Relationship of muscle capillary basement membrane thickness and diabetic retinopathy

We examined the relationship between the thickness of the quadriceps muscle capillary basement membrane and diabetic retinopathy. Basement membrane thickness was measured in two groups of patients with long-standing type II diabetes mellitus. One group of patients (N = 13) had no evidence of diabetic retinopathy on fluorescein angiography, whereas the other (N = 12) had proliferative microvascular disease. All the patients were male, and both groups were of similar ages, duration of diabetes, serum creatinines, and glycemic control as reflected by HbA1 levels. Mean muscle capillary basement membrane width (+/- SE) of the patients with proliferative retinopathy (3346 +/- 262) was significantly greater (P less than .05) than that observed in the patients without retinopathy (2660 +/- 177). The results of this study suggest that there is a relationship between capillary basement membrane thickness in skeletal muscle and the severity of microangiopathy in the eye. However, there was a substantial overlap between the two groups, indicating that for any individual patient the measurement of muscle capillary basement width will probably not be useful in identifying the presence or absence of retinopathy.     

Muscle capillary basement membrane width in patients with vacor-induced diabetes mellitus.

Muscle capillary basement membrane width is a sensitive marker for the presence of diabetic microangiopathy. Studies have indicated that genetic factors and alterations in glucose metabolism influence muscle capillary basement membrane width. To define the role of these factors we have measured muscle capillary basement membrane thickness in controls, insulin dependent diabetics, and individuals with diabetes secondary to the ingestion of Vacor, a rat poison, which results in hyperglycemia. Hemoglobin A1 concentrations were increased in both diabetic groups, but hemoglobin A1 levels and the duration of diabetes were similar in the two diabetic groups. The muscle capillary basement membrane width was increased to a similar extent in the insulin-dependent diabetics (control, 1,781 +/- 46 vs. IDD, 2,287 +/- 144 A, P less than 0.001) and in the Vacor diabetic group (2,320 +/- 149 A, P less than 0.001). In the insulin-dependent diabetic group, 63% of the patients had a muscle capillary basement membrane width greater than two standard deviations above the mean of the controls, while in the Vacor diabetic group this figure was 56%. Despite the relatively short duration of diabetes (6.2 +/- 0.3 yr), 44% of the Vacor diabetic patients had retinopathy and 28% had proteinuria. The present study provides strong evidence that even in the absence of genetic diabetes mellitus, hyperglycemia or some other abnormality related to insulin lack can cause microvascular changes.     

Studies of muscle capillary basement membranes in normal subjects, diabetic, and prediabetic patients

A technique is described for the measurement of muscle capillary basement membranes by electron microscopic examination of needle biopsies of the quadriceps muscle. With this procedure it has been possible to obtain an objective evaluation of the significance of capillary basement membrane hypertrophy in diabetic microangiopathy. The results of such studies of muscle capillary basement membrane thickness in 50 normal, 51 diabetic, and 30 prediabetic patients have demonstrated the following. First, that the average capillary basement membrane width of diabetic patients is over twice that of normal subjects; moreover, such basement membrane thickening is a very constant finding among overtly diabetic patients, in that approximately 98% of individual diabetic subjects demonstrated this lesion. The degree of basement membrane thickening in diabetic patients is, however, unrelated to age, weight, severity, or duration of diabetes. Second, capillary basement membrane hypertrophy has been found in approximately 50% of patients who are genetically prediabetic but who have not yet demonstrated evidence of the manifest carbohydrate disturbances of diabetes mellitus. Third, in contrast to the results obtained in genetically diabetic patients, subjects with severe hyperglycemia due to causes other than genetic diabetes only infrequently show basement membrane hypertrophy.These results indicate that thickening of the muscle capillary basement membranes is a characteristic of genetic diabetes mellitus, and further, that the hyperglycemia of diabetes is probably not the factor responsible for the microangiopathy characteristic of diabetes mellitus. Finally, the discovery of thickened capillary basement membranes in prediabetic patients suggests that basement membrane hypertrophy is a relatively early lesion of the diabetic syndrome and provides further support for the conclusion that this vascular defect is independent of carbohydrate derangements of diabetes mellitus.     

