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M J Sampson

Publications and source records attributed to M J Sampson.

At least 37 records · Page 2Linked to original sources
PubMed1997

The murine voltage-dependent anion channel gene family. Conserved structure and function.

Voltage-dependent anion channels (VDACs) are pore-forming proteins found in the outer mitochondrial membrane of all eucaryotes. VDACs are the binding sites for several cytosolic enzymes, including the isoforms of hexokinase and glycerol kinase. VDACs have recently been shown to conduct ATP when in the open state, allowing bound kinases preferential access to mitochondrial ATP and providing a possible mechanism for the regulation of adenine nucleotide flux. Two human VDAC cDNAs have been described previously, and we recently reported the isolation of mouse VDAC1 and VDAC2 cDNAs, as well as a third novel VDAC cDNA, designated VDAC3. In this report we describe the structural organization of each mouse VDAC gene and demonstrate that, based on conserved exon/intron boundaries, the three VDAC isoforms belong to a single gene family. The 5'-flanking region of each VDAC gene was shown to have transcription promoter activity by transient expression in cultured cells. The promoter region of each VDAC isoform lacks a canonical TATA box, but all are G+C-rich, a characteristic of housekeeping gene promoters. To examine the conservation of VDAC function, each mouse VDAC was expressed in yeast lacking the endogenous VDAC gene. Both VDAC1 and VDAC2 are able to complement the phenotypic defect associated with the mutant yeast strain. VDAC3, however, is only able to partially complement the mutant phenotype, suggesting an alternative physiologic function for the VDAC3 protein.

Amino Acid Sequence↗
PubMed1996

Isolation, mapping, and functional expression of the mouse X chromosome glycerol kinase gene.

Glycerol kinase (Gyk) participates in the metabolism of endogenously derived and dietary glycerol. Deficiency of the human enzyme activity is an X-linked recessive disorder with a clinical picture varying from childhood metabolic crisis to asymptomatic adults incidentally identified by hyperlipidemia screening (pseudohypertriglyceridemia). Gyk is a member of a small group of kinases termed ambiquitous enzymes that are found in the cytosol or as membrane-bound enzymes associated with the voltage-dependent anion channel of the mitochondrial outer membrane. It was recently reported that in humans there are X-linked and autosomal copies of Gyk sequences, both apparently functional genes and processed pseudogenes. To understand the role of Gyk in normal metabolism and the variable clinical features seen with Gyk deficiency, we have characterized the mouse Gyk gene. We present the sequence of a full-length mouse Gyk cDNA that is alternatively spliced in brain. The Gyk gene was mapped to the mouse X chromosome by both fluorescence in situ hybridization and an interspecies backcross panel, demonstrating conservation of synteny with dmd. To confirm the functional identity of the cDNA, transient transfection of the cDNA into COS7 cells was shown to cause a marked elevation in glycerol kinase activity.

Alternative Splicing↗
PubMed1996

A novel mouse mitochondrial voltage-dependent anion channel gene localizes to chromosome 8.

Voltage-dependent anion channels (VDACs) are small pore-forming channels found in the outer membrane of mitochondria. VDACs translocate adenine nucleotides and are the binding sites for several cytosolic kinases important in intermediary metabolism. Recently two human VDAC cDNAs (HVDAC1 and HVDAC2) were isolated, and possible orthologues of these genes have been isolated from mouse, bovine, and rat tissues. We report the isolation of a novel third VDAC cDNA from the mouse, designated MVDAC3. The deduced MVDAC3 protein is approximately 70% identical to the previously isolated MVDAC1 and MVDAC2 proteins. The MVDAC3 gene was mapped by an interspecies backcross panel to mouse chromosome 8. A database search using the mouse VDACs identified a second yeast VDAC-like gene that retains about 20% amino acid sequence identity with the mouse VDAC genes and 50% identity with the previously isolated yeast VDAC gene. The phylogenetic relationship of the eukaryotic VDAC genes is presented.

Amino Acid Sequence↗
PubMed1996

Isolation, characterization, and mapping of two mouse mitochondrial voltage-dependent anion channel isoforms.

