Teriparatide Treatment of Severe Osteoporosis Reduces the Risk of Vertebral Fractures Compared with Standard Care in Routine Clinical Practice

Teriparatide (TPTD) is often used for the treatment of patients with severe osteoporosis, but its effectiveness in this patient group has not been specifically studied. Here, we report upon the results of an observational study involving 323 patients with severe osteoporosis (bone density T-score of ?4 or less) who were treated at a specialist osteoporosis clinic with TPTD (n = 217) or standard care (n = 106) over a 5.5-year period. The standard care group did not receive TPTD because they declined to self-inject (59.4 %), had a contraindication (7.5 %), or were already stabilized on oral bisphosphonates (33 %). The two groups were matched for the severity of osteoporosis, fracture risk, and most other clinical variables. The annual percentage change in lumbar spine bone mineral density (BMD) was greater in the TPTD group (8.2 ± 6.0 vs. 5.0 ± 8.4, p = 0.002), but there was no difference in response of hip BMD. During follow-up, 3/217 (1.38 %) TPTD-treated patients had new vertebral fractures compared with 7/106 (6.6 %) receiving standard care (p = 0.011), but there was no difference between the groups in the rate of nonvertebral fractures (11.1 vs. 8.5 %, p = 0.47). Logistic regression analysis adjusting for baseline characteristics showed that the risk of vertebral fractures in TPTD-treated patients was significantly reduced compared with standard care (odds ratio = 0.12, 95 % confidence interval 0.03–0.55, p = 0.007). Treatment of severe spinal osteoporosis with TPTD substantially reduces the risk of vertebral fractures compared with standard care and may be the preferred treatment in this patient group.     

Hot Off the Press: Validation of the Pediatric NEXUS II Head Computed Tomography Decision Instrument for Selective Imaging of Pediatric Patients with Blunt Head Trauma

This is a validation of a preplanned secondary analysis of the NEXUS II Head computed tomography (CT) decision instrument, focusing on the pediatric population. A total of 1,018 patients less than 18 years old, who underwent head CT imaging for blunt head trauma, were included. The decision instrument correctly identified all patient (27/27) who required neurosurgical intervention and 48 of 49 patients who had clinically significant head injury on CT imaging.     

Hot off the Press: SGEM #226. I Want a New Drug—One That Doesn't Cause an Adverse Drug Event

Adverse drug events (ADEs) are a significant cause of emergency department (ED) visits in North America and are frequently misdiagnosed. Despite evidence supporting improved health care outcomes for ED patients who have a pharmacist‐led medication review, EDs do not have sufficient clinical pharmacists to perform medication reviews on all patients. The study reviewed in this article aimed to validate clinical decision rules for use by clinical pharmacists and physicians to prioritize ED patients with ADEs.     

Randomized comparison of low-dose versus high-dose interferon-alfa in chronic myeloid leukemia: prospective collaboration of 3 joint trials by the MRC and HOVON groups

The optimal dose of interferon-alfa (IFN) for chronic myeloid leukemia (CML) is unknown. Retrospective analyses suggest that low doses are as effective as high doses, with less toxicity and fewer patients abandoning the drug. The Dutch Hemato-Oncology Association (HOVON) and British Medical Research Council (MRC) cooperative groups jointly performed randomized trials in newly diagnosed CML patients, comparing high-dose IFN (5 MIU/m(2) daily) with low-dose (3 MIU, 5 times a week). Both arms allowed additional hydroxyurea to keep the white blood cell count lower than 5 x 10(9)/L. Quality of life data were collected in a subset of patients. Between 1993 and 2001, 407 patients were randomized. At a median follow-up of 53 months, there were no significant differences in overall survival (odds ratio = 1.09, 95% confidence interval, 0.81-1.46), progression-free survival, and complete hematologic or major cytogenetic responses. Fewer patients in the low-dose group abandoned IFN for reasons other than transplant or progressive disease (P =.002, 58% vs 72% at 5 years). Quality of life data showed comparable results in both arms for most factors. There is no evidence of benefit for high-dose IFN compared with low-dose for the treatment of CML. Therefore, when IFN is combined with other drugs, low-dose IFN is advised, to minimize toxicity and costs.     

