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Biomedical subjects

M W Steffes

Publications and source records attributed to M W Steffes.

At least 19 recordsLinked to original sources
PubMed2005

Stability of haemoglobin A1c (HbA1c) measurements from frozen whole blood samples stored for over a decade.

OBJECTIVE: Haemoglobin A1c (HbA1c), a measure of long-term glycaemic control, is at the centre of the clinical management of diabetes mellitus. However, the reproducibility of HbA1c measurements from whole blood samples which have been in long-term storage is unknown. We undertook this study to assess the reproducibility of HbA1c measurements from whole blood samples that had been in storage at -70 degrees C for over a decade. RESEARCH DESIGN AND METHODS: Three hundred and thirty-six samples of frozen whole blood from the Atherosclerosis Risk in Communities (ARIC) Study, stored at -70 degrees C for 11-14 years assayed for HbA1c using a dedicated ion-exchange HPLC assay (Tosoh A1c 2.2 Plus HPLC) were compared with measurements on these same samples conducted prior to storage (in 1990-92) using a Diamat (Bio-Rad) HPLC instrument. RESULTS: HbA1c measurements from long-term stored samples were strongly correlated with values obtained prior to long-term storage (r=0.97). The difference between HbA1c from long- and short-term stored samples had a mean of 0.35% HbA1c (sd=0.35) and a CV of 5.8%, which was approximately three times that of duplicate assays (CV 1.3 to 2.5%). CONCLUSIONS: These data demonstrate that highly correlated but more variable and slightly higher HbA1c results were obtained from frozen whole blood samples that have been in storage for more than a decade. This highly reproducible assay performance would lead to comparable ranking of individuals and unbiased estimates of relative risks and odds ratios in epidemiological studies (case-control and cohort designs), but results should be realigned when the absolute value is of interest. These results have important implications for epidemiological studies and clinical trials which have stored whole blood specimens.

Biomarkers↗
PubMed2001

Glomerular cell number in normal subjects and in type 1 diabetic patients.

BACKGROUND: The number of cells in glomeruli has been a challenging measure, especially in human kidneys, with only a small amount of tissue obtained by biopsy. However, the number of cells and their function are important determinants of renal function in health and disease. METHODS: Modern morphometric techniques have now provided the means to determine the numerical density (Nv) and number (with a measure of glomerular volume) of endothelial cells, mesangial cells, and podocytes in plastic-embedded renal tissue biopsied from nondiabetic subjects (N = 36) and type 1 diabetic patients (N = 46) over an extended age range from childhood through late adult. RESULTS: Nv values for all glomerular cells varied only slightly with age and did not change within the range of glomerular lesions of diabetes studied. Thus, the increase in glomerular volume during childhood to a steady level thereafter was the primary determinant of total glomerular cell number. The number of mesangial cells and endothelial cells increased with age, reflecting the increase in all cells, while the podocytes remained unchanged in number over all ages studied (10 to 69 years). Numbers of total glomerular cells, mesangial cells, and endothelial cells were not changed with diabetes, while podocytes were fewer in number in diabetic patients of all ages, with reduced podocyte numbers even in diabetes of short duration. CONCLUSIONS: The essentially constant glomerular cell density in nondiabetic and diabetic subjects under different circumstances possibly indicates an underlying propensity for the glomerulus to regulate its architecture to maintain a constant number of cells per volume, no matter the size of the glomerulus or the severity of diabetic nephropathy studied in this set of patients. The reductions in podocyte numbers in both younger and older diabetic patients indicate a significant risk for functional abnormalities as diabetic nephropathy progresses. Moreover, these observations do not support the suggestion of marked increases in glomerular cell number (and especially mesangial cells) with the development and progression of diabetic nephropathy.

Adolescent↗
PubMed2001

Glycohemoglobin: a primary predictor of the development or reversal of complications of diabetes mellitus.

