNA is increased in genetically obese (ob/ob) mice. In situ hybridization and immunohistochemical analysis of ob/ob livers demonstrate that UCP2 mRNA and protein expression are increased in hepatocytes, which do not express UCP2 in lean mice. Mitochondria isolated from ob/ob livers exhibit an increased rate of H+ leak which partially dissipates the mitochondrial membrane potential when the rate of electron transport is suppressed. In addition, hepatic ATP stores are reduced and these livers are more vulnerable to necrosis after transient hepatic ischemia. Hence, hepatocytes adapt to obesity by up-regulating UCP2. However, because this decreases the efficiency of energy trapping, the cells become vulnerable to ATP depletion when energy needs increase acutely.
Adenosine Triphosphate↗
Acute obstructive hydrocephalus complicating bacterial meningitis. Use of dexamethasone remains contentious.
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Child↗
Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver.
Fatty liver is common in nonalcoholic, obese individuals and in lean people who consume alcohol chronically. Although fatty liver is typically benign, a subset of individuals with steatosis develop steatohepatitis and eventually cirrhosis. The disparate outcomes of fatty liver suggest that it reflects a generally beneficial, adaptive response to obesity or alcohol-related stress, but may also increase hepatocyte vulnerability to other challenges. Thus, both protective factors (e.g., Bcl-2 and Bcl-xL) and factors that promote hepatocyte death by apoptosis (e.g., Bax) or necrosis (e.g., UCP2) may be increased in fatty livers. To evaluate this possibility, hepatocyte apoptosis, necrosis, and the expression of factors that regulate cellular viability were assessed in two models of fatty liver (i.e., genetically obese [ob/ob] mice and ethanol [EtOH]-fed lean mice). Findings in mice with fatty livers were compared with lean, control mice that did not have hepatic steatosis. Immunohistochemistry showed striking induction of hepatocyte proteins that promote (e.g., Bax) and inhibit (e.g., Bcl-2 and Bcl-xL) apoptosis in both groups with fatty liver. Both models of fatty liver also increased hepatic transcripts for UCP2, a mitochondrial uncoupling protein, and the protein itself was induced in ob/ob hepatocytes. Despite the up-regulation of factors that threaten cell viability, hepatocyte death was not increased in either ob/ob or EtOH-fed mice, confirming that the liver's protective responses were sufficient under the conditions studied. However, if UCP2 induction reduces the efficiency of adenosine triphosphate (ATP) synthesis, this initially harmless response might enhance the vulnerability of hepatocytes to necrosis.
Animals↗
Genetic alterations in hepatocellular carcinomas: association between loss of chromosome 4q and p53 gene mutations.
The major risk factors for hepatocellular carcinomas (HCC) in high incidence areas include infection with hepatitis B and C viruses (HBV, HCV) and exposure to aflatoxin. Genetic alterations in 24 liver resection specimens from Shanghai and Qidong were studied. Hepatitis B virus was integrated in all patient samples, and a null phenotype for the GSTM1 enzyme was present in 63% of patients. Alteration of p53 was present in 95% (23/24) of cases: mutations of the p53 gene in 12 HCC, p53 overexpression in 13 and loss of heterozygosity (LOH) of chromosome 17p in 17. All seven HCCs with a p53 mutation from Qidong and three of five from Shanghai had the aflatoxin-associated point mutation with a G to T transversion at codon 249, position 3. No HCC had microsatellite instability. LOH of chromosome 4q, 1p, 16q and 13q was present in 50%, 46%, 42% and 38%, respectively, and 4q was preferentially lost in HCCs containing a p53 mutation: LOH of 4q was present in 75% (9/12) of HCC with, but only 25% (3/12) of HCC without, a p53 gene mutation (P = 0.01). These data indicate a possible interaction between p53 gene mutation and 4q loss in the pathogenesis of HCC.
Carcinoma, Hepatocellular↗
'Brown bag' medication reviews as a means of optimizing patients' use of medication and of identifying potential clinical problems.