Voltage-dependent anion channels (VDACs) are small pore-forming channels found in the mitochondrial outer membrane of all eukaryotes. VDACs conduct adenine nucleotides and are the binding sites for several cytosolic enzymes, including the isoforms of hexokinase and glycerol kinase. VDAC binding is developmentally and metabolically regulated and allows the kinases preferential access to mitochondrial ATP. Two human VDAC cDNAs have recently been identified, and a total of four VDAC loci have been mapped. Here, the isolation of two mouse VDAC cDNAs (VDAC5 and VDAC6) is described. By Northern analysis the two mouse VDAC isoforms show nearly identical expression patterns, with high levels of expression detected in heart, kidney, brain, and skeletal muscle and lesser levels of expression in all other tissues examined. The only exception is the lack of expression of VDAC5 in testes, whereas VDAC6 expression is highest in this tissue. VDAC6 appears to be encoded by more than one transcript. The mouse VDAC5 gene was mapped using an interspecies DNA mapping panel to the proximal region of chromosome 11, and the mouse VDAC6 gene was mapped using a panel to the proximal region of chromosome 14.

Amino Acid Sequence↗
PubMed1996

An unusual cause for collapse in a patient with arthritis.

We present the clinical case of a patient who was admitted to the intensive care ward with severe central nervous system symptoms and cardiovascular collapse within a week of starting sulphasalazine; in the absence of any other diagnosis, these symptoms were felt to be due to a previously unreported adverse effect of sulphasalazine.

Aged↗
PubMed1996

Cellular sodium membrane transport and cardiovascular risk factors in non-insulin-dependent diabetes mellitus.

Association have been described between cardiovascular risk factors and abnormalities of both sodium-lithium countertransport (SLC) and sodium-hydrogen ion exchange in subjects with insulin-dependent diabetes mellitus. The data in subjects with non-insulin-dependent diabetes mellitus (NIDDM) are few and more conflicting. This investigation examines erythrocyte SLC rates and platelet sodium-hydrogen ion-exchange kinetics and their relationship to cardiovascular risk factors in 45 nondiabetic and 35 NIDDM white men. The two groups did not differ significantly in erythrocyte SLC or platelet buffering capacity, sodium-hydrogen ion-exchange maximal rate (Vmax), or Km for extracellular sodium. Within the whole group, controlling for the presence of diabetes, SLC correlated weakly with triglyceride concentration (r = .23, P = .05), but not with urinary albumin excretion rate (AER), systolic or diastolic blood pressure, body mass index (BMI), or concentrations of glucose, insulin, or total or high-density lipoprotein (HDL) cholesterol. Platelet sodium-hydrogen exchange was not significantly related to any cardiovascular risk factor studied. In conclusion, (1)SLC activity was not increased in NIDDM subjects; (2) SLC rates correlated weakly with serum triglyceride concentrations; (3) platelet sodium-hydrogen exchange Vmax and K(m) for extracellular sodium and platelet buffering capacity did not differ between diabetic and nondiabetic groups; and (4) there was no significant relationship between platelet Na+/H(+)-exchange kinetics and any of the cardiovascular risk factors studied.

Adult↗
PubMed1995

Association between left ventricular hypertrophy and erythrocyte sodium-lithium exchange in normotensive subjects with and without NIDDM.

The determinants of left ventricular mass in normal control subjects and subjects with non-insulin-dependent diabetes (NIDDM) are ill-defined. We therefore recorded M-mode and pulsed Doppler echocardiograms and 24-h ambulatory blood pressure in 57 normotensive subjects, 34 with NIDDM and 23 matched non-diabetic control subjects. Measurements of erythrocyte sodium-lithium counter-transport, plasma angiotensin II, plasma and platelet catecholamines and fasting plasma insulin were also made. Six control subjects (26%) and 15 diabetic subjects (44%) had some degree of left ventricular hypertrophy. Subjects with left ventricular hypertrophy (n = 21) had an elevated mean rate of sodium-lithium countertransport (0.40 +/- 0.13 vs 0.31 +/- 0.09 mmol.l-1.h-1; p < 0.01), parallel differences being observed in both the diabetic and control groups. Twelve of the subjects with left ventricular hypertrophy (57%) had elevated rates of sodium-lithium counter-transport compared to only seven (19%) of those without (p < 0.05). There was no consistent difference between those with and without left ventricular hypertrophy in any other clinical or biochemical variable. Multivariate analysis, with the presence or absence of left ventricular hypertrophy as the dependent variable, demonstrated that the maximal rate of sodium-lithium countertransport was the only variable that independently contributed to left ventricular hypertrophy (partial r = 0.35; F1.55 = 7.74; p = 0.007). This study demonstrates for the first time an association between left ventricular hypertrophy and erythrocyte membrane cation transport that is independent of hypertension, is present in both diabetic and non-diabetic groups, and may represent a link between elevated rates of membrane sodium transport and cardiovascular risk.

