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Biomedical subjects

B M Fisher

Publications and source records attributed to B M Fisher.

At least 19 recordsLinked to original sources
PubMed2006

A comparison of glycaemic and metabolic control over time among South Asian and European patients with Type 2 diabetes: results from follow-up in a routine diabetes clinic.

AIMS: Although South Asians have a higher prevalence of diabetes which develops at a younger age, data on change in metabolic parameters post-diagnosis are relatively sparse. We therefore wished to determine whether South Asians with diabetes had similar or greater year-on-year deterioration in metabolic parameters compared with Europeans. METHODS: We analysed longitudinal change in metabolic parameters [glycated haemoglobin (HbA(1c)), blood pressure, body mass index (BMI), lipids] among South Asian (n = 210) and European (n = 1557) patients consecutively attending the same diabetes clinic over a mean period of 5.3 years. RESULTS: South Asians were younger than Europeans at first recorded diagnosis of diabetes (mean age 45.9 vs. 57.3 years, P < 0.001) and had significantly lower ( approximately 1.2 units) BMI and blood pressure. Mean HbA(1c) was not different across ethnic groups at first visit, but with time glycaemic control was worse in South Asians than Europeans, with average deterioration 1.31% (= 0.23%/year) in Asians vs. 0.82% (0.16%/year) in Europeans, P = 0.003. This ethnic difference in mean change in HbA(1c) persisted after adjustment for age, sex, baseline HbA(1c), and weight change in linear regression analysis (beta = 0.46, 95% CI 0.24-0.69, P < 0.001), and with additional adjustment for time to referral and duration of diabetes (P = 0.01). Moreover, South Asians had significantly smaller improvements in blood pressure (P < 0.001) and cholesterol (P = 0.044) over the follow-up period in keeping with fewer prescriptions of anti-hypertensive agents and lipid-lowering agents. CONCLUSIONS: These data suggest the need to be more aggressive in the management of diabetes and related risk factors in South Asians.

Age Distribution↗
PubMed2001

A randomized, controlled trial to study the effect of exercise consultation on the promotion of physical activity in people with Type 2 diabetes: a pilot study.

AIM: To evaluate the effect of exercise consultation on promotion of physical activity in people with Type 2 diabetes. METHODS: Twenty-six sedentary people with Type 2 diabetes were randomly assigned to receive an exercise consultation and standard exercise information (experimental) or standard exercise information alone (control). Exercise consultation is a one-to-one discussion, based on the transtheoretical model, designed to educate, strengthen motivation and develop realistic strategies to promote physical activity. Changes from baseline at five weeks were assessed in (a) stage of exercise behaviour (b) physical activity levels (7-day recall questionnaire and an accelerometer) (c) quality of life (SF-36 Health Survey and 22-Item Well-Being Questionnaire). RESULTS: 82% (9/11) of participants receiving a consultation increased their stage of exercise behaviour compared to 33% (4/12) of controls (chi2 = 5.4, P = 0.02). Physical activity counts/week increased by 4% (1636 067/1696 191) in the experimental group and decreased by 9% (1560 960/1725 510) in controls. A significant difference was recorded for the change in activity counts per week from baseline to follow-up between the experimental and control group (98% CI = 60 673-710 827). The number of participants taking part in sport or leisure activity increased by 55% (6/11) in the experimental group and decreased by 6% (1/12) in controls. Positive changes were evident in the experimental group, compared to controls, in both quality of life questionnaires. CONCLUSION: Exercise consultation is more effective in stimulating exercise behaviour change in the short term than a standard exercise leaflet.

Diabetes Mellitus, Type 2↗
PubMed2001

Consultants workload due to alcohol related conditions in acute medical receiving gastroenterology and endocrinology.

A four-week survey was performed into the incidence of alcohol related problems in the acute medical receiving unit, and the prevalence of alcohol related cases in a ward shared between two gastroenterologists and an endocrinologist. Alcohol related conditions were the commonest reason for acute admission (19%). Gastroenterologists, in contrast to their colleagues have a substantial workload related to alcohol, especially chronic liver disease. These patients have longer lengths of stay with higher morbidity and mortality than those without alcohol related conditions. The reason for these differences and the implications for service planning are discussed.

Acute Disease↗
PubMed2001

What is the relevance of the HOPE study in general practice?

The unique findings from the HOPE (Heart Outcomes Prevention Evaluation) study strongly support extending the use of the angiotensin-converting enzyme (ACE) inhibitor ramipril as a preventive agent for patients at high risk of cardiovascular events with normal left ventricular function. In addition, ramipril provides significant benefit in diabetic patients. These findings will impact on how ramipril is used in primary care, where ACE inhibitors are currently underprescribed. Patients reflecting the inclusion criteria of the HOPE study should be considered as suitable candidates for long-term ramipril therapy as an addition to their existing drug regimen. Screening should include control of kidney function (by serum creatinine), particularly within the first two weeks of treatment, in addition to regular monitoring of serum potassium. However, the HOPE study shows that ramipril is well tolerated at high doses and over a long treatment period. The effectiveness of therapy should also be regularly reviewed and dose adjustments made where necessary. If concern remains, referral to a specialist--a cardiologist or a diabetologist--may ultimately be necessary.