BACKGROUND: 'Brown bag' medication reviews carried out by community pharmacists collaborating with GPs have become established, in the USA and elsewhere, as an effective means of helping primary care patients to derive maximum benefit from their medicines, of identifying medication-related problems and of reducing wastage of medicines. OBJECTIVE: We aimed to determine whether 'brown bag' medication review could be used successfully in the UK, and particularly whether it represents an efficient and potentially cost-effective means of identifying medication problems. METHOD: 'Brown bag' medication reviews were carried out on 205 volunteer patients in 23 pharmacies in south-east London. Pharmacists' interventions to improve patients' knowledge and usage of their medicines were analysed. Potential clinical problems identified by pharmacists were analysed in order to identify the drug groups most likely to cause problems. RESULTS: Interventions were made in 87% of reviews; interventions to improve patients' knowledge of the purpose and correct usage of their drugs were made in 65% of reviews. In 12% of reviews, problems were identified that could potentially result in a hospital admission, and the potential for an improved outcome for the patient if drug therapy was changed was identified in a further 34% of cases. Beta-blockers, NSAIDs and verapamil were identified as being associated with potential problems of the highest clinical significance. Patients taking psychoactive medication were at greatest risk of a medication-related problem from any cause. CONCLUSION: Pharmacists could contribute to patients' welfare and reduce health care costs by carrying out 'brown bag' medication reviews on behalf of GPs.
Aged↗
Meckel's diverticulum as a rare cause of chronic screaming: the importance of clinical examination during anaesthesia.
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Anesthesia↗
Antibodies to Shiga toxin in the serum of children with Shigella-associated haemolytic uraemic syndrome.
Antibodies to Shiga toxin (Stx) were measured in the sera of 49 children with Shigella dysenteriae serotype 1 infection, of whom 17 had haemolytic uraemic syndrome (HUS) and 32 had no complications (uncomplicated shigellosis, UCS). Children with HUS had lower levels of total IgG and IgM and lower IgM titres to Stx than those with UCS. The number of children with neutralising antibodies was similar in the two groups. Of the children with HUS, 11 had HUS on enrolment and six developed HUS subsequent to enrolment. Antibody titres in children who subsequently developed HUS were compared with those in children with UCS to assess whether differences in antibody titres occurred before the development of HUS. IgA titres to Stx were found to be higher in children who subsequently developed HUS than in those with UCS. However, logistic regression analysis revealed that titres of Stx antibodies in the serum were not significant risk factors for the development of HUS. Thus, although the levels of Stx antibodies were different in children with HUS, and higher IgA titres to Stx were identifiable in children who subsequently developed HUS compared with those with UCS, the relevance of these findings in the development of HUS remains to be elucidated.
Antibodies, Bacterial↗
A regionalised transport service, the way ahead?
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Child↗
Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas.
BACKGROUND: The genetic epidemiology of colorectal adenomas has not been studied prospectively in colonoscopy patients without cancer. AIMS: To study genetic alterations in colorectal adenomas and correlate these with patient demographics and adenoma characteristics. METHODS: Mutations and allelic deletions in 201 adenomas from 60 patients were compared with demographic features, adenoma characteristics, and family history. RESULTS: The most common alteration was K-ras proto-oncogene mutation, present in 35% of adenomas and 65% of patients. Patients 65 years of age and older had a decreased probability of K-ras mutations (26% versus 45%). Overexpression of p53 gene product was present in only 6% of adenomas but was more frequent in villous or tubulovillous adenomas (19% versus 3%). Allelic loss of chromosome 18q was present in only 2% of adenomas and was significantly less frequent than p53 overexpression. DNA replication errors (RER) were present in 7% of adenomas and 15% of patients, including multiple adenomas in four patients (two with hereditary non-polyposis colorectal cancer syndrome). Only 36% of RER positive adenomas had alteration of BAT-26 alleles, none had alteration of BAT-25, and only one (8%) had mutation in the transforming growth factor beta type II receptor gene. RER positive adenomas were more likely to have a K-ras mutation. In patients with multiple adenomas, there was concordance of p53 overexpression and RER but not of K-ras mutations. CONCLUSIONS: Genetic progression in colorectal adenomas is heterogeneous, involving factors related to patient age and the presence of RER for the occurrence of ras mutations, but different intraindividual characteristics for the occurrence of p53 alterations and RER.
Adenoma↗
Leucocyte-depleted cardioplegia does not reduce reperfusion injury in hypothermic coronary artery bypass surgery.
