Treatment of osteoporosis in men

Osteoporosis in men is recognised worldwide as an important and increasing public health problem. The causes are more heterogeneous than those in women. About 50% are diagnosed as secondary cases. In some secondary forms of osteoporosis the specific diagnosis results in additional therapeutic options (e.g. androgen therapy in proven hypogonadism). The basic therapy for osteoporosis in men is no different to that in postmenopausal women, namely recommendations for counteracting modifiable risk factors, especially with regard to diet, physical exercise, and calcium and vitamin D supplementation. Concerning specific drug medications, however, even today there is still a therapeutic dilemma in male osteoporosis. While older substances (e.g. calcitonin, fluoride, alfacalcidol) are approved for both sexes, all newer medications have primarily been approved for the treatment of postmenopausal osteoporosis. Health authorities request studies in purely male populations. For new drugs, fracture data are necessary while for new substances within a class (e.g. bisphosphonates), at the very least consistent effects on bone mineral density (BMD) and bone turnover markers are requested. Due to these regulatory rules, ibandronate, teriparatide and strontium ranelate are not approved in the European Union. Some years ago, alendronate was the first bisphosphonate that was approved for the treatment of men with osteoporosis, based on consistent results from two independent male studies using a daily 10 mg dosage. Very recently risedronate was approved by the FDA and EMEA. A randomised, placebo-controlled multicentre trial of 285 male patients showed, after 2 years, a 5.8% increase in lumbar spine BMD in the risedronate 35 mg once weekly group vs 1.2% in the placebo group. In a prospective controlled study on 316 men with primary or secondary osteoporosis we found, after 12 months, a lumbar spine BMD of +4.7% vs +1.0% in controls. The number of patients with one or more new vertebral fractures was 8 in the risedronate group and 20 in the placebo group (a fracture reduction of 60%). Furthermore, we found a significantly smaller decrease in height and a steeper decrease in back pain in the risedronate group. Risedronate is the first oral bisphosphonate available for men with the more comfortable once weekly dosage.     

A human amphotropic retrovirus receptor is a second member of the gibbon ape leukemia virus receptor family.

Retrovirus infection is initiated by binding of the viral envelope glycoprotein to a cell-surface receptor. The envelope proteins of type C retroviruses of mammals demonstrate similarities in structural organization and protein sequence. These similarities suggest the possibility that retroviruses from different interference groups might use related proteins as receptors, despite the absence of any relationship between retrovirus receptors isolated to date. To investigate this possibility, we have identified a human cDNA clone encoding a protein closely related to the receptor for gibbon ape leukemia virus and have found that it functions as the receptor for the amphotropic group of murine retroviruses. Expression of this protein (GLVR-2) is likely to be a requirement for infection of human cells by amphotropic retroviral vectors for purposes of gene therapy.     

Entwicklung einer neuen Säuglingsnahrung mit Thermobacterium bifidum. Ein Beitrag zum Problem der Sauermilchnahrung

Ohne Zusammenfassung     

Phase I trial of the polyelectrolyte carbetimer administered i.v. once every four weeks

Summary Carbetimer, a new synthetic low molecular weight polyelectrolyte with a novel structure displayed antitumor activiy in a number of animal tumor model systems and in vitro investigations. Based on these findings it was brought to a phase I clinical trial in patients with advanced malignant disease after failure of conventional treatment or with no conventional treatment available. Forty-eight patients received 98 courses. The schedule was a one hour i.v. infusion every four weeks. The starting dose was 180 mg/m² and dose escalation was performed according to a modified Fibonacci formula up to 16,690 mg/m². At least three patients were treated at each dose level and each patient was eligible to receive repeat courses at the same dose, until progressive disease or dose-limiting toxicity intervened. No hematological toxicity was encountered. Some adverse effects such as reversible proteinuria, hypercalcaemia, pain at infusion site, nausea and vomiting and fatigue were seen partly in a dose-related manner but did not represent the maximum tolerated dose (MTD). The limiting toxicity at the highest dose level of 16,690 mg/m² consisted of ocular symptoms (light flashes) accompanied by a modest decrease of blood pressure and nausea or vomiting during a one hour infusion. 16,690 mg/m²/1 hour was considered the MTD. There were four deaths on study, all considered diseaserelated. Fourteen patients had stable disease for more than two courses, which, however, could also be explained by the natural course of disease. No clear-cut antitumor responses were noted in our study center.The recommended dose for phase II trials derived from our results is 12,550 mg/m²/2 hours. However, with regard to experiences in other phase I studies, the subsequent phase II studies will be performed with a dose of 6,500 mg/m².     

Differential effects of interleukin 12 and interleukin 10 on superantigen-induced expression of cutaneous lymphocyte-associated antigen (CLA) and alphaEbeta7 integrin (CD103) by CD8+ T cells

At both cutaneous and mucosal sites, interleukin (IL)-10, IL-12 and transforming growth factor (TGF)-beta are important regulators of chronic inflammatory disease, where cutaneous lymphocyte-associated antigen (CLA) and alphaE integrin (CD103) may be expressed. Stimulation with streptococcal pyrogenic exotoxin C (SpeC) increased the expression of CD103 by CD8+ but not CD4+ T cells. While adding IL-12 augmented the expression of CLA, superantigen-induced expression of CD103 was markedly suppressed by IL-12, which could be reversed by TGF-beta. Antibodies against TGF-beta inhibited, and a combination of anti-TGF-beta and IL-12 completely abrogated the induced CD103 expression. IL-10 strongly decreased the frequency of CLA+ and although not increasing the frequency of CD103+CD8+ T cells, the amount of CD103 expressed per cell was markedly increased. Thus, the expression of CLA and CD103 may be antagonistically regulated by IL-10 and IL-12 and the balance between these cytokines could influence the T cell migration of inflammatory cells into epithelial tissues.     

Detection of Pseudomonas aeruginosa producing metallo-beta-lactamases in a large centralized laboratory

Metallo-beta-lactamases (MBLs) have been increasingly recognized from clinical isolates worldwide, but the laboratory detection of these strains is not well defined. We report a study that developed an EDTA disk screen test and a molecular diagnostic assay for the detection of MBL-producing Pseudomonas aeruginosa. Using NCCLS disk methodology, inhibition zone diameters were determined in tests with imipenem (IPM) and meropenem (MEM) disks alone and in combination with 930 microg of EDTA. This test was compared with the MBL Etest. The duplex PCR assay showed 100% sensitivity and specificity for detecting MBL-producing control strains. Of the 241 clinical strains of IPM-nonsusceptible P. aeruginosa from the Calgary Health Region isolated from 2002 to 2004, 110/241 (46%) were MBL positive using phenotypic methods while 107/241 (45%) were PCR positive for MBL genes: 103/241 (43%) for bla(VIM) and 4/241 (2%) for bla(IMP). The EDTA disk screen test using MEM showed 100% sensitivity and 97% specificity for detecting MBLs in control and clinical strains. The EDTA disk screen test is simple to perform and to interpret and can easily be introduced into the workflow of a clinical laboratory. We recommend that all IPM-nonsusceptible P. aeruginosa isolates be routinely screened for MBL production using the EDTA disk screen test and that PCR confirmation be performed at a regional laboratory.