BACKGROUND: Diabetes mellitus is a major health problem worldwide with long-term micro- and macrovascular complications responsible for a majority of its morbidity and mortality. The development and progression of these complications relate strongly to glycemic control. METHODS: We reviewed the literature extensively for studies that relate glycemic control to the development and progression of diabetic complications. We discuss the problems of standardizing glycohemoglobin measurements for monitoring diabetic therapy and also consider recently developed electrospray ionization mass spectrometry methods that have been considered as candidate reference methods for estimation of glycohemoglobin. RESULTS: Several clinical trials and studies have clearly shown that improved glycemic control is strongly associated with decreased development and/or progression of complications in both type 1 and type 2 diabetes mellitus. Irrespective of the methods used for estimating glycohemoglobin, these results underline the importance of glycohemoglobin for guiding therapy of diabetes mellitus. Recently developed candidate reference methods promise to yield greatly improved standardization for the measurement of glycohemoglobin. CONCLUSIONS: Glycohemoglobin measurement remains the optimal indicator of glycemic control in diabetic patients, but translation of findings from clinical trials to clinical practice worldwide demands consistent values across all assays. To ensure that the important prognostic information still applies to all diabetic patients with the application of the reference method(s), the hemoglobin A(1c) values reported in the major clinical trials will have to be translated into statistically and computationally compatible values based on the new reference system(s).

Biomarkers↗
PubMed1999

Is diabetic nephropathy inherited? Studies of glomerular structure in type 1 diabetic sibling pairs.

Only a minority of patients with type 1 diabetes develop diabetic nephropathy (DN). Poor glycemic control cannot fully explain DN risk, and family studies suggest genetic susceptibility factors. To understand familial DN concordance, we evaluated glomerular structure in families with type 1 diabetic sibling pairs. Kidney function and biopsy studies were performed in 21 probands (P) (first to develop diabetes) and 21 siblings (S) (second to develop diabetes), most with normal urinary albumin excretion rates (UAER). Glomerular structure was measured by morphometry. Intrafamilial correlation was estimated by one-way random-effects ANOVA and by mixed-effects ANOVA, adjusting for age and duration of diabetes. Diabetes duration was, by definition, longer in P than in S, while age and sex were similar. HbA1c over 5 years and blood pressure were not different in P and S and were without familial effect. UAER was greater in P than in S (P < 0.05), with strong familial effect (P = 0.03). A strong concordance among siblings for mesangial fractional volume (P < or = 0.01) remained significant after adjustment for diabetes duration and age (P = 0.04). Results were similar for mesangial cell (P = 0.01; adjusted P = 0.04) and mesangial matrix fractional volumes (P < 0.01; adjusted P = 0.06). There was also clustering of the patterns of glomerular lesions. For example, if P had relatively marked glomerular basement membrane thickening compared with mesangial matrix expansion, S had a similar pattern (chi2, P < 0.025). Strong concordance in severity and patterns of glomerular lesions in type 1 diabetic siblings, despite lack of concordance in glycemia, supports an important role for genetic factors in DN risk.

Adult↗
PubMed1999

Increased small dense LDL and intermediate-density lipoprotein with albuminuria in type 1 diabetes.

OBJECTIVE: This population study examines the relationship between LDL density and persistent albuminuria in subjects with type 1 diabetes at the end of the Diabetes Control and Complications Trial (DCCT). RESEARCH DESIGN AND METHODS: Subjects were classified as persistently normoalbuminuric (albumin excretion rate [AER] < 30 mg/d, n = 1,056), microalbuminuric (AER > or = 30-299 mg/day, n = 80), and macroalbuminuric (AER = 300 mg/day, n = 24) based on the last two AER measures. RESULTS: Triglyceride (P < 0.01) and LDL cholesterol (P < 0.01) levels were higher in macroalbuminuric subjects compared with normoalbuminuric subjects. Cholesterol distribution by density-gradient ultracentrifugation showed an increase in intermediate-density lipoprotein (IDL) and a shift in peak LDL from buoyant toward more dense particles with progressive albuminuria. In the entire group, there was a significant negative correlation between the peak buoyancy of LDL particles and albuminuria (r = -0.238, P < 0.001, n = 1,160). This correlation persisted in the normoalbuminuric DCCT group (r = -0.138, P < 0.001, n = 1,056). CONCLUSIONS: As albuminuria increases in subjects with type 1 diabetes, dyslipidemia occurs with an increase in IDL and dense LDL that may lead to increased cardiovascular disease.