儿童中枢性性早熟垂体MRI影像学特征及其与骨龄的相关性

目的  探讨儿童中枢性性早熟（CPP）垂体MRI影像学特征及其与骨龄的相关性。 方法  选取2019年11月~2021年11月于我院收治的CPP患儿96例作为研究组,另选取同期健康体检儿童90例作为对照组。比较两组MRI影像学表现和骨龄X线表现,并对CPP患儿MRI影像学特征与骨龄X线相关性进行分析。 结果  MRI参数中,研究组冠状高径和前后径均长于对照组（P < 0.05）,冠状宽径短于对照组（P < 0.05）;两组矢状高径差异比较无统计学意义（P>0.05）。研究组患儿垂体上缘呈“平坦形”所占比例低于对照组（P < 0.05）,“隆起形”所占比例高于对照组（P < 0.05）;两组垂体上缘呈“凹陷形”所占比例差异无统计学意义（P>0.05）。研究组患儿骨龄X线结果显示“骨龄正常”所占比例低于对照组（P < 0.05）,“骨龄提前”所占比例高于对照组（P < 0.05）;两组“骨龄延迟”所占比例差异比较无统计学意义（P>0.05）。研究组患儿垂体的冠状高径、冠状宽径、矢状高径、前后径均与骨龄提前呈负相关（r=-0.216、-0.345、-0.539、-0.478,P < 0.05）,与骨龄延迟呈正相关（r=0.516、0.609、0.784、0.542,P < 0.05）;垂体参数与骨龄正常相比相关性较弱,其中冠状高径、矢状高径与其呈相关（r=0.490、0.241,P < 0.05）,与冠状宽径及前后径均无明显相关性（均P>0.05）。 结论  排除器质性原因,CPP患儿垂体形态及高度可见明显异常,多呈“隆起形”,与骨龄提前及延迟均呈正相关,垂体影像学特征与骨龄结合可对CPP临床诊断及治疗提供指导价值。     

Accelerated glomerulosclerosis in alloxan-induced diabetic rabbits with anti-glomerular basement membrane nephritis

To find how diabetes affects the processes of proliferative glomerulitis, we induced anti-glomerular basement membrane (GBM) nephritis by injection of anti-GBM antiserum in rabbits with alloxan diabetes (the DM-GN group) and in rabbits without the diabetes (the GN group), and compared the glomerular lesions between the two groups. Rabbits with alloxan diabetes only (the DM group) were also studied as control. Morphological examination showed that in the acute phase, the DM-GN and GN groups underwent histolysis of the glomerular loops, which gave rise to proliferative glomerulitis. In the later stages of glomerulitis, proliferating cells were crowded toward the axial portion of glomerular loops with an increase of intercellular matrix, and glomerular capillaries in the periphery of the glomerular loops recanalized. The amount of intercellular matrix of the axial portion increased more in the DM-GN group than in the GN group. Some of the glomerular lesions in the DM-GN group showed a formation of large nodules. The results suggested that diabetes could accelerate the formation of the intercellular matrix of glomerular loops in proliferative glomerulitis in rabbits, resulting in accelerated glomerulosclerosis.     

Femur bone mineral density is independently associated with functional recovery after hip fracture in elderly women

OBJECTIVE: To evaluate the association between femur bone mineral density (BMD) and functional recovery after hip fracture. DESIGN: Cross-sectional study. SETTING: Rehabilitation hospital in Italy. PARTICIPANTS: A total of 233 of 263 white women with hip fracture consecutively admitted to a rehabilitation hospital. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients underwent BMD assessment by dual-energy x-ray absorptiometry (DXA) at the proximal femur (5 sites) on admission. Functional recovery was evaluated by using Barthel Index scores. RESULTS: A positive correlation was found between BMD and Barthel Index scores assessed on both admission and discharge (r range,.16-.24, depending on the site of BMD measurement). Linear multiple regression showed that the association between BMD and Barthel Index score was independent of 10 confounding variables: age, body mass index, fracture type, pressure ulcers, cognitive impairment, neurologic diseases, total lymphocyte count as a nutritional index, time between fracture occurrence and DXA assessment, comorbidity, and surgical procedure. Conversely, no significant associations were found between BMD and the change in Barthel Index score attributable to rehabilitation. CONCLUSIONS: In the study population, femur BMD was an independent predictor of the functional recovery assessed by Barthel Index score after hip fracture, but not of the change in the functional score resulting from rehabilitation.     

Glycemic control continues to deteriorate after sulfonylureas are added to metformin among patients with type 2 diabetes

