J. H. McKillop

Pravastatin and the Development of Diabetes Mellitus Evidence for a Protective Treatment Effect in the West of Scotland Coronary Prevention Study

BackgroundWe examined the development of new diabetes mellitus in men aged 45 to 64 years during the West of Scotland Coronary Prevention Study. Methods and ResultsOur definition of diabetes mellitus was based on the American Diabetic Association threshold of a blood glucose level of ≥7.0 mmol/L. Subjects who self-reported diabetes at baseline or had a baseline glucose level of ≥7.0 mmol/L were excluded from the analyses. A total of 5974 of the 6595 randomized subjects were included in the analysis, and 139 subjects became diabetic during the study. The baseline predictors of the transition from normal glucose control to diabetes were studied. In the univariate model, body mass index, log triglyceride, log white blood cell count, systolic blood pressure, total and HDL cholesterol, glucose, and randomized treatment assignment to pravastatin were significant predictors. In a multivariate model, body mass index, log triglyceride, glucose, and pravastatin therapy were retained as predictors of diabetes in this cohort. ConclusionsWe concluded that the assignment to pravastatin therapy resulted in a 30% reduction (P =0.042) in the hazard of becoming diabetic. By lowering plasma triglyceride levels, pravastatin therapy may favorably influence the development of diabetes, but other explanations, such as the anti-inflammatory properties of this drug in combination with its endothelial effects, cannot be excluded with these analyses.

Antioxidant systems in normal pregnancy and in pregnancy-induced hypertension

Increased free radical activity has been implicated in the pathogenesis of pregnancy-induced hypertension. This article investigates whether changes in antioxidant systems contribute to this condition. Two extracellular (plasma thiols and ceruloplasmin) and two intracellular (red blood cell lysate thiols and red blood cell superoxide dismutase) antioxidant markers were assayed in 25 nonpregnant women, 16 pregnant women with normal blood pressure, 19 women with pregnancy-induced hypertension, and 13 women with proteinuric pregnancy-induced hypertension. In the normotensive pregnant group (in comparison with the nonpregnant group) the plasma thiol level was reduced (p less than 0.001) and the ceruloplasmin level raised (p less than 0.005), suggesting increased free radical activity. The lysate thiol level increased (p less than 0.005), which may reflect a compensatory protective response. In the hypertensive pregnant groups the lysate thiol rise was not present. These red blood cells may be more prone to oxidative stress. Whether this situation is a cause or an effect of oxidative stress in pregnancy-induced hypertension has yet to be elucidated.

Pathophysiologic assessment of left ventricular hypertrophy and strain in asymptomatic patients with essential hypertension

To investigate the significance of the electrocardiographic (ECG) pattern of left ventricular hypertrophy and strain, two groups of asymptomatic patients with essential hypertension were compared. The patients were similar in terms of age, smoking habit, serum cholesterol and blood pressure levels, but differed in the presence (Group I, n = 23) or absence (Group II, n = 23) of the ECG pattern of left ventricular hypertrophy and strain. Group I patients had significantly more episodes of exercise-induced ST segment depression (14 versus 4, p less than 0.05) and reversible thallium perfusion abnormalities (11 of 23 versus 3 of 23, p less than 0.05) despite similar exercise capacity and absence of chest pain. Nonsustained ventricular tachycardia was detected on 24 h ambulatory ECG monitoring in two patients in Group I, but no patient in Group II. Coronary arteriography performed in 20 Group I patients demonstrated significant coronary artery disease in 8 patients. This study has shown that there is a subgroup of hypertensive patients with ECG left ventricular hypertrophy and strain who have covert coronary artery disease. This can be detected by thallium perfusion scintigraphy, and may contribute to the increased risk known to be associated with this ECG abnormality.

Antioxidants: their role in pregnancy and miscarriage.

The aim of this study was to examine the role of antioxidants within the normal menstrual cycle, in healthy pregnancy, and in women suffering first-trimester miscarriage. The antioxidants chosen comprised of two from peripheral blood-plasma thiol and ceruloplasmin-and two extracellular parameters-superoxide dismustase (SOD) and red cell lysate thiol. We found that antioxidant levels varied little throughout the menstrual cycle. Pregnancies that went successfully to term were associated with increased levels of ceruloplasmin and SOD early in the first trimester. These changes were thought to offer the cell protection from the damage caused by the increased oxidative stress associated with pregnancy. First-trimester miscarriage was associated with significantly reduced levels of SOD. A subgroup of patients who miscarried in their first pregnancy, but whose second pregnancies were successful, had higher levels of plasma thiol and significantly reduced levels of red cell lysate thiol in the on-going pregnancy compared to levels at the time of miscarriage. Miscarriage and pregnancy appear to be associated with increased oxidative stress. In a successful pregnancy, however, changes occurred within the peripheral blood that offered protection from oxidant attack.

Glass yttrium-90 microspheres for patients with colorectal liver metastases.

Total calculated uniform liver doses of up to 150 Gy were achieved using glass yttrium-90 microspheres administered via the hepatic artery and targeted to tumour using angiotensin II in seven patients with colorectal liver metastases. No toxicity was observed. Hepatic metastatic progression was delayed in six patients. Median survival was 11 months (range 5-25 + months).