Adult↗
PubMed1994

Blood pressure, diet and the progression of nephropathy in patients with type 1 diabetes and hypertension.

To examine the relationships between the normal dietary intakes of protein and phosphate, blood pressure, and the progression of diabetic nephropathy, we prospectively studied 20 Type 1 diabetic subjects of mean age 43 +/- 10 years (SD) with early nephropathy (mean serum creatinine 115 +/- 43 mumol l-1) over 1 year. Three-monthly measurements of blood pressure, glycaemic control, and normal dietary intake (3-day weighed food records) and 6-monthly measurements of glomerular filtration rate (using a single injection of chromium 51-EDTA) were made. GFR changed at a median rate of -0.89 ml min-1 1.73 m-2 month-1 (range +0.85 to -2.55 ml min-1 1.73 m-2 month-1). Mean dietary protein intake (1.22 g kg-1; range 0.78 to 1.55 g kg-1) and phosphate intake (21.5 mg kg-1; range 14.1 to 30.4 mg kg-1) were not significantly related to the rate of change in GFR. Only mean systolic blood pressure was significantly related to change in GFR, and accounted for 45% of the variability in GFR decline in the 18 subjects who completed the study (r = 0.67; R2 = 0.449; F1,16 = 13.2; p < 0.005; 95% confidence interval for r: 0.336-0.867). A mean systolic blood pressure of 140 mmHg or below was associated with no significant decline in GFR over a median period of 13 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Insulin resistance, insulin, proinsulin, and ambulatory blood pressure in type II diabetes.

Both insulin resistance and insulin concentrations correlate with blood pressure in nondiabetic subjects, but there is no consensus on these relations in subjects with non-insulin-dependent diabetes, perhaps because of the use of nonspecific insulin assays and clinic blood pressure measurement. Therefore, we have investigated the relation between ambulatory blood pressure, insulin sensitivity (measured by an insulin sensitivity test), and levels of insulin and its principal precursors, measured by specific assays, in 24 subjects with non-insulin-dependent diabetes. Insulin sensitivity (glucose metabolic clearance rate) correlated strongly with mean 24-hour ambulatory systolic blood pressure (r = -.650, P < .001). In contrast, there was no relation between this blood pressure index and fasting levels of insulin (r = .096, P = NS) or all insulin-like molecules (r = .077, P = NS). Dichotomized on 24-hour ambulatory systolic blood pressure levels, the hypertensive group was more insulin resistant than the normotensive group (metabolic clearance rate, 3.6 [0.7] versus 6.5 [3.0] mL.kg-1.min-1, P = .006), whereas there was no difference in insulin or proinsulin concentrations among the groups. In multiple regression analysis, insulin sensitivity was the major determinant of blood pressure. We conclude that in subjects with non-insulin-dependent diabetes mellitus, blood pressure is related to insulin sensitivity but not to fasting levels of insulin, suggesting that hyperinsulinemia is probably not the mediator of this relation.

Ambulatory Care↗
PubMed1992

Accurate estimation of glomerular filtration rate in diabetic nephropathy from age, body weight, and serum creatinine.

