Detection of red cell aggregation by low shear rate viscometry in whole blood with elevated plasma viscosity.

The viscosity of whole blood measured at low shear rates is determined partly by shear resistance of the red cell aggregates present, stronger aggregation increasing the viscosity in the absence of other changes. Effects of cell deformability can confound interpretation and comparison in terms of aggregation, however, particularly when the plasma viscosity is high. We illustrate the problem with a comparison of hematocrit-adjusted blood from type 1 diabetes patients and controls in which it is found the apparent and relative viscosities at a true shear rate of 0.20 s-1 are lower in the patient samples than age matched controls, in spite of reports that aggregation is increased in such populations. Because the plasma viscosities of the patients were higher on average than controls, we performed a series of experiments to examine the effect of plasma protein concentration and viscosity on normal blood viscosity. Dilution or concentration by ultrafiltration of autologous plasma and viscosity measurements at low shear on constant hematocrit red cell suspensions showed (a) suspension viscosity at 0.25 and 3 s-1 increased monotonically with plasma protein concentration and viscosity but (b) the relative viscosity increased, in concert with the microscopic aggregation grade, up to a viscosity of approximately 1.25 mPa-s but above this the value the relative viscosity no longer increased as the degree of aggregation increased in concentrated plasmas. It is suggested that in order to reduce cell deformation effects in hyperviscous pathological plasmas, patient and control plasmas should be systematically diluted before hematocrit is adjusted and rheological measurements are made. True shear rates should be calculated. Comparison of relative viscosities at low true shear rates appears to allow the effects of red cell aggregation to be distinguished by variable shear rate viscometry in clinical blood samples.

Post-transplant diabetic ketoacidosis--a possible consequence of immunosuppression with calcineurin inhibiting agents: a case series.

Post-transplant diabetes mellitus, a complication due to corticosteroids and the calcineurin inhibitors, cyclosporine and tacrolimus (FK506), is commonly regarded as a form of type-2 (adult-onset) diabetes mellitus. Diabetic ketoacidosis, which requires relative insulin deficiency to impair fatty acid metabolism, is a complication of type-1 diabetes mellitus. We report three patients who presented with diabetic ketoacidosis post-transplant. All three patients presented with severe hyperglycemia, significant ketosis and metabolic acidosis of variable severity. One patient was a renal transplant recipient on a cyclosporine-based regimen. The other two patients were liver transplant recipients receiving either cyclosporine or tacrolimus-based immunosuppression. Both of the liver transplant recipients were found to have moderate to high serum levels of calcineurin inhibitors on presentation. The liver recipient on cyclosporine (Neoral) had a 4 hour post-dose level of 388 ng/ml and the patient on tacrolimus was found to have a trough level of 21.2 ng/ml. Our experience suggests that post-transplant diabetes mellitus, in association with calcineurin inhibition, may result in ketoacidosis either secondary to relative beta cell dysfunction, peripheral insulin resistance, or a combination of the two effects. Post-transplant diabetes mellitus can be an atypical form of adult-onset diabetes with features of both type I and type II diabetes mellitus.

Preserved forearm endothelial responses with acute exposure to progesterone: A randomized cross-over trial of 17-beta estradiol, progesterone, and 17-beta estradiol with progesterone in healthy menopausal women.

Regularly menstruating women are relatively protected from cardiovascular disease. Epidemiological and endothelial function studies attribute this protection to estradiol (E(2)), but both progesterone (P) and E(2) are normally present. A range of vascular effects of added progestins have been described, from neutral to detrimental, but the effects of P per se on endothelial function in humans have not been reported. We therefore investigated the acute effects of E(2), P, and E(2) combined with P, on endothelium-dependent and -independent forearm blood flow responses. Using venous occlusion plethysmography, forearm blood flow (FBF) was measured during acute brachial artery infusions, achieving physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P in healthy menopausal women with no cardiovascular disease risk factors. Vehicle or hormones were infused, in random order, on 4 days, 1 week apart. Flow responses were measured during coinfusions of hormone with the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator sodium nitroprusside. Twenty-seven healthy menopausal women were studied, and all had normal baseline endothelial responses. Small ( approximately 15%), statistically nonsignificant increases in endothelium-dependent flow responses were seen after all acute hormone treatments. No impairment in response was seen with P alone or in combination with 17-beta-E(2). In healthy menopausal women without cardiovascular disease risk factors and without baseline defects in endothelial function, acute exposure to physiologic levels of 17-beta-E(2), P, and 17-beta-E(2) with P produced equivalent endothelium-dependent responses. These data suggest that P does not have detrimental vascular effects in humans.

Tips for a better local anaesthetic.

