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Biomedical subjects

O F James

Publications and source records attributed to O F James.

At least 73 records · Page 4Linked to original sources

The natural history of nonalcoholic fatty liver: a follow-up study.

Nonalcohol-induced fatty liver is widely believed to be a benign condition with little or no risk of disease progression. There have been occasional reports of progression to cirrhosis but none in the absence of preexisting fibrosis on the index biopsy specimen even when co-existing hepatitis was present (steatohepatitis). From our histological database (1978 to 1985), we identified 161 patients with fatty liver seen at our institution and traced the case notes of 156. One hundred five patients were initially excluded as having an alcohol-induced cause, and the remaining 51 either were seen in the clinic (37) or had died, in which cases copies of their death certificates were obtained (14). A further 7 patients were excluded after clinic attendance gave evidence of alcohol excess and another 4 after review of their initial biopsy showed the presence of fibrosis or steatohepatitis. The apparent cause of the steatosis in the 40 included patients with strictly nonalcohol-induced pure fatty liver was obesity in 12, diabetes in 4 (1 obese patient), and cachexia associated with extrahepatic malignancy in 6. Four of the remaining 19 had serological evidence of an autoimmune disorder, but none of these had any clinical or histological features of autoimmune liver disease. Nine patients had evidence of hyperlipidemia, 3 of whom were also obese. At a median follow-up of 11 years (7 to 16), 12 of 26 living patients had abnormal results of liver blood tests and had repeat liver biopsies performed. None had progressed to steatohepatitis or cirrhosis; 1 obese patient had developed mild fibrosis 9.8 years after her index biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Reduced awareness of hypoglycaemia in the elderly despite an intact counter-regulatory response.

We investigated awareness of hypoglycaemia and its counter-regulatory hormone response in six young (ages 24-49, mean 30 years) and seven elderly (ages 65-80, mean 72 years) healthy non-diabetic subjects. A hyperinsulinaemic glucose clamp was used to control blood glucose level on two separate occasions. During the hypoglycaemic study, blood glucose was lowered in a stepwise manner to plateaus of 3.5, 3.0 and 2.5 mmol/l. A symptom score, visual reaction time test and digit symbol substitution test was completed pre-study, and at the end of each plateau. Pulse rate, blood pressure and counter-regulatory hormone measurements were taken every 15-30 min. The euglycaemic study was identical except that blood glucose remained at the fasting level. During hypoglycaemia, the elderly group had lower symptom scores than the young group (total relative score at glucose 2.5 mmol/l, mean +/- SEM: elderly -1 +/- 2.5, young 23 +/- 6.7, p < 0.01) and fewer individual symptoms despite a similar counter-regulatory hormone response. There was no difference in deterioration of the visual reaction times or digit symbol substitution scores during hypoglycaemia between the age groups. Unlike the young group, the elderly subjects had no tachycardia in response to hypoglycaemia. Their reduced awareness of hypoglycaemia may be due to an impaired end-organ response to counter-regulatory hormones, resulting in fewer symptoms.

Adult↗

T-cell responses to the components of pyruvate dehydrogenase complex in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune condition that results in destruction of the intrahepatic biliary epithelial cells and is characterized by autoantibodies to pyruvate dehydrogenase complex (PDC). The portal tract T-cell infiltrate and up-regulation of HLA class I, HLA class II, and cell adhesion molecules such as intercellular adhesion molecule-1 on the biliary epithelial cells suggest that T cells play a significant role in mediating this damage. The authors have characterized the peripheral blood T-cell proliferative responses of 24 PBC patients and 48 controls (20 normal, 28 non-PBC chronic liver disease) to the dominant autoantigen PDC, and its constituent components E1, E2 and protein X (which co-purify), and E3. A significant proportion of both PBC patients and controls showed T-cell responses to whole PDC (12 of 24 vs. 24 of 48 SI > 2.5 P = NS) and E1 (15 of 24 vs. 25 of 48 P = NS). Responses to PDC and E1 are thus seen in normal individuals and are not limited to PBC patients. T-cell responses to E2/X were seen in most PBC patients (14 of 24), but in only a small number of controls (6 of 48, P < .0001), responses to E2/X being significantly more frequent in pre-cirrhotic PBC patients (stages I to III, 12 of 15) than cirrhotic (stage IV, 2 of 9 P < .05). Peripheral blood T-cell responses to E2/X are thus strongly associated with early PBC. Responses to E3 were low in both PBC patients and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

The effect of age on cerebral oedema, cerebral infarction and neuroprotective potential in experimental occlusive stroke.

