Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. INTRODUCTION: Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. MATERIALS AND METHODS: Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. RESULTS: Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized beta-catenin protein, a central feature of canonical Wnt signaling. CONCLUSIONS: These results showed that the PTH-mediated enhancement of fracture repair is primarily associated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways.     

Does short term placebo treatment of chronic schizophrenia produce long term harm?

A randomised double blind placebo controlled trial is the most reliable method of assessing putative new developments in medical treatment. In schizophrenia, however, some clinicians believe that relapse contributes to long term deterioration and therefore that patients exposed to either placebo or an inactive new treatment may be put at a disadvantage in the long run if the trial leads to an additional relapse. A seven year follow up of patients included in a randomised placebo controlled trial of fluphenazine decanoate, in which 66% of the group given placebo relapsed compared with 8% of those who received the active drug, permitted examination of any long term adverse consequences in those patients who had received placebo. Seventy six (94%) of the 81 patients in the original trial were followed up. At the end of the follow up period there were no consistent or important differences in any measure of clinical or social outcome between the patients who had received placebo and those who had received the active drug. This negative finding has implications for the debate on the risk of placebo controlled trials of maintenance treatment in chronic schizophrenia.     

A single-season prospective study of respiratory viral infections in lung transplant recipients.

The frequency and complications of respiratory viral infections (RVI) were studied in 50 ambulatory lung transplant patients during a single winter season, using viral antigens, viral cultures and PCR of nasal washes or bronchoalveolar lavages. Patients' survival, episodes of acute rejection and occurrence of bronchiolitis obliterans (BO) or BO syndrome (BOS) were monitored for 1 yr after the study. Overall, 32 (64%) patients had 49 symptomatic episodes. Documented infections included eight due to respiratory syncytial virus (RSV), one due to parainfluenza virus (PIV) and 10 due to influenza (FLU). Four of the FLU infections were serological rises without symptoms. Overall, 17 (34%) patients had documented viral infection; four patients had lower respiratory involvement and two (one RSV, one PIV) were hospitalised for aerosolised ribavirin treatment. After 1 yr there were three (6%) deaths unrelated to RVI. BO or BOS had occurred in one (6%) out of 17 patients with and three (12%) out of 33 without RVI. Respiratory viruses infected one-third of ambulatory lung transplant recipients in a single season. In conclusion, respiratory viral infection was not associated with subsequent graft dysfunction. Larger prospective studies are required to better define the acute and long-term morbidity of these infections.     

Serum interleukin 5 concentrations in atopic and non-atopic patients with glucocorticoid-dependent chronic severe asthma.

BACKGROUND--Interleukin (IL)-5 is thought to play a part in asthmatic bronchial mucosal inflammation and is a potential therapeutic target. Detectable serum IL-5 concentrations have been found previously in a proportion of patients with acute severe asthma, but not in the same patients following oral glucocorticoid therapy or in normal controls. A study was undertaken to investigate whether or not IL-5 is detectable in the serum of patients with glucocorticoid-dependent chronic severe asthma. METHODS--Serum concentrations of IL-5 were measured in 29 patients with stable oral glucocorticoid-dependent chronic severe asthma (mean PEFR 59.7% predicted) and seven normal controls using a specific enzyme-linked immunoassay calibrated with recombinant human IL-5 standards (lower limit of sensitivity 40 pg/ml). RESULTS--Interleukin 5 was detectable in the serum of 15 of the 29 patients at a median concentration of 150 pg/ml (range 40-690), but was undetectable in the serum of all the control subjects. The patients with detectable serum IL-5 concentrations did not differ from those with undetectable concentrations in terms of atopic status, disease severity (percentage predicted PEFR or FEV1), prednisolone dosage, serum IgE concentrations, or peripheral eosinophil count. CONCLUSIONS--Interleukin 5 is detectable in the serum of a proportion of both atopic and non-atopic patients with chronic severe asthma, and concentrations in these patients were higher than in normal controls. These observations are compatible with the hypothesis that IL-5 release occurs in these patients during a period of stable asthma despite systemic glucocorticoid therapy.     

Effect of short-term hormone replacement in the treatment of obstructive sleep apnoea in postmenopausal women.

BACKGROUND--Women appear to be increasingly susceptible to snoring and sleep disordered breathing after the menopause. This observation, coupled with the considerable sex difference in sleep apnoea, may be explained on the basis of a protective effect of female hormones. This study was carried out to determine whether hormone replacement therapy has a role in the management of obstructive sleep apnoea in postmenopausal women. METHODS--The effect of short-term (mean (SE) 50 (3) days) hormone replacement therapy with either oestrogen alone or in combination with progesterone on sleep disordered breathing was investigated in 15 postmenopausal women with moderate obstructive sleep apnoea. The effect of treatment on the ventilatory response to hypoxia and hypercapnia was assessed in 10 patients. RESULTS--There was no reduction in the clinical severity of obstructive sleep apnoea after hormone treatment despite an increase in the serum oestrogen level from 172 (23) to 322 (33) pmol/l. There was a small but clinically insignificant reduction in the apnoea/hypopnoea index during REM sleep from 58 (6) to 47 (7). There was no difference in response between the oestrogen only group and the oestrogen plus progesterone group. Hypercapnic ventilatory responsiveness did not change with hormone treatment, but an change with hormone treatment, but an increase in hypoxic ventilatory responsiveness was observed. CONCLUSIONS--These data indicate that short-term hormone replacement is unlikely to have an effective role in the clinical management of postmenopausal women with obstructive sleep apnoea. The observed reduction in the apnoea/hypopnoea index during REM sleep, however, suggests that longer term treatment, or the use of higher doses, may have an effect.