OBJECTIVE: To assess, in diabetic nephropathy, the accuracy of a method that estimates glomerular function with age, body weight, and serum creatinine as parameters. RESEARCH DESIGN AND METHODS: Glomerular filtration rate (GFR) was measured 57 times in 20 subjects with insulin-dependent diabetes mellitus and nephropathy with a single injection of 51Cr-EDTA. At the same time, the estimated creatinine clearance (ml/min) was calculated with the Cockroft-Gault formula (140 - age [yr]) x body wt [kg] x K/serum creatinine [mumol/L]) K = 1.23 for men, 1.05 for women These values were then corrected for body surface area (1.73 m2). RESULTS: For GFR measurements less than 100 ml.min-1.1.73 m-2 (n = 41), there was a strong positive correlation with the estimated creatinine clearance corrected for body surface area (r = 0.94, P less than 0.0001). The slope of this regression line did not differ significantly from identity or the y-intercept from zero. On average, the Cockroft-Gault formula (corrected for body surface area) underestimated the GFR by only 3.1 ml.min-1.1.73 m-2 (9.7 SD). CONCLUSIONS: This formula, corrected for body surface area, gives accurate estimates of GFR when GFR less than 100 ml.min-1.1.73 m-2. This formula could be used with an acceptable degree of confidence when repeated isotope assessments of renal function in diabetic nephropathy are impracticable.

Adult↗
PubMed1990

QT prolongation on the electrocardiogram in diabetic autonomic neuropathy.

Patients with Type 1 diabetes and autonomic neuropathy have an increased risk of sudden death for which the mechanism remains obscure. Prolongation of the QT interval on the electrocardiogram may occur with sympathetic dysfunction and is also associated with ventricular arrhythmia and sudden death. We have therefore measured the QT interval in patients with Type 1 diabetes with normal, borderline, and definitely abnormal autonomic function tests and in non-diabetic control subjects. The maximum QT interval was measured on 12-lead electrocardiograms recorded at rest and then plotted against the RR interval. The QT interval was above the upper 95% limit for the non-diabetic control subjects in 5 diabetic patients with abnormal autonomic function tests (33%), but in no cases with normal or borderline tests. Multivariate analysis confirmed that autonomic score contributed significantly (p less than 0.025) to the variance in QT interval. The raw Valsalva ratio alone also contributed significantly to the variance in QT interval (p = 0.025). Heart rate variability, heart rate response to standing, age, sex, and the presence of symptoms of autonomic neuropathy did not contribute significantly.

Arrhythmias, Cardiac↗
PubMed1990

Intraventricular septal hypertrophy in type 1 diabetic patients with microalbuminuria or early proteinuria.

To investigate whether the slightly increased blood pressure that occurs in early diabetic renal disease is associated with hypertensive left ventricular hypertrophy, M-mode echocardiograms were recorded in 11 non-diabetic control subjects and four groups of Type 1 diabetic patients. These were 15 patients without microvascular complications, 10 with microalbuminuria, 12 with early persistent proteinuria, and 8 with established renal impairment. Mean blood pressure was 133/80 mmHg (uncomplicated patients), 143/85 mmHg (microalbuminuria), 147/92 mmHg (early proteinuria) and 158/85 mmHg (renal impairment). Mean intraventricular septal width in the uncomplicated diabetic patients was 9.8 (SE 1.2) mm which did not differ from non-diabetic control subjects. Mean septal width was significantly greater in the other groups (microalbuminuria, 12.7 (1.1) mm, p less than 0.02; proteinuria, 12.0 (0.7) mm, p less than 0.05; renal impairment, 15.5 (1.8) mm, p less than 0.001). Left ventricular mass increased progressively between groups and was significantly increased in those with renal impairment (140 (21) vs 103 (5) g m-2 in uncomplicated patients, p less than 0.05). Septal width in the diabetic population not receiving antihypertensives (n = 37) was significantly correlated with systolic blood pressure (r = 0.45, p less than 0.005) which was the only variable independently related to septal width and ventricular mass. It appears that the slight increase in blood pressure that occurs in microalbuminuria and early proteinuria is frequently associated with hypertensive left ventricular hypertrophy.

Adult↗
PubMed1990

Abnormal diastolic function in patients with type 1 diabetes and early nephropathy.