A model of occlusive stroke in the aging brain has been developed and used to evaluate the effects of age upon cerebral infarction, cerebral oedema and neuroprotective potential. Focal ischaemia following left middle cerebral artery occlusion has been compared in aged (30 month) and adult (< 17 month) rats, with histological assessment of infarct volume and analysis of specific gravity as an index of cerebral oedema. Aging was associated with a significant increase in cerebral infarct size. The mean infarct volume in aged rats was 40.5% +/- 2.6% of the hemisphere volume, compared to 30.9% +/- 0.7% in adults (p < 0.01). Pre-treatment with the competitive N-Methyl-D-Aspartate (NMDA) receptor antagonist 3-(2-Carboxy Piperazin-4-yl)Propyl-l-Phosphonate (D-CPP-ene) reduced infarct volumes in both age groups to 33.0% +/- 1.8% and 20.7% +/- 3.2% in aged and adult animals, respectively (p < 0.05). There was significantly less oedema of the cerebral cortex in D-CPP-ene pre-treated rats; mean cortical specific gravity 4 hours post-infarction was 1.0381 +/- 0.0013 in untreated aged rats and 1.0391 +/- 0.0014 in untreated adults, compared to 1.0458 +/- 0.0031 in treated aged rats and 1.0442 +/- 0.0014 in treated adults (p < 0.05). At 24 hours post-infarction, D-CPP-ene pre-treated aged rats had a mean cortical specific gravity of 1.0403 +/- 0.0006 compared to 1.0361 +/- 0.0014 in untreated aged animals (p < 0.05). This study has demonstrated an age-related increase in cerebral infarct size, but has shown that the aging brain is amenable to neuroprotection by NMDA receptor antagonism.

Age Factors↗

Reduced serum lipoprotein(a) levels in patients with primary biliary cirrhosis.

Lipoprotein(a) (Lp(a)) is a unique lipoprotein, elevated serum levels of which are independently associated with an increased risk of coronary heart disease (CHD). Primary biliary cirrhosis (PBC) is often associated with high serum cholesterol, itself a risk factor for CHD. Despite this, patients with PBC are thought to have a lower than expected incidence of CHD. We hypothesised that this may be related to low serum levels of Lp(a) in PBC patients. This was investigated by collecting fasting blood samples from 42 patients with PBC, 39 age- and sex-matched subjects with non-PBC liver disease and 432 community control subjects. Serum was analysed for total cholesterol, triglycerides, high density lipoprotein (HDL) cholesterol and apolipoproteins A1 and B (apo A1 and apo B). Lp(a) was measured by an enzyme-linked immunosorbent assay (ELISA) technique. There was a significant reduction of Lp(a) concentrations in the PBC group compared with the healthy controls (median value 28.5 mg/l vs. 75.0 mg/l, P < 0.005) and between the non-PBC liver disease group (median value 52.0 mg/l) and control group (P = 0.001). Within both the liver disease and PBC patient groups there were significant negative correlations between Lp(a) levels and bilirubin (R = -0.564, P < 0.001 and R = -0.395, P = 0.010 respectively). This preliminary study has demonstrated reduced Lp(a) levels in PBC patients which may be a contributory factor to explain a possible cardioprotective effect in such patients, despite elevated LDL cholesterol levels.

Bilirubin↗

Non-parenchymal cell responses in paracetamol (acetaminophen)-induced liver injury.

