BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways.

We have recently shown that human recombinant BMP-6 (rhBMP-6), given systematically, can restore bone in animal models of osteoporosis. To further elucidate the underlying mechanisms of new bone formation following systemic application of BMPs, we conducted gene expression profiling experiments using bone samples of oophrectomised mice treated with BMP-6. Gene set enrichment analysis revealed enrichment of insulin-like growth factor-I and epidermal growth factor related pathways in animals treated with BMP-6. Significant upregulation of IGF-I and EGF expression in bones of BMP-6 treated mice was confirmed by quantitative PCR. To develop an in vitro model for evaluation of the effects of BMP-6 on cells of human origin, we cultured primary human osteoblasts. Treatment with rhBMP-6 accelerated cell differentiation as indicated by the formation of mineralised nodules by day 18 of culture versus 28-30 days in vehicle treated cultures. In addition, alkaline phosphatase gene expression and activity were dramatically increased upon BMP-6 treatment. Expression of IGF-I and EGF was upregulated in human osteoblast cells treated with BMP-6. These results collectively indicate that BMP-6 exerts its osteoinductive effect, at least in part, through IGF-I and EGF pathways, which can be observed both in a murine model of osteopenia and in human osteoblasts.

Role of EP2 and EP4 receptor-selective agonists of prostaglandin E(2) in acute and chronic kidney failure.

We tested the efficacy of three selective agonists of prostaglandin E(2) (PGE(2)) receptor, EP2 (CP-536,745-01), EP2/4 (CP-043,305-02), and EP4 (CP-044,519-02), in two models of acute and chronic kidney failure. In the nephrotoxic mercury chloride (HgCl(2)) rat model of acute kidney failure systemically administered EP4 agonist reduced the serum creatinine values and increased the survival rate. Although the EP2 or the EP2/4 agonist did not change the serum creatinine values, the EP2 receptor agonist increased the survival rate. Histological evaluation of kidneys from EP4-treated rats indicated less proximal tubular necrosis and less apoptotic cells. In a rat model of chronic renal failure, the three receptor agonists decreased the serum creatinine and increased the glomerular filtration rate at 9 weeks following therapy. Kidneys treated with the EP4 agonist had less glomerular sclerosis, better preservation of proximal and distal tubules and blood vessels, increased convoluted epithelium proliferation and less apoptotic cells. Nephrectomy had no influence on the expression of the EP4 receptor, whereas EP2 receptor expression was reduced by 50% and then corrected following treatment with EP2 and EP2/4 receptor agonists. These findings suggest that PGE(2) has an important role in acute kidney failure via the EP4 receptor, whereas in chronic kidney failure both EP2 and EP4 receptors are equally important in preserving the progression of chronic kidney failure. Thus, agonism of EP2 and EP4 receptors may provide a basis for treating acute and chronic kidney failure.

Osteogenic protein-1 (BMP-7) accelerates healing of scaphoid non-union with proximal pole sclerosis.

We randomly assigned 17 patients with scaphoid non-union at the proximal pole to three treatment groups: (1) autologous iliac graft (n=6), (2) autologous iliac graft + osteogenic protein-1 (OP-1; n=6), and (3) allogenic iliac graft + OP-1 (n=5). Radiographic, scintigraphic, and clinical assessments were performed throughout the follow-up period of 24 months. OP-1 improved the performance of both autologous and allogenic bone implants and reduced radiographic healing time to 4 weeks compared with 9 weeks in group 1. Helical CT scans and scintigraphy showed that in OP-1-treated patients sclerotic bone was replaced by well-vascularised bone. The addition of OP-1 to allogenic bone implant equalised the clinical outcome with the autologous graft procedure. Consequently the harvesting of autologous graft can be avoided.

Inadequate use of preventive strategies in patients receiving NSAIDs.

OBJECTIVE: Little is known about the factors that influence the decision to use NSAIDs in combination with gastroprotective drugs. The aims of this observational study were to evaluate the extent to which NSAID users are prescribed concomitant gastroprotective drug regimens ('preventive strategies'), and to determine how patient risk factors for NSAID-associated gastrointestinal toxicity and physician prescribing preferences influenced the decision to prescribe a gastroprotective drug in combination with an NSAID. DESIGN AND PATIENTS: The study was conducted on 29 June 2004 and comprised 109 eligible adult patients hospitalised at the Clinical Hospital Center, Zagreb. Use of NSAIDs and gastroprotective drugs, risk factors for NSAID-associated gastrointestinal toxicity, and physician prescribing preferences were monitored throughout the study. RESULTS: Sixty-six percent of patients receiving proton pump inhibitors or histamine H(2)-receptor antagonists with NSAIDs had no risk factors for gastrointestinal toxicity. Furthermore, 29% of patients who used NSAIDs had risk factors for gastrointestinal toxicity but were not receiving gastroprotective drugs. Even though patients at risk of NSAID-associated gastrointestinal complications had higher odds of receiving preventive strategies (odds ratio 1.25), the absolute rate of utilisation of these therapies in at-risk populations was unacceptably low (69%). However, the strongest independent correlation for gastroprotective drug use was the prescribing physician, with an odds ratio of 6.40. CONCLUSION: This study demonstrates that an individual physician's prescribing style largely determines the odds of receiving preventive strategies with NSAID treatment and is more important than the patient's risk factors for gastrointestinal toxicity.

Anomalous branch of the left common carotid artery.

A previously unreported anomalous branch of the left common carotid artery (LCCA) was observed during dissection at the Zagreb Medical School. The anomalous branch arose from the anterior surface of the LCCA approximately 2 cm superior to the aortic arch, and subsequently bifurcated into a right and left branch. We describe its anatomic features. Clinical implications are also discussed.