Adrenergic beta-Antagonists↗
PubMed1998

A new remote subsite in ribonuclease A.

The interaction between bovine pancreatic ribonuclease A (RNase A) and its RNA substrate extends beyond the scissile bond. Enzymic subsites interact with the bases and the phosphoryl groups of a bound substrate. We evaluated the four cationic residues closest to known subsites for their abilities to interact with a bound nucleic acid. Lys-37, Arg-39, Arg-85, and Lys-104 were replaced individually by an alanine residue, and the resulting enzymes were assayed as catalysts of poly(cytidylic acid) (poly(C)) cleavage. The values of Km and kcat/Km for poly(C) cleavage were affected only by replacing Arg-85. Moreover, the contribution of Arg-85 to the binding of the ground state and the transition state was uniform---Km increased by 15-fold and kcat/Km decreased by 10-fold. The contribution of Arg-85 to binding was also apparent in the values of Kd for complexes with oligonucleotides of different length. This contribution was dependent on salt concentration, as expected from a coulombic interaction between a cationic side chain and an anionic phosphoryl group. Together, these data indicate that Arg-85 interacts with a particular phosphoryl group of a bound nucleic acid. We propose that Arg-85 comprises a new distal subsite in RNase A---the P(-1) subsite.

Amino Acid Substitution↗
PubMed1998

Coulombic effects of remote subsites on the active site of ribonuclease A.

The active-site cleft of bovine pancreatic ribonuclease A (RNase A) is lined with cationic residues that interact with a bound nucleic acid. Those residues interacting with the phosphoryl groups comprise the P0, P1, and P2 subsites, with the scissile P-O5' bond residing in the P1 subsite. Coulombic interactions between the P0 and P2 subsites and phosphoryl groups of the substrate were characterized previously [Fisher, B. M., Ha, J.-H., and Raines, R. T. (1998) Biochemistry 37, 12121-12132]. Here, the interactions between these subsites and the active-site residues His12 and His119 are described in detail. A protein variant in which the cationic residues in these subsites (Lys66 in the P0 subsite and Lys7 and Arg10 in the P2 subsite) were replaced with alanine was crystallized, both free and with bound 3'-uridine monophosphate (3'-UMP). Structures of K7A/R10A/K66A RNase A and the K7A/R10A/K66A RNase A.3'-UMP complex were determined by X-ray diffraction analysis to resolutions of 2.0 and 2.1 A, respectively. There is little observable change between these structures and that of wild-type RNase A, either free or with bound 3'-cytidine monophosphate. K7A/R10A/K66A RNase A was evaluated for its ability to cleave UpA, a dinucleotide substrate that does not span the P0 or the P2 subsites. In comparison to the wild-type enzyme, the value of kcat was decreased by 5-fold and that of kcat/Km was decreased 10-fold, suggesting that these remote subsites interact with the active site. These interactions were characterized by determining the pKa values of His12 and His119 at 0.018 and 0.142 M Na+, both in wild-type RNase A and the K7A/R10A/K66A variant. The side chains of Lys7, Arg10, and Lys66 depress the pKa values of these histidine residues, and this depression is sensitive to the salt concentration. In addition, the P0 and P2 subsites influence the interaction of His12 and His119 with each other, as demonstrated by changes in the cooperativity that gives rise to microscopic pKa values. Finally, the affinity of 3'-UMP for wild-type RNase A and the K7A/R10A/K66A variant at 0.018 and 0.142 M Na+ was determined by isothermal titration calorimetry. 3'-UMP binds to the variant protein with 5-fold weaker affinity at 0.018 M Na+ and 3-fold weaker affinity at 0.142 M Na+ than it binds to wild-type RNase A. Together these data demonstrate that long-range Coulombic interactions are an important feature in catalysis by RNase A.

Alanine↗
PubMed1998

Coulombic forces in protein-RNA interactions: binding and cleavage by ribonuclease A and variants at Lys7, Arg10, and Lys66.