We have analysed Kupffer cell and 'activated' perisinusoidal cell populations in liver biopsies from patients with paracetamol (acetaminophen)-induced hepatic necrosis of varying degrees of severity. Kupffer cells were identified immunohistochemically using the monoclonal antibody KPJ and perisinusoidal cells by identification of alpha-smooth muscle actin expression. Material was available from four groups of individuals: (i) 11 cases with mild (grade I) injury; (ii) six cases with moderate (grade II) injury; (iii) six cases with severe (grade III) injury; and (iv) controls with normal liver histology (n = 23). Biopsies in groups (i)-(iii) were obtained within 5 days of drug ingestion. All patients in this study survived and follow-up biopsies were obtained at 4 months, by which time the histological abnormalities had fully resolved. Kupffer cells and perisinusoidal cell numbers were assessed in immunostained preparations of acute and recovery phase biopsies and in control specimens. In acute phase biopsies from patients with grade II and III injury there was expansion of the Kupffer cell and perisinusoidal cell populations within areas of injury. There was a strong correlation between the size of these two cell populations (r = 0.886). No significant difference in cell numbers was found between those with grade I injury and controls. In recovery phase biopsies from patients with paracetamol-induced injury, perisinusoidal cell numbers did not differ significantly from normal controls. Kupffer cells numbers also decreased in recovery phase biopsies compared with the acute phase, although there was persistent expansion of the Kupffer cells population in those who originally had grade III injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

Effect of 'autonomic blockade' on cardiac beta-adrenergic chronotropic responsiveness in healthy young, healthy elderly and endurance-trained elderly subjects.

1. Cardiac chronotropic responses to isoprenaline are reduced with ageing in man. It is unclear whether this is due to reduced cardiac beta-adrenergic sensitivity or to age-associated differences in reflex cardiovascular responses to the vasodilatory effects of isoprenaline. Age-associated changes in physical activity are also reported to influence beta-adrenergic sensitivity. 2. The aim of the present study was to determine the contribution of alterations in reflex changes in para-sympathetic and sympathetic influences and physical fitness to the age-associated reduction in cardiac chronotropic responses to beta-adrenergic agonists. 3. The effect of 'autonomic blockade' with atropine (40 micrograms/kg intravenously) and clonidine (4 micrograms/kg intravenously) on blood pressure, heart rate and chronotropic responses to intravenous bolus isoprenaline doses was determined in eight healthy young (mean age 21 years), nine healthy elderly (72 years) and 10 endurance-trained elderly (69 years) subjects. 4. Elderly subjects had a reduced increase in heart rate after atropine (young, 49 +/- 9 beats/min; elderly, 36 +/- 5 beats/min; endurance-trained elderly, 34 +/- 12 beats/min; P < 0.01) and did not demonstrate the transient increase in systolic blood pressure after clonidine observed in young subjects (young, 11 +/- 10 mmHg; elderly, -12 +/- 16 mmHg; endurance-trained elderly, -18 +/- 11 mmHg; P < 0.01). 5. Cardiac chronotropic sensitivity to isoprenaline after 'autonomic blockade' increased in the young but decreased in the elderly subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Clinical features and prognosis of hepatocellular carcinoma in Britain in relation to age.

A retrospective review of 110 cases of hepatocellular carcinoma (HCC) from the North East of England was undertaken to examine clinical features and prognosis in the 52 patients 65 years of age or more at presentation in comparison with 58 patients under 65. Symptoms and signs at the time of presentation were similar in the two age groups. Only 25% of patients were known to be cirrhotic at the time of presentation, but this increased to 75% after investigation. Although tumour stage at diagnosis was no worse in the elderly group, these patients received less intensive investigation and were significantly more likely to receive conservative therapy (p = 0.03). Although median survival was significantly worse in those aged > or = 65 years than in those < 65 years (10.5 and 18.5 weeks respectively; p = 0.02) this adverse effect disappeared when adjusted for the effects of treatment.

Adolescent↗

Colorectal carcinoma: do elderly patients present differently?