Adolescent↗
PubMed1998

Reversal of lesions of diabetic nephropathy after pancreas transplantation.

BACKGROUND: In patients with type I diabetes mellitus who do not have uremia and have not received a kidney transplant, pancreas transplantation does not ameliorate established lesions of diabetic nephropathy within five years after transplantation, but the effects of longer periods of normoglycemia are unknown. METHODS: We studied kidney function and performed renal biopsies before pancreas transplantation and 5 and 10 years thereafter in eight patients with type I diabetes but without uremia who had mild to advanced lesions of diabetic nephropathy at the time of transplantation. The biopsy samples were analyzed morphometrically. RESULTS: All patients had persistently normal glycosylated hemoglobin values after transplantation. The median urinary albumin excretion rate was 103 mg per day before transplantation, 30 mg per day 5 years after transplantation, and 20 mg per day 10 years after transplantation (P=0.07 for the comparison of values at base line and at 5 years; P=0.11 for the comparison between base line and 10 years). The mean (+/-SD) creatinine clearance rate declined from 108+/-20 ml per minute per 1.73 m2 of body-surface area at base line to 74+/-16 ml per minute per 1.73 m2 at 5 years (P<0.001) and 74+/-14 ml per minute per 1.73 m2 at 10 years (P<0.001). The thickness of the glomerular and tubular basement membranes was similar at 5 years (570+/-64 and 928+/-173 nm, respectively) and at base line (594+/-81 and 911+/-133 nm, respectively) but had decreased by 10 years (to 404+/-38 and 690+/-111 nm, respectively; P<0.001 and P=0.004 for the comparisons with the base-line values). The mesangial fractional volume (the proportion of the glomerulus occupied by the mesangium) increased from base line (0.33+/-0.07) to 5 years (0.39+/-0.10, P=0.02) but had decreased at 10 years (0.27+/-0.02, P=0.05 for the comparison with the baseline value and P=0.006 for the comparison with the value at 5 years), mostly because of a reduction in mesangial matrix. CONCLUSIONS: Pancreas transplantation can reverse the lesions of diabetic nephropathy, but reversal requires more than five years of normoglycemia.

Adult↗
PubMed1998

Effect of excessive weight gain with intensive therapy of type 1 diabetes on lipid levels and blood pressure: results from the DCCT. Diabetes Control and Complications Trial.

CONTEXT: Intensive treatment of type 1 diabetes results in greater weight gain than conventional treatment. OBJECTIVE: To determine the effect of this weight gain on lipid levels and blood pressure. DESIGN: Randomized controlled trial; ancillary study of the Diabetes Control and Complications Trial (DCCT). SETTING: Twenty-one clinical centers. PARTICIPANTS: The 1168 subjects enrolled in DCCT with type 1 diabetes who were aged 18 years or older at baseline. INTERVENTION: Randomized to receive either intensive (n = 586) or conventional (n = 582) diabetes treatment with a mean follow-up of 6.1 years. MAIN OUTCOME MEASURES: Plasma lipid levels and blood pressure in each treatment group categorized by quartile of weight gain. RESULTS: With intensive treatment, subjects in the fourth quartile of weight gain had the highest body mass index (BMI) (a measure of weight adjusted for height), blood pressure, and levels of triglyceride, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B compared with the other weight gain quartiles with the greatest difference seen when compared with the first quartile (mean values for the highest and lowest quartiles: BMI, 31 vs 24 kg/m2; blood pressure, 120/77 mm Hg vs 113/73 mm Hg; triglyceride, 0.99 mmol/L vs 0.79 mmol/L [88 mg/dL vs 70 mg/dL]; LDL-C, 3.15 mmol/L vs 2.74 mmol/L [122 mg/dL vs 106 mg/dL]; and apolipoprotein B, 0.89 g/L vs 0.78 g/L; all P<.001). In addition, the fourth quartile group had a higher waist-to-hip ratio; more cholesterol in the very low density lipoprotein, intermediate dense lipoprotein, and dense LDL fractions; and lower high-density lipoprotein cholesterol and apolipoprotein A-I levels compared with the first quartile. Baseline characteristics were not different between the first and fourth quartiles of weight gain with intensive therapy except for a higher hemoglobin A1c in the fourth quartile. Weight gain with conventional therapy resulted in smaller increases in BMI, lipids, and systolic blood pressure. CONCLUSIONS: The changes in lipid levels and blood pressure that occur with excessive weight gain with intensive therapy are similar to those seen in the insulin resistance syndrome and may increase the risk of coronary artery disease in this subset of subjects with time.