The interactions between bovine pancreatic ribonuclease A (RNase A) and its RNA substrate extend beyond the scissile P-O5' bond. Enzymic subsites interact with the bases and phosphoryl groups of the bound substrate. Those residues interacting with the phosphoryl group comprise the P0, P1, and P2 subsites, with the scissile bond residing in the P1 subsite. Here, the function of the P0 and P2 subsites of RNase A is characterized in detail. Lys66 (P0 subsite) and Lys7 and Arg10 (P2 subsite) were replaced with alanine residues. Wild-type RNase A and the K66A, K7A/R10A, and K7A/R10A/K66A variants were evaluated as catalysts for the cleavage of poly(cytidylic acid) [poly(C)] and for their abilities to bind to single-stranded DNA, a substrate analogue. The values of kcat and Km for poly(C) cleavage were affected by altering the P0 and P2 subsites. The kcat/Km values for poly(C) cleavage by the K66A, K7A/R10A, and K7A/R10A/K66A variants were 3-fold, 60-fold, and 300-fold lower, respectively, than that of wild-type RNase A. These values indicate that the P0 and P2 subsites contribute 0.70 and 2.46 kcal/mol, respectively, to transition-state binding. Binding experiments indicate that the P0 and P2 subsites contribute 0.92 and 1.21 kcal/mol, respectively, to ground-state binding. Thus, the P0 subsite makes a uniform contribution toward binding the ground state and the transition state, whereas the P2 subsite differentiates, binding more tightly to the transition state than to the ground state. In addition, nucleic acid binding to wild-type RNase A is strongly dependent on NaCl concentration, but this dependence is diminished upon alteration of the P0 or P2 subsite. The logarithm of Kd is a linear function of the logarithm of [Na+] over the range 0.018 M </= [Na+] </= 0.14 M, with partial differential log Kd/ partial differential log [Na+] = 2.3 +/- 0.1, 1.8 +/- 0.1, 1.4 +/- 0.1, and 0.9 +/- 0.2 for nucleic acid binding to wild-type RNase A and the K66A, K7A/R10A, and K7A/R10A/K66A variants, respectively. Similar experiments with NaF and the wild-type enzyme yield partial differential log Kd/ partial differential log [Na+] = 2.0 +/- 0.2, indicating that the anion makes only a small contribution to nucleic acid binding. Together these data provide a detailed picture of the contributions of Coulombic interactions to binding and catalysis by RNase A, and illuminate the general role of Coulombic forces between proteins and nucleic acids.

Amino Acid Substitution↗
PubMed1997

Attenuated neutrophil respiratory burst following acute hypoglycaemia in diabetic patients and normal subjects.

The effects of insulin-induced hypoglycaemia on the neutrophil respiratory burst were investigated in six patients with type 1 diabetes and six non-diabetic control subjects. Plasma glucose reached similar nadirs in control subjects (0.9 +/- 0.1 mmol 1(-1); mean +/- SEM) and diabetic patients (1.2 +/- 0.2 mmol 1(-1)) (NS). The resting neutrophil respiratory burst was similar in control subjects (1.26 +/- 0.15 mV) and diabetic patients (1.03 +/- 0.18 mV) (NS). The neutrophil respiratory burst fell following hypoglycaemia in control subjects and diabetic patients to 0.38 +/- 0.05 mV (P < 0.001) and 0.54 +/- 0.09 mV (P < 0.05), respectively. This fall was significantly greater in control subjects (ANOVA; P < 0.001). Resting neutrophil counts were not significantly different in control subjects (3.2 +/- 0.3 x 10(9) 1(-1)) and diabetic patients (6.1 +/- 1.5 x 10(9) 1(-1)). Following hypoglycaemia, neutrophil numbers increased in control subjects and diabetic patients to 11.5 +/- 1.4 x 10(9) 1(-1) (P < 0.01) and 9.7 +/- 1.7 x 10(9) 1(-1) (P < 0.05), respectively. This increase was significantly greater in control subjects (ANOVA; P < 0.001). These results suggest that the neutrophil respiratory burst is suppressed in response to hypoglycaemia and that this phenomenon is more pronounced in non-diabetic subjects.

Acute Disease↗
PubMed1997

Recreational overdosage of carbamazepine in Paisley drug abusers.

Oral drug abuse is a major social and medical issue. Paisley, in the West of Scotland, has become infamous for its problem with oral temazepam abuse. With the crack down on the prescription of temazepam in our area and the resultant lack of its supply on the streets, drug abusers appear to be experimenting with new drugs for their psychotropic effects. We report five cases of recreational carbamazepine overdosage in young temazepam abusers.

Adult↗
PubMed1995

Neutrophil bactericidal function in diabetes mellitus: evidence for association with blood glucose control.

