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Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD (estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m 2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks' treatment with standard of care plus subcutaneous cotadutide uptitrated to 100, 300, or 600 μg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m 2 , geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 μg (-43.9% [95% confidence interval -54.7 to -30.6]) and 600 μg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 μg were comparable to semaglutide. Thus, our study shows that in patients with T2D and CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Medium to large scalp defects with exposed bone can pose particular challenges to the dermatologic surgeon. Most of the publications pertaining to the repair of such defects are presented in the plastic surgery literature. Dermatologic surgeons may have less experience in this area and be hesitant to pursue surgery when these defects may be encountered. The technique described below is a simple, one-stage reconstruction, with a short healing period, providing adequate cosmesis, and is within the capability of most dermatologic surgeons., (© 2020 The Australasian College of Dermatologists.)

Background: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease., Methods: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m 2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed., Results: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m 2 in the allopurinol group and 67.3 ml per minute per 1.73 m 2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m 2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m 2 per year with allopurinol and -2.5 ml per minute per 1.73 m 2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m 2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups., Conclusions: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.)., (Copyright © 2020 Massachusetts Medical Society.)

Objective: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics., Research Design and Methods: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m 2 , SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m 2 /year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period., Results: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA 1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m 2 , and historical eGFR slope -3.5 mL/min/1.73 m 2 /year. Compared with participants with albuminuria ( n = 419), those with NDKF ( n = 94) were significantly older (56 vs. 52 years), had lower HbA 1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m 2 ) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m 2 /year). These differences persisted when comparing groups with similar rates of historical eGFR loss., Conclusions: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity., (© 2019 by the American Diabetes Association.)

Background/objectives: There is a paucity of Australian data on the use of Mohs micrographic surgery for treating melanoma in situ and lentigo maligna. We share an Australian centre's experience with the technique., Methods: A total of 62 patients with 62 lesions of melanoma in situ and lentigo maligna referred for treatment between 2015 and 2017 comprised the study group. All melanomas were excised with Mohs micrographic surgery utilising melanoma-associated antigen recognised by T-cells (MART-1) immunostaining., Results: Follow up ranged from 3 to 30 months with no reported recurrences or melanoma-related deaths. 94% (58/62) of lesions were primary melanomas and 6% were locally recurrent. 89% of lesions involved head and neck sites with 11% involving trunk or limbs. In total 55% (12/62) of lesions were cleared with 3-mm clinical margins, 68% with 6 mm, 92% with 9 mm and 100% with 12-mm. The mean clinical excision margin was 6.7 mm. All lesions with a tumour diameter greater than 2.2 cm required a 9-mm clinical margin or greater for excision. The mean clinical excision margin for recurrent tumours was 9 mm., Conclusion: We provide the first Australian data on the use of Mohs micrographic surgery for melanoma., (© 2018 The Australasian College of Dermatologists.)

Objectives: Regular measurement of glycated hemoglobin (A1C) is logistically demanding. Home blotter-paper collection offers an alternative. This study tested the viability of at-home blotter-paper A1C measurement., Methods: Objective: compare accuracy of A1C levels collected on blotter paper at home (home-blotter) and blotter-paper collection in laboratory (lab-blotter) with venous A1C (routine measurement). Agreement was assessed by Pearson correlation, Lin concordance correlation coefficient (CCC), positive and negative predictive values (PPVs, NPVs) and Bland-Altman plots and associated statistics., Results: Home-blotter, lab-blotter and venous A1C correlated strongly (0.93, 0.93). Home- and lab-blotter results were upwardly biased (0.387%, 0.1%). Bias increased with time. Bias correction provided agreement for both blotters (CCC >0.9); blotters correctly identifying levels above 7% (53 mmol/mol) were 100% for corrected home-blotters and 87% (95% confidence interval) for corrected lab-blotters. NPVs (% blotters correctly identifying levels of 7% or lower [53 mmol/mol]) were 100% for corrected home-blotters and 83% for corrected lab-blotters. After correction, >92% of corrected blotters had errors of 8% or less. Of our subjects, 88.5% found home sampling preferable to routine laboratory sampling., Conclusions: Home-blotter collection is an alternative to routine collection., (Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Objectives: The objectives of this study were to determine rates of diabetes distress and depression in patients with type 2 diabetes in a tertiary care setting, to examine the relationship among glycemic control, diabetes distress and depression, and to identify predictors of diabetes distress and depression on the basis of demographic and clinical characteristics., Methods: We recruited 148 adults with type 2 diabetes who were presenting to a specialty diabetes clinic in Vancouver, British Columbia, Canada. Participants completed a questionnaire measuring diabetes distress, depressive symptoms and demographic backgrounds. The Diabetes Distress Scale was used to assess overall distress as well as 4 distinct distress dimensions, including emotional burden, physician-related, regimen-related and interpersonal distress. The Personal Health Questionnaire-9 was used to assess depressive symptoms. Glycated hemoglobin (A1C) data were also collected., Results: The prevalence of diabetes distress and depression was 39% and 12% in our population, respectively. A1C levels emerged as a significant predictor of emotional burden (p=0.03) and regimen-related distress (p=0.01); higher A1C levels were associated with increased distress regarding emotional functioning and regimen adherence. A1C levels (p=0.02) and education levels (p=0.03) emerged as predictors of physician-related distress, with higher A1C levels associated with decreased distress regarding confidence in physicians., Conclusions: Our findings reveal that the rate of diabetes distress for patients in a tertiary care setting is high. Furthermore, diabetes distress, particularly emotion- and self-care-related distress, plays a significant role in glycemic control, whereas depression does not. Routine screening for diabetes distress as part of an initial specialty clinic evaluation should be explored., (Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Background: Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation., Methods and Results: We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1∶1) women (55 ± 4 years, body mass index 25 ± 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 ± 189%, n = 18) compared with placebo (408 ± 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo., Conclusions: Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change)., Trial Registration: ClinicalTrials.gov NCT00152438.