Adult↗
PubMed1998

Proximal tubular basement membrane width in insulin-dependent diabetes mellitus.

Although glomerular structure has been studied, careful evaluation of tubular basement membrane (TBM) structure in diabetes in humans has not been done. We measured proximal TBM width, glomerular basement membrane (GBM) width, mesangial fractional volume [Vv(Mes/glom)], mesangial matrix fractional volume [Vv(MM/glom)], and cortical interstitial fractional volume [Vv(Int/cortex)] in 35 insulin-dependent diabetic (IDDM) patients and 20 controls. The patients' mean age was 28 +/- 10 years (X +/- SD) and IDDM duration was 17 +/- 8 years. Twenty-five patients were normoalbuminuric, four microalbuminuric, and six had overt proteinuria. Tubular basement membrane and GBM widths were measured by the orthogonal intercept method and mesangial and interstitial parameters by point counting. The TBM width was 915 +/- 320 nm in IDDM patients and 558 +/- 116 nm in controls (P = 0.0005); the TBM width was also increased in normoalbuminuric patients (849 +/- 297 nm, P = 0.0005). The TBM width was strongly directly related to GBM width (r = 0.67, P < 0.001), Vv(Mes/glom) (r = 0.52, P < 0.01), and Vv(MM/glom) (r = 0.61, P < 0.001), but only weakly to Vv(Int/cortex) (r = 0.29, NS). The TBM width (r = 0.65, P < 0.001) and GBM width (r = 0.65, P < 0.001) were strongly related to hemoglobin A1C (HbA1C), while the Vv(Mes/glom) (r = 0.35, P < 0.05) and Vv(Int/cortex) (r = 0.30, NS) were only weakly related to HbA1C. Thus, increased proximal TBM width is an integral component of early nephropathology in IDDM patients. This study suggests that the metabolic disturbances of diabetes are strong determinants of the constellation of structural abnormalities occurring in human diabetic nephropathy.

Adolescent↗
PubMed1997

Standardization of glycated haemoglobin assays throughout the Northern region of England: a pilot study.

We describe a pilot study designed to assess the comparability of measurements of glycated haemoglobin among 15 laboratories in the North of England. We also evaluated a means of improving agreement and aligning results by referencing locally measured values to those obtained by the central biochemistry laboratory of the Diabetes Control and Complications Trial research group. Blood samples from 50 diabetic and non-diabetic subjects were analysed for glycated haemoglobin content in the participating and reference laboratories using a variety of routinely available methods. The mean CV for these results was 15.3% (95% confidence interval 14.0% to 16.5%). Using a regression equation relating a subset of seven of these results to their assigned reference values, a glycated haemoglobin index was calculated for all the other samples distributed. The mean inter-laboratory CV improved to 4.6% (95% confidence interval 4.0% to 5.1%), p<0.0001. The percentage bias of results from the reference method also improved from 15.1% (95% confidence interval 9.4 to 20.1) to 4.67% (95% confidence interval 4.05 to 5.25) after alignment, p<0.001. This study demonstrated that substantial method related differences between reported glycated haemoglobin results exist. These can be reduced using a simple calibration strategy in which data are correlated to an established method with associated extensive clinical interpretive value as established by the DCCT.