A cohort of patients with a histological diagnosis of colorectal carcinoma was enrolled prospectively. All subjects were interviewed by one observer using a structured questionnaire. One hundred and fifty 'young' (under 70 years) and 123 'elderly' (70 years or more) subjects formed the study sample. The elderly patients did not present more frequently as emergencies than the young, but were more often referred to medical or geriatric rather than surgical units (p < 0.01). There was no difference in median overall delay from symptom onset to histological diagnosis between the age groups (19.5 weeks in each). Symptomatic anaemia and nonspecific symptoms were more often the presenting complaint in the elderly subjects (p < 0.05). On direct questioning, there were no differences in symptom reporting with respect to age group for subjects with colonic cancer. For rectal cancer the following symptoms were more common in the young group: tenesmus (odds ratio 4.2; 95% confidence intervals 2.0-10.0), abdominal or rectal pain (4.0; 1.9-10.6), change in flatus production (2.6; 1.3-5.8), passage of mucus per rectum (2.2; 1.1-4.8). Anorexia was more common in the elderly patients (0.4; 0.1-0.8). This study suggests that symptomatic presentation of rectal cancer is different in the elderly but does not necessarily lead to greater delays in diagnosis nor higher rates of non-elective presentation.

Adenocarcinoma↗

Comparison of omeprazole and histamine H2-receptor antagonists in the treatment of elderly and young patients with reflux oesophagitis.

Retrospective analyses of two multicentre clinical trials were carried out to examine the association of age with endoscopically verified reflux oesophagitis lesions and symptoms before and after 4 or, if necessary, 8 weeks randomized double-blind treatment with omeprazole (20 mg o.m.) or histamine H2-receptor antagonists (H2RA) (cimetidine 400 mg q.d.s. or ranitidine 150 mg b.d.). Of the elderly patients (> or = 65 years) 79 received omeprazole, 39 cimetidine and 36 ranitidine; of the young patients (< 65 years) 200 received omeprazole, 94 cimetidine and 102 ranitidine. The objective of treatment was to heal the oesophagus and to relieve the patient's symptoms. On completion of the studies the proportion of elderly omeprazole-treated patients (68%) healed and symptom-free was nearly three times that of elderly H2RA-treated patients (23%, p < 0.001). In the young patient group the proportion of omeprazole-treated patients (57%) both healed and symptom-free was nearly twice that of H2RA-treated patients (29%, p < 0.001). The advantage of omeprazole over H2RA, in terms of endoscopic healing and symptom relief, is at least as great in elderly patients as in younger patients.

Adult↗

Liver disease in the elderly.

While there are no liver diseases specific to advanced age, the presentation, clinical course and management of liver diseases in the elderly may differ in important respects from younger individuals. The management of older patients with specific liver diseases should be informed by these differences. Alcoholic liver disease presents at a more advanced stage, drug induced liver disease and viral hepatitis may also be more severe. It is increasingly recognised that primary hepatocellular cancer arises in elderly cirrhotics regardless of the etiology of the cirrhosis, the risk highest in hemochromatosis and cirrhosis arising from hepatitis B and C.

Aged↗

Flumecinol for the treatment of pruritus associated with primary biliary cirrhosis.

OBJECTIVE: To determine whether flumecinol (3-trifluoromethyl-alpha-ethylbenzhydrol, Zixoryn) is effective in ameliorating pruritus of cholestasis, particularly in primary bilary cirrhosis. METHODS AND RESULTS: 50 patients (46 with primary biliary cirrhosis, PBC) took oral flumecinol 600 mg or identical placebo once weekly for 3 weeks. Patients assessed pruritus by scoring a daily 100 mm visual analogue scale (VAS; 0 = no itch, 100 = severe, continuous, day and night intolerable itch). Quality of life was similarly measured. Patients scored the VAS daily for a 7-day baseline and for a further 21 days. Subjectively, pruritus improved in 13 of 24 on flumecinol and 10 of 26 on placebo (chi 2 = 1.24, P = 0.27). Median difference in fall in VAS pruritus score between baseline week (mean score for each individual used) and the last week was 8.0 [95% confidence interval (CI) -2.1 to 20.8] and for VAS quality of life was 5.0 (95% Cl 0.4 to 13.0) both in favour of flumecinol over placebo. Later, 19 patients (all PBC) were randomised to flumecinol 300 mg or placebo daily for 3 weeks. Subjectively, pruritus improved in 7 of 10 on flumecinol and 1 of 9 on placebo (Fisher's exact test, P = 0.02). Median difference in fall in VAS pruritus score was 19.8 mm (95% CI 3.3 to 40.7 mm) in favour of flumecinol over placebo and for quality of life was 3.5 mm (95% Cl -5.9 to 24.9 mm). Flumecinol did not significantly affect liver function tests, antipyrine clearance or serum total bile acids, and was not associated with any significant side-effects. CONCLUSION: Flumecinol was safe at the above doses and short term treatment with 300 mg daily, significantly ameliorated pruritus in primary biliary cirrhosis.