This study investigated the effects of leucocyte-depleted cardioplegia on postreperfusion oxidative stress and myocardial injury in elective hypothermic coronary artery bypass surgery. Forty patients were randomized to receive either cardioplegia with leucocytes depleted by an in-line Pall BC1B filter, or blood cardioplegia without leucocyte depletion. Transmyocardial oxidative stress was assessed by oxidized glutathione measurements in samples taken simultaneously from the coronary sinus and aortic root, and myocardial injury by postoperative CKMB and troponin-T measurements. The BC1B filters reduced numbers of cardioplegia leucocytes by a mean of 90.7%. Both patient groups demonstrated significant increases (p < 0.001) in transcardiac oxidized glutathione gradients after crossclamp release. No significant differences were found between the groups for postreperfusion oxidized glutathione gradients, postoperative levels of CKMB or troponin-T, or in the frequency of perioperative and postoperative complications. These results suggest that leucocyte-depleted cardioplegia does not significantly improve myocardial protection in patients undergoing elective coronary artery bypass surgery.
Aged↗
Primary sclerosing cholangitis: MR imaging findings with pathologic correlation.
OBJECTIVE: The purpose of this study was to evaluate MR imaging findings of primary sclerosing cholangitis, to compare them with histopathologic findings, and to determine if these findings help differentiate primary sclerosing cholangitis from other disorders that result in end-stage liver disease. MATERIALS AND METHODS: MR imaging was performed in 40 patients (27 men, 13 women; age range, 13-72 years; mean, 47 years) with primary sclerosing cholangitis over a 9-year period. In 16 patients who underwent orthotopic hepatic transplantation and in seven patients who underwent needle biopsy, correlation was made between MR imaging and pathologic findings. RESULTS: Focal signal changes in the liver parenchyma were seen on T2-weighted images as peripheral wedge-shaped zones of increased signal intensity in 29 patients (72%), as a reticular pattern in 15 patients (38%), and as periportal edema in 16 patients (40%). Lobar atrophy involved the right lobe in three patients (8%) and the left lobe in 11 patients (28%); hypertrophy of the caudate lobe was seen in nine patients (23%). Features of portal hypertension were seen in 14 patients (35%). Histologic assessment showed zones of segmental atrophy and scarring on the periphery of the liver. CONCLUSION: Peripheral wedge-shaped areas of high T2 signal intensity and dilatation of bile ducts are characteristic MR features of primary sclerosing cholangitis. Pathologic correlation suggests that these features may be related to underlying perfusion changes and bile duct inflammation in patients with primary sclerosing cholangitis.
Adolescent↗
Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences.
A subset of hereditary and sporadic colorectal carcinomas is defined by microsatellite instability (MSI), but the spectra of gene mutations have not been characterized extensively. Thirty-nine hereditary nonpolyposis colorectal cancer syndrome carcinomas (HNPCCa) and 57 sporadic right-sided colonic carcinomas (SRSCCa) were evaluated. Of HNPCCa, 95% (37/39) were MSI-positive as contrasted with 31% (18/57) of SRSCCa (P < 0.000001), but instability tended to be more widespread in SRSCCa (P = 0.08). Absence of nuclear hMSH2 mismatch repair gene product by immunohistochemistry was associated with germline hMSH2 mutation (P = 0.0007). The prevalence of K-ras proto-oncogene mutations was similar in HNPCCa and SRSCCa (30% (11/37) and 30% (16/54)), but no HNPCCa from patients with germline hMSH2 mutation had codon 13 mutation (P = 0.02), and two other HNPCCa had multiple K-ras mutations attributable to subclones. 18q allelic deletion and p53 gene product overexpression were inversely related to MSI (P = 0.0004 and P = 0.0001, respectively). Frameshift mutation of the transforming growth factor beta type II receptor gene was frequent in all MSI-positive cancers (85%, 46/54), but mutation of the E2F-4 transcription factor gene was more common in HNPCCa of patients with germline hMSH2 mutation than in those with germline bMLH1 mutation (100% (8/8) versus 40% (2/5), P = 0.04), and mutation of the Bax proapoptotic gene was more frequent in HNPCCa than in MSI-positive SRSCCa (55% (17/31) versus 13% (2/15), P = 0.01). The most common combination of mutations occurred in only 23% (8/35) of evaluable MSI-positive cancers. Our findings suggest that the accumulation of specific genetic alterations in MSI-positive colorectal cancers is markedly heterogeneous, because the occurrence of some mutations (eg, ras, E2F-4, and Bax genes), but not others (eg, transforming growth factor beta type II receptor gene), depends on the underlying basis of the mismatch repair deficiency. This genetic heterogeneity may contribute to the heterogeneous clinical and pathological features of MSI-positive cancers.
Adaptor Proteins, Signal Transducing↗