OBJECTIVE: To describe the course and predictors of glycemic control among patients with type 2 diabetes after sulfonylureas (SUs) are added to metformin (MF). RESEARCH DESIGN AND METHODS: Patients (n = 2,220) treated with MF monotherapy for >90 days before initiating MF plus SU combination therapy between January 1998 and March 2004 were studied in a retrospective analysis of electronic medical records from U.K. primary care practices using the General Practice Research Database. Median glycoslyated hemoglobin A(1c) (A1C) before and after SU initiation was described, and patient characteristics were evaluated as predictors of time until A1C > or =8.0% or glucose-lowering therapy was intensified (by starting insulin or adding a third oral agent). RESULTS: At 6 months post-SU initiation, median A1C resumed deteriorating at a somewhat comparable rate to that observed on MF monotherapy. Higher pre-SU A1C, younger age, female sex, shorter diabetes duration, higher serum creatinine, and being an ex-smoker predicted time until A1C > or =8.0% or glucose-lowering therapy was intensified in various analyses. Median A1C was 9.5% when therapy was intensified. A1C > or =8.0% was estimated to occur in 85% of patients 4 years after SU initiation and in 68% 4 years after initially achieving A1C <7% on MF plus SU therapy. CONCLUSIONS: In this population, glycemic control is improved following the addition of SUs to MF, but deterioration resumes as early as 6 months. The high proportion of patients remaining on MF plus SU therapy despite having A1C > or =8.0% suggests that there are significant barriers to starting insulin or adding a third agent when treatment goals are not achieved with this combination.     

Biochemical properties of human glomerular basement membrane in normal and diabetic kidneys

To determine the presence of any significant structural abnormalities in the glomerular basement membrane (GBM) of diabetic individuals, GBM from normal and diabetic human kidneys were isolated and analyzed chemically and structurally. The amino acid composition of the normal GBM revealed the presence of significant amounts of hydroxyproline, hydroxylysine, glycine, and carbohydrate suggesting the presence of a collagen-like protein. There was no significant increase in the amount of hydroxylysine, hydroxyproline, or in the hydroxylysine-linked glycoside glucosyl-galactose in the diabetic kidneys. There was, however, a significant decrease in the cystine and sialic acid content of GBM from diabetic kidneys. It was further shown that the alpha-chains isolated from the collagens of normal and diabetic basement membranes had similar amino acid and carbohydrate compositions. The hydroxylysine, hydroxyproline, glycine, and hexose contents were higher by 82, 56, 74, and 94%, respectively in the alpha-chains compared with the intact basement membranes from both the normal and diabetic kidneys. The results indicate that the slight increases in hydroxylysine and hexose content observed occasionally in diabetic GBM preparations are of no statistical significance and cannot be attributed to increases in the activities of enzymes which hydroxylate lysine or glycosylate hydroxylysine, respectively.     

Neopterin levels are independently associated with cardiac remodeling in patients with chronic heart failure

ObjectivesNeopterin, a marker of inflammation and monocyte activation, is found increased in patients with heart failure (HF). This study investigates whether neopterin levels correlate with left ventricular (LV) remodeling and brain natriuretic peptide (BNP), a marker of cardiac stress, in chronic HF (CHF) patients with different severity of disease.Design and methodsThe relationship between neopterin and LV dimensions, NT-proBNP, and pro-inflammatory cytokines were studied in 98 CHF patients, while nineteen healthy subjects were enrolled as controls. Nineteen (19%) patients were in NYHA class I, 38 (39%) in NYHA class II, 27 (28%) in NYHA class III, and 14 (14%) in NYHA class IV.ResultsNeopterin levels were higher in CHF patients than in age- and gender-matched healthy controls, and related with indexed LV end-diastolic volume (LVEDVi). Prospectively CHF patients were separated into tertiles of low, medium and high neopterin levels. Among patients, male gender, LVEDVi, diuretic treatment, NYHA class I, NT-proBNP and IL-8 levels were significant determinants of urine neopterin levels by bivariate analysis. Neopterin levels were associated only to LV remodeling, as assessed by LVEDVi, and IL-8 levels, a crucial monocyte chemoattractant, by multivariate ordinal regression analysis.ConclusionsThe relationship between elevated neopterin levels and LV enlargement in CHF patients suggests a crucial role of monocyte activation in the development of cardiac dysfunction in CHF patients. Assessment of neopterin levels is a potential biomarker to evaluate the progression of LV remodeling in CHF patients.     

Glomerular basement membrane: biosynthesis and chemical composition in the streptozotocin diabetic rat.

To study the effect of streptozotocin induced diabetes on glomerular basement membrane (GBM) synthesis, an isolated rat glomerular preparation has been developed, and its metabolic properties have been defined. The chemical composition of normal rat GBM isolated from this preparation closely resembles human GBM. Incubation with [U-14C] lysine leads to prompt incorporation of label into GBM and the subsequent appearance of labeled hydroxylysine. A 1-h lag before detection of labeled hydroxylysine in GBM suggests a delay in the release of GBM precursors. Significantly lower counts appeared in the nondialyzable fraction of the medium than in insoluble GBM during pulse-chase experiments, and labeled hydroxylysine accounted for a lower portion of the total counts in the medium (0.85%) than in the GBM (1.98%). Isolated glomeruli were prepared from streptozotocin diabetic rats of 4-6 wks duration. After incubation with [ U-14C] lysine recovery of label in diabetic GBM (88.98+/-8.26 nmol/g GBM) did not differ from age matched controls (82.52 +/- 8.26 nmol/g GBM). In pulse-chase experiments recovery of label in hydroxylysine of diabetic GBM (o.473 +/- 0.082 nmol/g GBM) did not differ from age matched controls (0567+/-0.065 nmol/g GBM). These findings indicate normal rates of GBM synthesis and hydroxylation of lysine residues in animals with streptozotocin diabetes.     