Administration, Oral↗

Quantitative analysis of macrophages and perisinusoidal cells in primary biliary cirrhosis.

Immunohistochemistry and image analysis were used to quantify alterations in the Kupffer cell and 'activated' perisinusoidal cell populations in the different stages of primary biliary cirrhosis. Anti-CD68 macrophage antibodies were used to detect Kupffer cells, and anti-alpha-smooth muscle actin (alpha-SMA), PR 2D3 and anti-desmin antibodies to detect perisinusoidal cells. Liver biopsy material was available from 26 patients with primary biliary cirrhosis and 23 patients with histologically normal liver. Increased Kupffer cell numbers were observed in periportal/periseptal zones of stage 3 primary biliary cirrhosis (n = 9), and in random parenchymal areas of stage 3 and stage 4 cases. Significantly increased 'activated' perisinusoidal cell numbers were seen only in periportal/periseptal zones of stage 3 and stage 4 primary biliary cirrhosis. Neither Kupffer cell nor perisinusoidal cell numbers altered significantly in stage 1 and 2 primary biliary cirrhosis (n = 6). PR 2D3 positivity and increased alpha-SMA immunoreactivity by perisinusoidal cells in primary biliary cirrhosis support myofibroblastic differentiation of these cells. Human perisinusoidal cells, unlike their rodent counterparts, did not express desmin in primary biliary cirrhosis or control liver. Kupffer cells and 'activated' perisinusoidal cell accumulation in periportal/periseptal zones of the precirrhotic and cirrhotic primary biliary cirrhosis liver support the concept of Kupffer cell-mediated stimulation of perisinusoidal cells. Furthermore, these findings indicate that Kupffer cell-perisinusoidal interactions play an important role in the development of liver fibrosis and cirrhosis in primary biliary cirrhosis.

Actins↗

Comparison of gastrointestinal symptoms in colorectal carcinoma patients and community controls with respect to age.

Early diagnosis of colorectal cancer may be delayed by the wide prevalence of gastrointestinal symptoms in the general population. This study assessed, with respect to age, the frequency of gastro-intestinal symptoms in patients with colorectal carcinoma in comparison with community controls and also compared the frequency of such symptoms between 'young' (under 70 years) and 'old' (70 year or over) subjects. Two hundred and seventy three consecutive unselected colorectal cancer patients and 273 age and sex matched community controls were interviewed in a structured manner. Among controls, the 'old' group compared with the 'young' reported abdominal pain (p < 0.05), mucous discharge (p < 0.01), faecal incontinence (p < 0.05), change in flatus production (p < 0.05) significantly more often. There were no significant differences in regularity and frequency of bowel habit by age group. All the symptoms considered were significantly more common in colorectal cancer cases than controls (except abdominal bloating), but the association was less strong in the 'old' group. This study confirms that symptoms attributable to the lower gastrointestinal tract are reported by a clinically important number of community subjects and by a significantly higher proportion of elderly people.

Abdominal Pain↗

Defining the immunogenetic susceptibility to primary biliary cirrhosis.