Analysis of Variance↗
PubMed1997

Glomerular volume in congestive cardiac failure.

Glomerular volume has been reported to be increased in patients with congenital cyanotic heart disease and cor pulmonale; however it has not been systematically studied in patients with congestive cardiac failure (CCF). Glomerular volume was therefore measured by point-counting serially sectioned glomerular profiles of 25 randomly selected glomeruli using the Cavalieri principle in autopsy specimens from 8 patients dying from CCF and 6 age-matched controls with no renal or cardiac pathology. Mean glomerular volume was not different between patients dying from CCF and controls, 2.49 (0.21) vs. 2.25 (0.26) x 10(6) microm3, and the distribution of individual glomerular volumes was similar in the two groups. We conclude that severe CCF is not associated with significant glomerular enlargement and that the previously reported glomerular enlargement in cyanotic heart disease is likely to be mediated through hypoxemia.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Glycemic control and the initiation and progression of the complications of diabetes mellitus.

The effect of improved glycemic control on the prevention or reversal of diabetic nephropathy has been optimally shown by the reduced incidence of albuminuria (accompanied by an increased risk of hypoglycemia) in the Diabetes Control and Complications Trial (DCCT). The earliest detection of the risk or of the presence of diabetic nephropathy continues to be elevated (and confirmed) levels of albuminuria. However, micro- and macroalbuminuria are frequently associated with increased glycated hemoglobin values, complicating attempts to separate the influence of glycemia from an inherent susceptibility for diabetic nephropathy. In the type 1 diabetic patient levels of c-peptide (co-secreted with insulin by the islets of Langerhans) in plasma reflect sustained islet function. C-peptide may be measured in plasma for as long as a decade after the clinical diagnosis of diabetes mellitus, and its presence may be prolonged with better management of diabetes. The consequent improved glycemic control afforded by sustained islet function will reduce the incidence of the retinopathic and nephropathic complications, uniquely accompanied by a lower risk of hypoglycemia. Optimal diabetic management (that is, normal glycemic indices for all diabetic subjects) remains the goal of diabetic therapy. However, failure to normalize glycemic control may remain a reality of contemporary diabetic management. Thus, renal function assays or genetic protocols (each proposed for the earliest detection of diabetic nephropathy) will need to identify individuals at risk against a broadly variable background of glycated hemoglobin levels.

Blood Glucose↗
PubMed1996

Can you count on the mitotic index?

The mitotic index (MI) is the most commonly use quantitative measure in anatomic pathology but has been widely criticized for supposed "irreproducibility." In this article, the authors show that mitotic figure (MF) counts may be described by a Poisson distribution, give confidence intervals for the MI, and show that the supposed irreproducibility is largely a consequence of the counting techniques. They also show how to obtain the MI to a predetermined level of precision and present an analysis of why mitotic figure counting works, when properly used, despite the inherently low precision of the estimates that are usually obtained.

Breast Neoplasms↗
PubMed1996

Delivering clinical laboratory services to intensive care units.

In response to the pressures of cost reduction, we established and evaluated a carefully integrated program to deliver clinical laboratory services more promptly and efficiently to the intensive care units (ICUs). The new protocol reduced the steps and turnaround time from ordering tests by physicians to reporting results by as much as 80% on all ICUs, permitting significant reductions in personnel (exceeding $400,000 per year). For the surgical ICU there were also fewer blood collections (mean preprotocol: 7.0 per patient per 24 h; mean last 12 months: 6.0; P= 0.002). The volume of blood collected fell from 8.1 to 3.5 mL per collection, primarily following an emphasis on small containers. Consequently, the amount of blood taken from each surgical ICU patient decreased from 56 to 21 mL per 24 h (P <0.001).

Blood Specimen Collection↗