Fracture Risk in Type 2 Diabetes: Update of a Population‐Based Study

We found no significant excess of fractures among Rochester, MN, residents with diabetes mellitus initially recognized in 1950–1969, but more recent studies elsewhere have documented an apparent increase in hip fracture risk. To explore potential explanations for any increase in fractures, we performed an historical cohort study among 1964 Rochester residents who first met glycemic criteria for diabetes in 1970–1994 (mean age, 61.7 ± 14.0 yr; 51% men). Fracture risk was estimated by standardized incidence ratios (SIRs), and risk factors were evaluated in Andersen‐Gill time‐to‐fracture regression models. In 23,236 person‐years of follow‐up, 700 diabetic residents experienced 1369 fractures documented by medical record review. Overall fracture risk was elevated (SIR, 1.3; 95% CI, 1.2–1.4), but hip fractures were increased only in follow‐up beyond 10 yr (SIR, 1.5; 95% CI, 1.1–1.9). As expected, fracture risk factors included age, prior fracture, secondary osteoporosis, and corticosteroid use, whereas higher physical activity and body mass index were protective. Additionally, fractures were increased among patients with neuropathy (hazard ratio [HR], 1.3; 95% CI, 1.1–1.6) and those on insulin (HR, 1.3; 95% CI, 1.1–1.5); risk was reduced among users of biquanides (HR, 0.7; 95% CI, 0.6–0.96), and no significant influence on fracture risk was seen with sulfonylurea or thiazolidinedione use. Thus, contrary to our earlier study, the risk of fractures overall (and hip fractures specifically) was increased among Rochester residents with diabetes, but there was no evidence that the rise was caused by greater levels of obesity or newer treatments for diabetes.     

Transforming growth factor-β (TGF-β) activity in urine of patients with glomerulonephritis is related to their renal functional and structural changes

SUMMARY: Transforming growth factor-β (TGF-β) has been considered the principal cytokine involved in the pathogenesis of renal fibrosis. In the present study, we evaluated TGF-β activity in occasional samples from 22 normal individuals and 29 patients (11 with focal glomerulosclerosis, 11 with membranous nephropathy, five with Berger disease, one with type I membranoproliferative glomerulonephritis and one with postinfectious glomerulonephritis) using a CCL-64 mink lung cell growth inhibition assay.
A significantly increased urinary TGF-β activity (reported in relation to urine creatinine, Ucreat, and median) was observed in patients with glomerulonephritis compared with normal individuals ( P <0.01). the patients with Berger disease [median (Md) = 9.96/10 μg Ucreat.], membranous glomerulonephritis (Md = 7.23/10 μg Ucreat.) and focal glomerulosclerosis (Md = 16.6/10 μg Ucreat.) showed higher urinary TGF-β than normal individuals (Md = 1.09/10 μg Ucreat.) ( P <0.01). We found a positive correlation between the TGF-β activity in the urine of these patients and the incidence of segmental glomerulosclerosis ( r = 0.45, P <0.05) and their plasma creatinine levels ( r = 0.87, P <0.01). A negative correlation was observed between the TGF-β activity in the urine of these patients and their creatinine clearance ( r =−0.75, P <0.01).
Our data suggest that measurement of urinary TGF-β activity could be a useful non-invasive procedure for the evaluation of renal TGF-β production, permitting the assessment of prognosis and the evaluation of therapeutic efficacy in patients with renal disease.     

Subcellular localization of transforming growth factor-alpha in human eosinophil granulocytes

Eosinophils are involved in the inflammatory response seen in allergy and helminthic infestations. Eosinophils synthesize transforming growth factor-alpha (TGF-alpha), which may play a role in the development of the characteristic fibrosis seen in longstanding high eosinophilia. Using immunoelectron microscopic techniques, eosinophils from peripheral blood of healthy individuals and from one patient with high eosinophilia showed presence TGF-alpha in matrix of the specific crystalloid-containing granules. In cryosections, TGF-alpha was also visualized in a vesicular compartment of the cytoplasm. In double- labeling experiments, the TGF-alpha of this latter compartment did not colocalize with CD63, a marker for lysosomes, nor with albumin of secretory vesicles. In extracts from eosinophils, obtained from healthy donors, immunoreactive TGF-alpha could be detected by enzyme-linked immunosorbent assay-technique. In addition, sera from two patients with high eosinophilia showed TGF-alpha concentrations of 1.5 ng/mL and 164 pg/mL, respectively, whereas TGF-alpha could not be detected in serum from healthy controls. In conclusion, TGF-alpha is present in the specific granules, and in an additional vesicular compartment of the cytoplasm of eosinophils.     