Increase in chloride from baseline is independently associated with mortality in critically ill children

Purpose

To determine if there is an association between mortality and admission chloride levels and/or increases in the chloride level in critically ill children.

Methods

We performed a retrospective cohort study of all patients admitted to the paediatric intensive care unit (PICU) from January 2014 to December 2015. Patients were excluded for the following reasons: (1) age <?90 days or >?18 years, (2) admission to the cardiac intensive care unit, (3) no laboratory values upon admission to the PICU, (4) history of end-stage renal disease, (5) a disorder of chloride transport, and (6) admission for diabetic ketoacidosis. The patients were stratified on the basis of admission chloride levels (hypochloraemia, <?96 mEq/L; normochloraemia, 96–109 mEq/L; and hyperchloraemia,?≥?110 mEq/L) and dichotomised on the basis of an increase in chloride in the first day (<?5 mEq/L, ≥?5 mEq/L). Our primary outcome was in-hospital mortality.

Results

A total of 1935 patients [55% female, median age 6.3 years IQR (1.9–13.4)] were included. The overall mortality was 4% (n?=?71) and day 2 AKI occurred in 17% (n?=?333. Hypochloraemia, hyperchloraemia, and an increase in serum chloride?≥?5 mEq/L occurred in 2%, 21%, and 12%, respectively. After adjusting for confounders, increase in chloride?≥?5 mEq/L was associated with a 2.3 (95% CI 1.03–5.21) greater odds of mortality.

Conclusions

An increase in serum chloride level in the first day of admission is common and an independent risk factor for mortality in critically ill children. Further studies are warranted to identify how chloride disturbances contribute to mortality risk in critically ill children.

     

Antibodies to basement membrane collagen and to laminin are present in sera from patients with poststreptococcal glomerulonephritis

Sera from patients with poststreptococcal glomerulonephritis (PSGN) known to have antibodies to proteoglycans were studied for the presence of antibodies against other basement membrane (BM) components. BM collagen (type IV) was isolated in the native state by extracting bovine anterior lens capsule (ALC) with 0.5 M acetic acid. The 7-S (collagenous) domain and the NC-1 (noncollagenous) domain of type IV collagen were obtained after bacterial collagenase digestion of ALC followed by gel filtration. Laminin was isolated from the mouse EHS tumor and fibronectin from human plasma. Immunologic studies, using an ELISA and electroimmunoblot, revealed the presence of antibodies that reacted with intact, native type IV collagen and the 7-S collagenous domain of this molecule. Reaction with the NC-1 (noncollagenous) domain was minimal, and not higher than that obtained with control sera. Laminin reaction strongly with the patients' sera, but fibronectin did not. Unlike sera from patients with Goodpasture syndrome, which contain antibodies primarily against the NC-1 (noncollagenous) domain of type IV collagen, sera from patients with acute PSGN contain antibodies against all the major macromolecular components of BM. This difference in immunologic reactivity may account for the observed differences in the pathologic picture at the glomerular level.     

Glomerulopathy in rats with streptozotocin diabetes. Accumulation of glomerular basement membrane analogous to human diabetic nephropathy

Glomeruli from streptozotocin-diabetic and age-matched nondiabetic rats were quantitatively isolated by a differential sieving technique. The insoluble glomerular basement membranes were purified following sonic disruption in the presence of proteolytic inhibitors. The yield of glomeruli and of glomerular basement membrane relative to the amount of renal cortex and the body weight of the animals, as well as the calculated amount of basement membrane per glomerulus, were all significantly greater in diabetic rats when compared to non-diabetic controls. Glomerular basement membranes from normal and diabetic rats were solubilized by reduction and denaturation in the presence of SDS and subjected to agarose gel analysis. About 65% of both normal and diabetic basement membrane was solubilized by this procedure, and the elution profiles of non-diabetic and diabetic preparations were similar. These results suggest that rat renal basement membrane is qualitatively similar but quantitatively increased in streptozotocin-diabetes. Since glomerular enlargement and accumulation of basement membrane are characteristic of human diabetic nephropathy, the findings also suggest that the streptozotocin-diabetic rat is an appropriate animal model for studies relating to the pathogenesis of this complication of diabetes.