Ultrastructural localization of human platelet thrombospondin, fibrinogen, fibronectin, and von Willebrand factor in frozen thin section

We have investigated the localization of thrombospondin (TSP), fibrinogen, fibronectin, and von Willebrand factor in human platelets by transmission electron microscopy of antibody-stained ultrathin frozen sections. In negatively stained thin sections, alpha granules were identified on the basis of their smooth, roughly spherical shape, size, single limiting electron-lucent 100 A membrane, and frequent presence of electron-dense nucleoid. In contrast, mitochondria exhibited characteristic double membranes and cristae. Sections were separately stained with affinity-purified polyclonal antibodies to these proteins as well as with three monoclonal anti-TSP antibodies. Antibody specificity was documented in radioimmunoassays, by immunofluorescent cross-blocking, and by staining of bands of appropriate mobility in Western blots of whole platelets. Bound antibody was visualized using a 5-nm colloidal gold-avidin conjugate. In resting cells, staining of virtually all alpha granules was observed for all four proteins. In contrast, consistent staining was absent from other organelles, including plasma membranes, mitochondria, and vacuolar structures that may represent the open canalicular system.     

Expression of platelet-derived growth factor and its receptors by two pre-B acute lymphocytic leukemia cell lines

Platelet-derived growth factors (PDGF) are potent regulators of cell proliferation. The three isoforms of PDGF AA, AB, and BB are encoded by two genes: PDGF A and PDGF B. The v-sis oncogene is homologous to the PDGF-B gene. v-sis can transform cells that express the appropriate PDGF receptors. Two different types of receptors, PDGF-alpha and PDGF- beta, also encoded by two genes, have been identified. We show that two cell lines. SMS-SB and NALM-6, both derived from pre-B-cell acute lymphocytic leukemias, express the PDGF-A chain gene, and one of them, SMS-SB, releases PDGF-A chains into the media. The SMS-SB cells also express the PDGF-beta receptor, whereas NALM-6 cells express the PDGF- alpha receptor and bind PDGF. This extends the possible targets for PDGF to the B-cell lineage lymphocytes.     

Response to 2'-deoxycoformycin after failure of interferon-alpha in nonsplenectomized patients with hairy cell leukemia

Two patients with hairy cell leukemia with massive splenomegaly and severe pancytopenia were treated with recombinant alpha-A interferon (IFN-alpha-2a). There was no significant response to a trial of IFN- alpha-2a (11 and 20 weeks) with respect to blood counts or spleen size. Subsequent treatment with 2'-deoxycoformycin (dCF) for 8 consecutive weeks (4 mg/m2/wk) resulted in normalization of spleen size and a normalization of peripheral blood counts and bone marrow in one patient. The second patient demonstrated a reduction in spleen size and improved blood counts following 9 weeks of dCF therapy but eventually became refractory. This demonstrates that dCF is non-cross-resistant with interferon and confirms the efficacy of dCF in nonsplenectomized patients.     

Knockdown of Glyoxalase 1 Mimics Diabetic Nephropathy in Nondiabetic Mice

Differences in susceptibility to diabetic nephropathy (DN) between mouse strains with identical levels of hyperglycemia correlate with renal levels of oxidative stress, shown previously to play a central role in the pathogenesis of DN. Susceptibility to DN appears to be genetically determined, but the critical genes have not yet been identified. Overexpression of the enzyme glyoxalase 1 (Glo1), which prevents posttranslational modification of proteins by the glycolysis-derived α-oxoaldehyde, methylglyoxal (MG), prevents hyperglycemia-induced oxidative stress in cultured cells and model organisms. In this study, we show that in nondiabetic mice, knockdown of Glo1 increases to diabetic levels both MG modification of glomerular proteins and oxidative stress, causing alterations in kidney morphology indistinguishable from those caused by diabetes. We also show that in diabetic mice, Glo1 overexpression completely prevents diabetes-induced increases in MG modification of glomerular proteins, increased oxidative stress, and the development of diabetic kidney pathology, despite unchanged levels of diabetic hyperglycemia. Together, these data indicate that Glo1 activity regulates the sensitivity of the kidney to hyperglycemic-induced renal pathology and that alterations in the rate of MG detoxification are sufficient to determine the glycemic set point at which DN occurs.