Background/objectives: Dermatologists commonly perform surgical procedures, including Mohs micrographic surgery, in an outpatient, office-based setting. Although this may be widely perceived to be safe and effective, formal data on the practice are limited. The aim of this study was to examine the range of surgical procedures and associated complications in an Australian specialist dermatology and Mohs surgery practice., Methods: All surgical procedures over a 55-week period were prospectively logged, with data collection on sex, age, type of procedure, body site, diagnosis and complications. All procedures were performed under conditions that were usual for the practice, with a combination of sterile and clean surgical techniques, depending on the procedure., Results: In all, 2370 surgical procedures were performed during the study period, including 934 Mohs surgery cases. Most procedures (68%) were performed on head and neck sites. A total of 56 complications were recorded in 51 patients. Bacterial wound infections occurred in 13 cases (0.5%). Bleeding complications occurred in five cases (0.2%). There were no complications requiring hospital admission or i.v. antibiotics., Conclusions: This study supports the view that dermatological surgery, including significant procedures such as Mohs micrographic surgery, flaps and grafts, can be performed on an ambulatory basis in an office-based procedure room setting, with low complication rates., (© 2012 The Authors. Australasian Journal of Dermatology © 2012 The Australasian College of Dermatologists.)

A retrospective study was performed on all liver transplant recipients from British Columbia from 1989 to March 2000 to determine the prevalence and predictive factors of diabetes mellitus (DM) post-liver transplantation. DM was defined as hyperglycemia requiring treatment with insulin or oral hypoglycemic agents. Patient characteristics, cause of liver disease at transplantation, and immunosuppression regimen were considered. Both univariate and multiple logistic regression analyses were performed. Posttransplantation DM (PTDM) occurred in 43 of 177 transplant recipients (24%). Of these, 13 transplant recipients had DM pretransplantation, whereas 30 patients developed de novo PTDM. The majority of patients were treated with insulin (80%). In univariate analysis, transplantation for hepatitis C virus (HCV) liver disease was associated with a greater incidence of PTDM (odds ratio [OR], 3.01; 95% confidence interval [CI], 1.46 to 6.23) and de novo PTDM (OR, 5.20; 95% CI, 2.25 to 11.99). Patients administered tacrolimus had a greater incidence of PTDM (OR, 2.04; 95% CI, 1.01 to 4.13), and there was a trend toward increased PTDM in older patients (mean age, 49 years). Recipient sex, steroid dosage, and acute rejection were not predictive of PTDM. The incidence of graft loss and death rates were similar between the two groups. On logistic regression, HCV was the only independent predictor of PTDM (OR, 4.12; 95% CI, 1.91 to 8.90) and de novo PTDM (OR, 6.02; 95% CI, 2.55 to 14.20). In conclusion, DM post-liver transplantation is a common occurrence and is associated with HCV.

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.

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.

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.

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.

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.

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.

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)

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.

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.

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.

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.