Left ventricular diastolic function was assessed by pulsed Doppler echocardiography in non-diabetic controls (n = 11) and in patients with type 1 diabetes without microvascular disease (n = 16; diabetic controls), with microalbuminuria (n = 9), or with early persistent proteinuria (n = 11). The peak filling velocities during the early and atrial phases of left ventricular diastole and their ratio (E:A ratio) were measured. All patients with diabetes had a normal serum concentration of creatinine and exercise electrocardiogram. The mean E:A ratio was significantly lower in those with proteinuria than in the diabetic controls because of an increase in peak atrial filling velocity; most patients with proteinuria had an abnormal E:A ratio of less than 1.0. Multiple regression analysis showed that systolic blood pressure was the major determinant of both the peak filling velocity during the atrial phase of diastole and also left ventricular mass. Blood pressures were significantly higher in the proteinuria group than in the diabetic controls. Glycaemic control and autonomic function did not influence diastolic filling. The slightly raised blood pressures at the earliest stages of diabetic nephropathy are sufficient to alter left ventricular diastolic compliance--this may reflect early hypertensive heart disease. These data do not preclude a specific heart muscle disease related to diabetes, but suggest that these slightly raised blood pressures contribute significantly to left ventricular dysfunction in these patients, in whom the risk of cardiovascular disease is already greatly increased.

Adult↗
PubMed1990

Progression of diabetic autonomic neuropathy over a decade in insulin-dependent diabetics.

The prognosis for diabetics with autonomic neuropathy is little known. We therefore studied the progress of young insulin-dependent diabetics, first identified as having abnormal autonomic function 10-15 years ago. We have shown that the mortality of diabetics with symptomatic autonomic neuropathy is increased, but is less than previously reported. Mortality in asymptomatic diabetics with an isolated abnormality in autonomic function tests is not increased. The heart rate variability declines at 1.02 +/- 0.47 (SD) per annum in diabetics with an initially normal heart rate variability. While symptoms of autonomic neuropathy do not usually remit even over a decade, they do not commonly progress. Three groups of young insulin-dependent diabetics had heart rate variability tested between 1972 and 1977 and have been reviewed 10-15 years later. Group A (n = 49) had symptomatic autonomic neuropathy and an abnormal heart rate variability (less than 12), Group B (n = 24) were asymptomatic yet had an abnormal heart rate variability and Group C (n = 38) were asymptomatic and had a normal heart rate variability (16-26). The 10-year survival in Group A (73.4 per cent) was less (P less than 0.05) than in Groups B (91.7 per cent) or C (89.5 per cent) which did not differ from each other. The 18 Group A deaths were due predominantly to renal failure (n = 4), myocardial infarction in patients with nephropathy (n = 3) and sudden unexpected death (n = 3). The chief symptoms of autonomic neuropathy--diarrhoea, postural hypotension and gustatory sweating, were very persistent but did not necessarily deteriorate or become disabling in the majority of patients. The development of autonomic symptoms in asymptomatic patients with abnormal heart rate variability was uncommon over a decade.

Adult↗
PubMed1987

The conservative management of primary hyperparathyroidism.

Sixty-eight patients with mild primary hyperparathyroidism were studied for a mean period of 4.5 years (median 3.3). Seven of these patients presented with renal colic while the rest had no symptoms. There was no significant deterioration in mean serum creatinine, total calcium or ionized calcium concentrations during this period. No patient had progressive renal stone or parathyroid bone disease. Hypertension was defined as a systolic or diastolic blood pressure greater than one standard deviation from the age-sex mean, or if hypotensive drugs were required. Thirty-nine per cent were hypertensive at presentation and 42 per cent became hypertensive later. Four patients died from causes unrelated to hypercalcaemia and three required parathyroidectomy when serum calcium concentration rose above 3.0 mmol/l. Patients over 55 with mild asymptomatic primary hyperparathyroidism may be managed conservatively for several years without significant renal impairment, progressive stone disease, parathyroid bone disease or worsening hypercalcaemia. We suggest that observation in these patients could be restricted to six-monthly checks of physical state, blood pressure and serum biochemistry, particularly concentration of calcium creatinine and alkaline phosphatase.

Adult↗