THE EFFECT OF ANTITHYROID DRUGS ON B AND T CELL ACTIVITY IN VITRO

This study examined the abilities of methimazole, propylthiouracil (PTU) and propranolol to exert an immunosuppressive effect in vitro. Incubation of peripheral blood lymphocytes (PBL) with propranolol showed the drug to have no effect on either B‐ or T‐cell activity. Methimazole or PTU at concentrations of ≥ 10−5M resulted in significantly lower amounts of IgG and IgM being released into the culture medium. Both drugs were also found to have a direct effect on T‐cell function as they caused the percentage of total and suppressor cells to increase towards normal levels. The three drugs were all found to have some free radical scavenging ability. These ranked PTU > methimazole > propranolol. These in‐vitro findings would suggest that both methimazole and PTU have some direct effect on the immune system. It would seem more likely however that these effects are mediated via interleukin 2 rather than by their ability to act as free radical scavengers.

Significance of ventricular arrhythmias in systemic hypertension with left ventricular hypertrophy

Hypertensive patients with the electrocardiographic (ECG) pattern of left ventricular (LV) hypertrophy and strain are at increased risk of sudden death. It has been suggested that ventricular arrhythmias may be responsible. The prevalence and significance of ventricular arrhythmias was therefore studied in 90 hypertensive patients with LV hypertrophy and strain by undertaking 48-hour ambulatory ECG monitoring, ECG signal-averaging and programmed ventricular stimulation. Complex ventricular ectopic activity (Lown grade greater than or equal to 3) was detected in 59 patients (66%). Eleven patients (12%) had episodes of nonsustained ventricular tachycardia. There were no sustained arrhythmias either on ambulatory ECG monitoring or induced by programmed ventricular stimulation. Only 1 patient had ventricular late potentials recorded by the signal-averaged electrocardiogram. Therefore, there was little to suggest an underlying arrhythmogenic substrate in these patients. In conclusion, whereas ventricular arrhythmias occur often in patients with LV hypertrophy associated with systemic hypertension, their significance, if any, remains to be established.

Thyroid antibody titer and avidity in patients with recurrent miscarriage

OBJECTIVE To determine whether the titer and avidity of the thyroid peroxidase antibody differs between pregnant women in their first trimester who have a history of recurrent miscarriage and whose pregnancies continue to term and those whose pregnancies fail again later in the first trimester. DESIGN Controlled clinical study. SETTING Healthy volunteers in an academic research environment. PATIENT(S) Pregnant women in their first trimester who had a history of recurrent miscarriage (> or = 3 miscarriages) and who were known to be positive for the thyroid peroxidase antibody. INTERVENTION(S) None of the patients received any medication. MAIN OUTCOME MEASURE(S) Thyroid peroxidase antibody titer and avidity (i.e., the net binding strength between antibody and antigen). RESULT(S) At the time of presentation, thyroid peroxidase antibody titer and avidity was significantly higher in those women who later miscarried compared with those whose pregnancies continued. In those whose pregnancies continued to term, titer and avidity declined as the pregnancy progressed. CONCLUSION(S) Autoimmunity plays a role in recurrent miscarriage. Among a group of patients who had had recurrent miscarriages, there appeared to be differences in the humoral response to the pregnancy between those whose pregnancies continued to term and those whose pregnancies failed again.

Altered interleukin 12 and nitric oxide levels in recurrrent miscarriage

The causes of recurrent miscarriage are not fully understood. Recent studies have suggested that whilst a TH 2 type immune response may be associated with a healthy pregnancy, miscarriage may be associated with a TH 1 type response. Serum levels of nitric oxide (NO) and Interleukin 12 (IL 12) were measured in; healthy non-pregnant women; healthy pregnant women; women suffering spontaneous abortion; pregnant women with a history of recurrent miscarriage; non-pregnant women with a history of recurrent miscarriage. Normal pregnancy was associated with a significant decrease in serum levels of nitrite (13.0 vs. 22.0 P < 0.0001). In women admitted with spontaneous abortion there was a significant increase in the levels of nitrite (16.0 vs. 13.0 P < 0.05), but no change in IL 12 compared to normal pregnant women. In pregnant women with a history of recurrent miscarriage levels of nitrite (16.0 vs. 13.0 P < 0.05) and IL 12 (10.0 vs. 6.0 P < 0.0006) were significantly elevated compared to normal pregnancy. When these women were sampled prior to becoming pregnant the levels of NO were found to be significantly lower than those in the non-pregnant control group (13.1 vs. 22.0 P < 0.05) although levels of IL 12 were unchanged. No correlation was found between serum nitrite and IL 12 levels. This report further supports the idea that polarisation of the immune response during pregnancy may predispose to recurrent miscarriage.

Erythrocyte glutathione balance and membrane stability during preeclampsia

This study aimed to determine whether oxidative damage to the erythrocyte occurs in preeclampsia, and relates to disease severity. The oxidative status of intact erythrocytes from preeclamptic patients and normal pregnant women was determined using spin echo 1H-NMR, which measures both the concentration and redox state of intracellular glutathione. Previous studies of preeclampsia have only measured total glutathione levels. Membrane fragility was determined from the degree of lysis caused by incubation in hypotonic saline. Erythrocytes from moderate-severe preeclamptic patients underwent more lysis than erythrocytes from control pregnant women (p < .05) or mild preeclamptic patients. It is suggested that increased lysis results from oxidative damage to the erythrocyte membrane, causing a decrease in membrane fluidity and reducing its ability to withstand osmotic changes. Intracellular glutathione was more oxidized in erythrocytes from pregnant women compared to nonpregnant controls (p < .05), and there was a less significant trend toward more oxidized glutathione with increasing severity of preeclampsia. The moderate-severe group showed a clear division in glutathione redox status: some patients had very oxidized glutathione while others had a normal redox balance. This novel finding suggests that some patients may be unusually susceptible to erythrocyte glutathione oxidation, possibly leading to general cellular damage, in particular HELLP Syndrome.