The expert use of local anaesthetics is simple and will greatly enhance patients' acceptance of office-based procedures. Correct equipment and techniques will enable all dermatologists to practise local anaesthesia as effectively and painlessly as possible. Suggested equipment varies according to the situation, but in general Luer-Lock syringes of the smallest volume and needles of the narrowest gauge and shortest length appropriate for the procedure are recommended. Making the anaesthetic agent less acidic will minimize the pain. Techniques to minimize pain involve careful explanation to the patient, slow injection of the anaesthetic and making use of the special anatomy of the region to be anaesthetized. The number of needle pricks should be kept to a minimum. Timing of the surgical procedure should take into account the delay in onset of anaesthesia for subcutaneously injected solution and the time for injected adrenaline to produce full vasoconstriction. Planned surgical incision lines drawn out precisely prior to the injection will avoid the problem of distortion caused by tissue expansion. Gloves and appropriate eye protection should be standard and needles and syringes must be disposed of correctly.

Effects of vitamin E on endothelial function in men after myocardial infarction.

This study showed that endothelial dysfunction is present in men 3 to 6 months after myocardial infarction, but was unable to show any improvement in endothelial function after 3 months of therapy with vitamin E 800 IU/day. Further studies are necessary to determine whether higher doses or a longer course of vitamin E, or whether other antioxidant agents with or without lipid-modifying activity, would improve endothelial function.

Lipoprotein(a) in type 1 diabetic patients with renal disease.

Lp(a) was measured in 64 normoalbuminuric, 52 microalbuminuric, and 37 proteinuric Type 1 diabetic patients and 54 healthy subjects. Microalbuminuric and proteinuric Type 1 diabetic patients had higher median Lp(a) values (133 (16-1932) and 169 (17-1149) mg l-1) than patients with normal AER (73 (15-1078) mg l-1; p = 0.048 and p = 0.027). Lp(a) in healthy subjects (110 (15-1630)mg l-1) did not differ from the diabetic subgroups. The frequency of Lp(a) values in the upper quarter of the normal distribution was similar in the diabetic groups and did not differ between diabetic and control subjects. The cumulative distribution of Lp(a) was similar in all groups. Lp(a) concentrations were not related to AER, age, gender, duration of diabetes, body mass index, glycaemic control, serum creatinine, free insulin or systolic blood pressure. Cholesterol, LDL-cholesterol, triglycerides, and apo B were higher in microalbuminuric and proteinuric than in normoalbuminuric Type 1 diabetic patients. Lp(a) was independently related to diastolic blood pressure, fibrinogen, and macroangiopathy. In conclusion, median Lp(a) concentrations tend to be higher in Type 1 diabetic patients with early and established renal disease, although the differences are small and the overlap between groups large. Lp(a) is related to diastolic blood pressure and fibrinogen, and this association of powerful risk factors suggests that Lp(a) may play a role in the pathogenesis of cardiovascular disease in Type 1 diabetic patients with proteinuria. Whether Lp(a) is an independent determinant of increased cardiovascular risk in these patients needs to be elucidated by prospective studies.

LDL subclasses in IDDM patients: relation to diabetic nephropathy.

To answer the question whether the elevation of LDL-cholesterol in IDDM patients with incipient and established diabetic nephropathy is accompanied by changes in LDL size or composition, we studied distribution of LDL particles in 57 normoalbuminuric [AER 7 (1-9) micrograms/min, median and range], in 46 microalbuminuric [AER 50 (20-192) micrograms/min] and in 33 proteinuric [AER 422 (233-1756) micrograms/min] IDDM patients as well as in 49 non-diabetic control subjects with normoalbuminuria. The three diabetic groups were matched for duration of diabetes and glycaemic control. The mean particle diameter of the major LDL peak was determined by nondenaturing gradient gel electrophoresis. Composition and density distribution of LDL were determined in the subgroups of each patient group by density gradient ultracentrifugation. Normoalbuminuric IDDM patients had larger LDL particles than non-diabetic control subjects (260 A vs 254 A, p < 0.05). LDL particle diameter was inversely correlated with serum triglycerides in all groups (p < 0.05 for normoalbuminuric and p < 0.001 for other groups). Triglyceride content of LDL was higher in three IDDM groups compared to control group (p < 0.05). The elevation of LDL mass in microalbuminuric and proteinuric IDDM groups compared to normoalbuminuric IDDM group (p < 0.05 for both) was mainly due to the increment of light LDL (density 1.0212-1.0343 g/ml). There were no significant changes in the density distribution or composition of LDL between the three diabetic groups. In conclusion the increase of LDL mass without major compositional changes suggests that the elevation of LDL in incipient and established diabetic nephropathy is primarily due to the increased number of LDL particles.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of nitric oxide synthesis in forearm vasculature of insulin-dependent diabetic patients: blunted vasoconstriction in patients with microalbuminuria.