Neutrophil bactericidal activity was assessed in patients with type 1 (n = 45) and Type 2 diabetes mellitus (n = 68) and non-diabetic control subjects (n = 40) by measurement of whole blood chemiluminescence. Though chemiluminescence values tended to be highest in the non-diabetic subjects these differences were not statistically significant (mean +/- SD) (2.73 +/- 1.65 mV (controls), 2.33 +/- 1.41 mV (Type 1 diabetes) and 2.38 +/- 1.12 mv (Type 2 diabetes), F = 1.12, p = 0.33). Significant negative correlations were evident, however, in patients with both Type 1 and Type 2 diabetes between chemiluminescence and glycated haemoglobin (rs = -0.35, p = 0.005 (Type 1), rs = -0.45, p = 0.002 (Type 2), fructosamine (rs = -0.36, p = 0.003 (Type 1), r = -0.42, p = 0.004 (Type 2)), and random blood glucose (rs 0 -0.25, p = 0.04 (Type 1), rs = -0.48, p = 0.001 (Type 2)). Changes in whole blood chemiluminescence in a further group of 10 patients with Type 2 diabetes mellitus commenced on insulin therapy were followed for 21 days. Serum fructosamine concentrations fell significantly over this time (524 +/- 58 mumol l-1 to 405 +/- 47 mumol l-1, p < 0.001), however, although chemiluminescence values tended to rise these changes were not statistically significant (1.01 +/- 0.38 mV to 1.60 +/- 0.91 mV, S = 4.24, df = 5, p = 0.52). These results suggested that impaired neutrophil bactericidal function is associated with poor blood glucose control. While it is likely that neutrophil bactericidal function will improve as blood glucose control improves, further studies are required both to confirm this and to demonstrate a reduction in the incidence of clinical bacterial infection.

Adult↗
PubMed1994

Insulin-like growth factor binding protein 1 response to acute insulin induced hypoglycaemia in type 1 diabetes.

OBJECTIVES: Insulin is believed to be the prime regulator of insulin-like growth factor binding protein 1 (IGFBP-1) secretion, and in normal subjects acute insulin induced hypoglycaemia exerts a rapid effect on concentrations of IGFBP-1, and may also influence insulin-like growth factor I (IGF-I) concentrations. The rise in IGFBP-1 concentrations in normal subjects following hypoglycaemia has been suggested to be due to suppression of endogenous insulin secretion. We have examined this further by studying diabetics with no endogenous insulin secretion. DESIGN: We have compared the IGFBP-1 response to acute insulin induced hypoglycaemia in normal subjects and patients with Type 1 (insulin dependent) diabetes mellitus. METHODS: Insulin tolerance tests were performed using a bolus of insulin (0.15 U/kg), in six control subjects and six patients with Type 1 diabetes. MEASUREMENTS: Serum levels of IGFBP-1, insulin, glucose, and IGF-I were measured at regular intervals during the insulin tolerance test. RESULTS: Blood glucose fell to a nadir which coincided with the onset of the acute autonomic reaction 'R' in both groups. The basal concentration of IGF-I was significantly lower in the diabetic group at 0.4 +/- 0.1 kU/l, compared to 0.9 +/- 0.1 kU/l in the control group, but there was no significant change in IGF-I concentrations in response to hypoglycaemia in either group. Hypoglycaemia provoked a fall in IGFBP-1 in patients with Type 1 diabetes, from 38 +/- 9 micrograms/l basally to 17 +/- 3 micrograms/l at R + 120 minutes, with a return to basal values of 45 +/- 11 micrograms/l at R + 180 minutes. In the control subjects there was no fall in IGFBP-1, but a significant increase to 71 +/- 14 micrograms/l at R + 180 minutes. CONCLUSION: This difference in the IGFBP-1 response in the presence of a similar glucose response suggests that in Type 1 diabetes there may be different sensitivities to the actions of exogenous insulin on IGFBP-1 regulation.

Adult↗
PubMed1993

An evaluation of bone density and turnover in premenopausal women with type 1 diabetes mellitus.

Measurement of bone density and turnover was assessed in 20 premenopausal females with Type 1 diabetes mellitus and 27 age-sex-matched controls. Measurement was made of spinal (L2-4) and neck of femur bone density by dual-energy X-ray absorptiometry. L2-4 density was significantly higher in the diabetic patients compared with controls (1.224 +/- 0.021 g cm-2 vs. 1.161 +/- 0.020 g cm-2: p = 0.016). No significant difference was noted between the groups in neck of femur density. Measurement of bone formation was assessed by serum alkaline phosphatase and bone resorption by fasting urinary hydroxyproline/creatinine ratio. Alkaline phosphatase was significantly higher in the diabetic patients (185 +/- 16 Ul-1 vs 135 +/- 10 Ul-1: p < 0.01) as was hydroxyproline/creatinine ratio (0.028 +/- 0.003 vs 0.017 +/- 0.002: p = 0.002). No significant correlation was found between L2-4 density and glycated haemoglobin, duration of diabetes or daily dose of insulin taken. These data suggest that osteopenia is not associated with Type 1 diabetes mellitus; however these patients do have evidence of increased bone turnover and may therefore be at risk of osteoporosis in later life, particularly after the menopause.

Absorptiometry, Photon↗