Primary biliary cirrhosis is a chronic cholestatic disease, thought to be immune-mediated with genetic susceptibility encoded in the major histocompatibility complex. In northern Europeans, the best established associations are with HLA-DR8 and the complement allele, C4B2. These associations could be due to a single susceptibility locus on an extended haplotype linking HLA-DR8 and C4B2 or to both HLA-DR8 and C4B2 independently conferring disease susceptibility. C4B2 genotyping was performed on 64 patients with primary biliary cirrhosis and 61 controls matched for ethnic background and frequency of HLA-DR8. C4B2 was associated with HLA-DR8 (p < 0.05) in PBC. No difference in the frequency of C4B2 was detected between control and disease populations, suggesting that HLA-DR8 and C4B2 are in linkage disequilibrium and that C4B2 is not a susceptibility locus for PBC. Taq I polymorphisms were screened in the disease and control populations with the cosmid probe G91, located midway between the HLA-DR and complement loci. One G91 restriction fragment (G91A) was found to be associated with both HLA-DR8 and C4B2, at equal frequency in health and disease, providing evidence of an HLA-DR8-G91A-C4B2 extended haplotype. The frequency of G91A was the same in the disease and control populations, suggesting that G91A does not confer disease susceptibility. These findings establish G91 as the telomeric boundary for disease susceptibility associated with HLA-DR8, encoded on chromosome six. These studies help define the immunogenetic susceptibility locus for primary biliary cirrhosis.

Alleles↗

Analysis of HLA-class-II-encoded antigen-processing genes TAP1 and TAP2 in primary biliary cirrhosis.

The search for genes involved in the aetiology of primary biliary cirrhosis (PBC) has centred on the major histocompatibility complex (MHC) on chromosome 6. Genotyping studies have confirmed an association with HLA class II allele DR8. We investigated polymorphisms in two newly identified genes (TAP1 and TAP2) situated close to the DR locus and thought to encode membrane transporter molecules involved in endogenous antigen processing. Genomic DNA extracted from PBC patients was compared with local healthy controls. TAP1 was analysed by amplification refractory mutation system (ARMS) PCR, and two alleles (A and B) were identified. In 126 PBC patients and 116 controls, allele frequencies were (A:B) 81:19% and 79:21%, respectively (NS). TAP2 analysis was by PCR followed by Bfal restriction digest, and again two alleles (A and B) were identified. Their frequencies in 109 PBC patients and 96 controls were (A:B) 76:24% and 73:27%, respectively (NS). No TAP1-TAP2 haplotype was associated with PBC. TAP allele frequencies were estimated within the DR8 subgroups (22 PBC, 14 controls). B allele frequency for TAP1 was increased in both DR8-positive PBC patients and controls compared with DR8-negative patients and controls (41% vs. 14% in PBC; 43% vs. 18% in controls), but no disease association was found. However, the increased frequency of TAP1B in DR8-positive subjects (42% DR8-positive vs. 16% DR8-negative, p < 0.001) indicates linkage disequilibrium between these two loci.

Base Sequence↗

QT prolongation and sudden cardiac death in patients with alcoholic liver disease.

Cardiovascular death is the most important cause of mortality in alcoholics, yet alcohol may protect against ischaemic heart disease. This could be explained if deaths were a consequence of alcohol-related arrhythmias rather than of coronary atheroma. In many conditions, abnormalities of the QT interval are markers of arrhythmia and for risk of sudden death. We examined the relation between QT intervals and mortality in patients with alcoholic liver disease. Simultaneous 12-lead electrocardiographic recordings were obtained from 69 patients with histologically proven alcoholic liver disease (without evidence of structural heart disease), and from 40 healthy non-drinking controls matched for age and sex. Patients were abstinent for at least 7 days before investigation to exclude acute effects of alcohol. QT intervals were corrected for rate with Bazett's and cube root formulae to define QTc and QTcub, respectively. Unlike QTc, QTcub was independent of rate. Patients were followed for up to four years. For those who died, the cause was determined from case records and postmortem reports. Maximum QT intervals were longer in alcoholics than in controls (QTcub 450 vs 439, p = 0.016). This difference was not explained by variations in electrolytes. QT intervals were prolonged in the 14 patients who died compared with survivors (QTcub 471 vs 446, p = 0.007). This difference was mainly due to the long QT intervals in the 6 patients with sudden cardiac deaths (QTcub 493). The only other factor independently associated with death was sex. QT interval prolongation occurs in some patients with alcoholic liver disease and is associated with an adverse prognosis, especially sudden cardiac death. QT measurement should be included in the initial assessment of alcoholic patients, particularly in those considered for liver transplantation.

Adult↗