1. Microalbuminuria is a risk factor for cardiovascular disease in patients with insulin-dependent diabetes mellitus, and may be a marker of microvascular dysfunction including endothelial damage. The purpose of this study was to determine whether vasoconstrictor responses to NG-monomethyl-L-arginine, an inhibitor of endothelium-derived relaxing factor/nitric oxide biosynthesis, differ between healthy subjects and insulin-dependent patients with or without microalbuminuria. 2. Twenty-eight insulin-dependent diabetic patients (14 with normal albumin excretion, 14 with microalbuminuria) were studied under euglycaemic conditions, together with 14 healthy control subjects. Forearm vascular responses to brachial artery infusions of NG-monomethyl-L-arginine, sodium nitroprusside (an endothelium-independent nitrovasodilator) and carbachol (an endothelium-dependent vasodilator) were determined by strain gauge plethysmography. 3. Basal blood flow and vasodilator responses were similar in each group. NG-Monomethyl-L-arginine reduced blood flow by 41.3 +/- 2.3% (mean +/- SEM) in healthy control subjects, 34.0 +/- 3.4% in diabetic patients without microalbuminuria and 29.2 +/- 2.0% in diabetic patients with microalbuminuria. Diabetic patients differed from healthy subjects (P = 0.005), due to a difference between control subjects and microalbuminuric diabetic patients (P < 0.001). NG-Monomethyl-L-arginine did not influence nitroprusside responses but reduced carbachol responses in control subjects and normoalbuminuric diabetic patients but not in microalbuminuric diabetic patients. 4. These results provide evidence of abnormal endothelium-derived relaxing factor/nitric oxide biosynthesis in insulin-dependent diabetic patients with microalbuminuria.

Relationship between insulin resistance and coronary heart disease in diabetes mellitus and the general population: a critical appraisal.

The hypothesis that a causal relationship exists between insulin resistance and atherogenesis was first proposed over 23 years ago, and has given rise to a vast literature. Biological plausibility has been lent to the hypothesis by studies in which insulin has produced some effects in cell and tissue culture, and in vivo in arterial tissue, consistent with our understanding of the pathogenesis of atherosclerosis. Clinical studies demonstrating a complex interrelationship between insulin resistance-hyperinsulinaemia and established risk factors for CHD--hypertension, hypertriglyceridaemia, low HDL cholesterol levels and abdominal obesity--are reviewed. A review of the studies examining an independent association between hyperinsulinaemia and coronary heart disease is presented. Cross-sectional studies in both the general population and diabetes support the relationship; however, prospective studies in the general population provide limited and inconsistent support for this hypothesis and highlight the confounding effects of blood pressure, dyslipidaemia and obesity on the effects of hyperinsulinaemia. In subjects with NIDDM and impaired glucose tolerance, prospective studies have not shown a deleterious effect of insulin treatment per se, nor have they consistently shown a significantly increased risk for those with higher endogenous insulin levels. The therapeutic implications of the evidence to date are less complex and involve weight reduction by diet and exercise, the lowering of elevated blood pressure with metabolically neutral agents, the judicious use of lipid lowering drugs and, in diabetes, the use of insulin where clinically indicated.

Lack of effect of enalaprilat on the action of vasoactive intestinal polypeptide in the human forearm.

It has been proposed that angiotensin converting enzyme (ACE) may play a role in the metabolism of the vasodilator peptide vasoactive intestinal polypeptide (VIP). Reduced metabolism following treatment with ACE inhibitors may cause accumulation of VIP which in turn may mediate some of the beneficial haemodynamic effects of ACE inhibition observed in patients with heart failure. This study has shown that inhibition of local vascular ACE does not interfere with the vascular effects of VIP on forearm resistance vessels when this peptide is infused into the brachial artery of normal volunteers. These results suggest that endothelial ACE plays little part in the metabolism of intravascular VIP.

Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study.

A cohort of 63 Type 1 insulin-dependent diabetic patients were first characterized for overnight urinary albumin excretion rate (AER) in 1967. In 1981, seven out of eight (87%) patients with initial AER greater than or equal to 30 less than or equal to 140 micrograms/min (microalbuminuria) developed clinical proteinuria compared to only 2 out of 55 (4%) patients with initial AER less than 30 micrograms/min. The same cohort of patients was reassessed in 1990 after a total follow-up period of 23 years. The aim was to investigate the role of microalbuminuria in the prediction of total/cardiovascular mortality and the development of renal failure, in addition to clinical proteinuria. The initially microalbuminuric patients had a significantly higher risk of developing not only clinical proteinuria (relative risk 9.3, 95% C.I. 1.36 to 3.10, P less than 0.05), but also of dying from a cardiovascular cause (relative risk 2.94, 95% C.I. 1.18 to 7.34, P less than 0.05). The rate of progression to renal failure was higher but not significantly so in the microalbuminuric (2 of 8) compared to the normoalbuminuric (4 of 53) group (relative risk 3.31, 95% C.I. 0.72 to 15.24, NS). In insulin-dependent diabetic patients microalbuminuria is a powerful predictor of clinically overt diabetic renal disease as well as cardiovascular mortality.

Factitious septic arthritis.

Septic arthritis is an uncommon manifestation of factitious illness. We report 2 patients who developed septic arthritis of the knee after repeated self-administered intraarticular injections. Multiple unusual infective agents were isolated. These cases illustrate malingering and Munchausen syndrome, 2 examples from the spectrum of factitious disease syndromes.