A sustainable approach to planning housing and social care: if not now, when?

The publication of Supporting People (Department of Social Security 1998) has given urgency to discussions around needs analysis, planning, user voice and the development of 'normal' housing for people with support needs. This paper explores a project, which aimed to design a collaborative model for identifying supported housing needs. We provide an overview of the research background, local imperatives and findings, and point to the probability of increasing conflict between the policy of developing 'sustainable communities' and the development of housing for people with support needs.

L-threonine export: use of peptides to identify a new translocator from Corynebacterium glutamicum.

Bacterial mechanisms for the uptake of peptides and their hydrolysis to amino acids are known in great detail, whereas much less is known about the fates of the peptide-derived amino acids. We show that the addition of L-threonine-containing di- or tripeptides results in reduction of the growth of Corynebacterium glutamicum, with concomitant high intracellular accumulation of L-threonine to up to 130 mM. Using transposon mutagenesis and isolation of mutants with increased Thr peptide sensitivity, nine open reading frames (ORFs) were identified, almost all encoding hypothetical proteins of unknown function. Three ORFs encode membrane proteins. Their individual functional characterizations in the wild-type background led to the identification of thrE. Upon thrE overexpression, growth is no longer sensitive to the presence of the Thr peptide, and L-threonine is exported at a rate of 3.8 nmol min(-1) mg of dry weight(-1), whereas the rate of export of a thrE inactivation mutant is reduced to 1.1 nmol min(-1) mg of dry weight(-1). In addition to L-threonine, L-serine is also a substrate for the exporter. The exporter exhibits nine predicted transmembrane-spanning helices with long charged C and N termini and with an amphipathic helix present within the N terminus. All these data suggest that the carrier encoded by thrE serves to export small molecules such as L-threonine and that the carrier is a prototype of a new translocator family. Homologues of ThrE are present in Mycobacterium tuberculosis and Streptomyces coelicolor.

[Mastocytosis: an important differential diagnosis in anaphylactoid reaction to Hymenoptera sting. A case report and overview of clinical aspects, diagnosis and current therapy of mastocytosis]. / Mastozytose: Eine wichtige Differentialdiagnose bei anaphylaktischer Reaktion auf Hymenopterenstiche. Ein Fallbericht und eine Ubersicht über Klinik, Diagnostik und aktuelle Therapie der Mastozytose.

A 77-year old farmer presented with a history of three severe anaphylactoid reactions after hymenoptera stings for the last three years. No sensitisation to hymenoptera venoms could be shown on allergological work-up. The serum level of tryptase however was clearly elevated (37.1 micrograms/l; normal value: < 13.5 micrograms/l). The diagnosis of systemic mastocytosis could be confirmed by bone marrow biopsy. Patients with mastocytosis are at increased risk of anaphylactic/anaphylactoid reactions. They should be educated how to avoid trigger factors and they should always carry an emergency kit (H1 blocker, corticosteroid, adrenalin) and a "mastocytosis pass" with them. Venom immunotherapy is indicated in patients with proven hymenoptera allergy. Selected patients at very high risk of anaphylactic reactions may need a continuous prophylactic medication with H1 and H2 blocker and eventually a cyclooxygenase inhibitor.

The short term outcome of elderly patients with hip fractures.

A prospective outcome study was performed of 100 hip fracture patients at an urban medical center in the United States. After hospitalization 19% were discharged to a rehabilitation facility and 59% were discharged home. At a mean follow-up of 8 months, 81% of patients lived at home, compared to 89% who lived at home prior to the fracture. At follow-up 71% of the patients were able to walk outside with one cane or no aids at all, and 81% were able to perform basic activities of daily living. Half of all patients did not require any home assistance at follow-up. Ten patients had died at follow-up. The goal of operatively treating the patient with a hip fracture is fixation of the fracture with a return to the patient's pre-fracture functional ability. This study illustrates that patients with hip fractures can be effectively treated and discharged home or to a short-term rehabilitation facility with restoration of their pre-fracture functional status.

The importance of monitoring colorectal adenomas by tumor markers (ROC analysis).

Are the increased values of specific tumor markers significant in monitoring colorectal adenomas at the beginning of malignant alteration? Tumor markers (CEA, CA 19-9 and CA 72-4) were determined in sera by IRMA kits. The increased levels of tumor markers CEA and CA 19-9 were statistically very significant in patients (28) with colorectal adenomas at the beginning of malignant alteration and in the group with colorectal adenocarcinomas (96). By ROC analysis the sensitivities, positive predictive values and negative predictive values of CEA and CA 19-9 were quite acceptable with high accuracies for all determined tumor markers in colorectal adenomas at the beginning of malignant alteration. Those findings suggest the importance of monitoring of colorectal tumours and precancerouses by tumor markers serum levels and it confirms the usefulness of counting results by ROC analysis.

Polyneuropathy with osteosclerotic myeloma--POEMS syndrome. A case report.

A rare form of plasma cell dyscrasia characterized by associated polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes has been termed the POEMS syndrome. The pathophysiology is unknown; plasma cell dyscrasia is essential; secondary manifestations are unexplained. We report a 67-year-old man with a 7-month history of progressive weakness and numbness of the legs. Clinical examination revealed sensorimotor polyneuropathy, predominantly affecting the lower extremities, hepatomegaly, and skin haemangiomas. Additional investigations disclosed IgG-lambda monoclonal serum protein, endocrine abnormalities, elevated cerebrospinal fluid protein level and an osteoblastic lesion of the lumbar vertebra. Biopsy of the osteosclerotic vertebra showed a marked lymphoplasmocytic infiltrate. MRI of the liver disclosed two haemangiomas; this association has not been reported previously.