Transplantation potential of hematopoietic cells released into the circulation during routine chemotherapy for non-Hodgkin's lymphoma [see comments]

Primitive hematopoietic cells released into the peripheral blood (PB) were studied in 50 patients with high-grade non-Hodgkin's lymphoma enrolled in a phase III trial of intensive weekly chemotherapy (VAPEC- B) alone or with granulocyte colony-stimulating factor (G-CSF). Mononuclear cells numbers were monitored and their in vitro growth potential assessed in clonogenic progenitor cell assays and in long- term culture. Total colony-forming cells (granulocyte-macrophage [GM], burst-forming unit, erythroid [BFU-E], Mix-CFC) were increased 40-fold (median) over baseline with chemotherapy alone and 106-fold with chemotherapy and G-CSF after the final dose. CD34+ cells were increased to a median of 4%, equivalent to that in normal bone marrow (BM) controls. Circulating colony-forming cell levels were maximal when the recovering total white blood cell (WBC) count reached 5 to 10 x 10(9)/L. The timing of the maximum was reproducible in individual patients. Therefore the WBC count can be used as a guide to the timing of leukapheresis. PB cells from normal controls' and patients' prechemotherapy were unable to sustain hemopoiesis in two-stage long- term cultures. In contrast, PB cells collected from patients primed with chemotherapy alone or chemotherapy with G-CSF at the time of predicted maximal colony-forming cell release were able to generate and sustain hematopoiesis in long-term cultures at a level comparable or superior to normal BM. These findings indicate that the use of G-CSF after routine outpatient chemotherapy stimulates maximal release of primitive hemopoietic cells into the circulation, including colony- forming cells and long-term culture-initiating cells. Their numbers are comparable with those in normal BM and are such that a single leukapheresis will usually yield enough cells for hemopoietic reconstitution after myeloablative chemotherapy.     

Peripheral blood B cell labeling indices are a measure of disease activity in patients with monoclonal gammopathies

Labeling indices (LI) provide a rapid measure of the bone marrow (BM) plasma cell proliferation rate and are useful in the diagnosis and prognosis of monoclonal gammopathies. Because circulating B cells may be a part of the neoplastic clone, we examined peripheral blood B cells that were producing the same cytoplasmic light chain isotype as the patient's monoclonal; protein (M-protein) and determined the peripheral blood LI (PBLI) by a two-color immunofluorescence bromodeoxyuridine method. The 105 patients studied were divided into three disease activity groups by standard clinical criteria. Median PBLI was 0.2% for the 29 patients with inactive monoclonal gammopathies (monoclonal gammopathy of undetermined significance [MGUS] and smoldering multiple myeloma [SMM]), 0.8% for the 35 patients with new, untreated multiple myeloma (MM), and 1.7% for the 41 patients with relapsed MM. These differences between groups were statistically significant (P less than .001, Wilcoxon). Four patients had high PBLI but clinically inactive gammopathy at the time of study, and all developed active MM within 6 months that required treatment. In 92 patients a BMLI was performed simultaneously with the PBLI (rank correlation coefficient, 0.69). In patients with new, untreated MM, use of both tests identified 72% of patients (23 of 32) with high LI, rather than 56% (18 of 32) by BMLI alone or 63% (20 of 32) by PBLI alone. These results suggest that PB B cells bearing the same cytoplasmic light chain isotype as the monoclonal protein are part of the malignant clone and can be kinetically active. The LI of these cells can provide a measure of disease activity and may help to differentiate active from inactive disease.     

Association of hip strength estimates by finite‐element analysis with fractures in women and men

Finite‐element analysis (FEA) of quantitative computed tomography (QCT) scans can estimate site‐specific whole‐bone strength. However, it is uncertain whether the site‐specific detail included in FEA‐estimated proximal femur (hip) strength can determine fracture risk at sites with different biomechanical characteristics. To address this question, we used FEA of proximal femur QCT scans to estimate hip strength and load‐to‐strength ratio during a simulated sideways fall and measured total hip areal and volumetric bone mineral density (aBMD and vBMD) from QCT images in an age‐stratified random sample of community‐dwelling adults age 35 years or older. Among 314 women (mean age ± SD: 61 ± 15 years; 235 postmenopausal) and 266 men (62 ± 16 years), 139 women and 104 men had any prevalent fracture, whereas 55 Women and 28 men had a prevalent osteoporotic fracture that had occurred at age 35 years or older. Odds ratios by age‐adjusted logistic regression analysis for prevalent overall and osteoporotic fractures each were similar for FEA hip strength and load‐to‐strength ratio, as well as for total hip aBMD and vBMD. C‐statistics (estimated areas under ROC curves) also were similar [eg, 0.84 to 0.85 (women) and 0.75 to 0.78 (men) for osteoporotic fractures]. In women and men, the association with prevalent osteoporotic fractures increased below an estimated hip strength of approximately 3000 N. Despite its site‐specific nature, FEA‐estimated hip strength worked equally well at predicting prevalent overall and osteoporotic fractures. Furthermore, an estimated hip strength below 3000 N may represent a critical level of systemic skeletal fragility in both sexes that warrants further investigation. © 2011 American Society for Bone and Mineral Research.