The role of morphogens in endochondral ossification

Summary The formation of bone occurs normally by one of two developmental processes: intramembranous or endochondral ossification. Endochondral ossification occurs in the morphogenesis of the limb buds and growth plates, and in the regeneration of bone following injury (fracture callus). Two classes of diffusible morphogen-like molecules (MLMs) involved in limb development are the bone morphogenetic proteins (BMPs) and retinoic acid (RA). These MLMs are associated, respectively, with the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) of the primitive limb bud. They function as potent regulators of pattern formation and are involved in tissue proliferation and differentiation. The presence of endochondral ossification in fracture callus suggests a role for MLMs in that process as well. To date, virtually nothing is known about the role of morphogens in the regeneration of bone (fracture healing). In this article, we review the current knowledge of MLMs in bone formation and propose a theory on their role in fracture healing. We hypothesize that MLMs involved in fracture healing may also express spatial and temporal information. A more complete understanding of the role of morphogens in both limb development and fracture healing is of major importance to practicing orthopedists and their patients.     

Antiarrhythmic activity of 17 beta-aminoestratrienes. Comparison of 3-ols and 3-acetates with the corresponding 3-(3-amino-2-hydroxypropyl) ethers

The antiarrhythmic efficacy of 17 beta-amino- and 17 beta-amino-16 alpha-hydroxyestratrien-3-ols and 3-acetates (group 1) was compared with the efficacy of corresponding 3-[2-hydroxy-3-(isopropylamino)propyl] and 3-[2-hydroxy-3-(tert-butylamino)propyl] ethers (group II), substituents which are usually associated with beta-adrenoceptor blocking activity. Group I compounds exerted potent antiarrhythmic activity against both aconitine-induced arrhythmias in mice and ischemia-induced arrhythmias in rats and reduced the maximum following frequency of isolated guinea pig atria. Electrophysiological studies indicated that their mechanism of action is due to an ability to reduce the fast inward sodium current in cardiac cells (class I antiarrhythmic action). Group II compounds were inactive in the aconitine and atrial tests and electrophysiological studies confirmed that they were devoid of class I activity. However, these compounds, like both class I antiarrhythmic and beta-adrenoceptor blocking drugs, were active against ischemia-induced arrhythmias. Group II compounds, unlike group I compounds, exerted nonspecific beta-adrenoceptor blocking actions, which may account for their activity in the rat test. It was concluded that introduction of the 3-substituted ether group did not confer any advantage over the parent 3-ol or 3-acetate compounds.     

Management of major colonic haemorrhage

Major colonic haemorrhage remains a difficult diagnostic and therapeutic problem. We propose that those patients who continue to bleed after resuscitation are best served by immediate laparotomy. High flow antegrade irrigation and intra-operative colonoscopy can then be used to localize the site of bleeding and allow appropriate excisional surgery rather than blind colonic resection.     

Acute interstitial nephritis: clinical features and response to corticosteroid therapy.

BACKGROUND: Acute interstitial nephritis (AIN) is a recognized cause of reversible acute renal failure characterized by the presence of an interstitial inflammatory cell infiltrate. METHODS: In order to evaluate the clinical characteristics and management of this disorder, we performed a retrospective study of all cases of AIN found by reviewing 2598 native renal biopsies received at our institution over a 12 year period. Presenting clinical, laboratory and histological features were identified, as was clinical outcome with specific regard to corticosteroid therapy response. RESULTS: AIN was found in 2.6% of native biopsies, and 10.3% of all biopsies performed in the setting of acute renal failure during the period analysed (n = 60). The incidence of AIN increased progressively over the period observed from 1 to 4% per annum. AIN was drug related in 92% of cases and appeared to be idiopathic in the remainder. The presenting symptoms included oliguria (51%), arthralgia (45%), fever (30%), rash (21%) and loin pain (21%). Median serum creatinine at presentation was 670 micromol/l [interquartile range (IQR) 431-1031] and 58% of cases required acute renal replacement therapy. Corticosteroid therapy was administered in 60% of cases. Serum creatinine at baseline was similar in the corticosteroid-treated and conservatively managed groups; 700 micromol/l (IQR 449-1031) vs 545 micromol/l (IQR 339-1110) P = 0.4. In this, the largest retrospective series to date, we did not detect a statistically significant difference in outcome, as determined by serum creatinine, between those patients who received corticosteroid therapy and those who did not, at 1, 6 and 12 months following presentation. CONCLUSION: The results of this study do not support the routine administration of corticosteroid therapy in the management of AIN.     

Central fat predicts deterioration of insulin secretion index and fasting glycaemia: 6-year follow-up of subjects at varying risk of Type 2 diabetes mellitus.

AIMS: To examine the relationships between body composition and changes in fasting glycaemia, and in indices of insulin secretion and insulin action over 6 years in females with a family history of Type 2 diabetes with or without prior gestational diabetes ('at risk' group, AR) and control females (control group, C). METHODS: At baseline and at follow-up, an oral glucose tolerance test and dual energy X-ray absorptiometry assessment of body composition were performed. Indices of insulin resistance (HOMA R') and insulin secretion (HOMA beta') were obtained from fasting insulin and glucose concentrations. RESULTS: At baseline, the groups were similar for age, body mass index, fasting levels of plasma glucose and insulin, HOMA R' and HOMA beta'. Despite similar total body fatness, AR had significantly greater waist circumference and central fat (both P < 0.02) compared with C. At follow-up there was a significant increase in central adiposity only in AR, and the fasting plasma glucose (FPG) level was higher in AR compared with C (5.0 +/- 0.2 vs. 4.3 +/- 0.2 mmol/l, P = 0.02). This rise in plasma glucose in AR was related to a decline in HOMA beta' (r = 0.45, P = 0.0065). Both the baseline and the increments in total and central abdominal fat mass were associated with the time-related decline in HOMA beta'. CONCLUSIONS: Six years after initial assessment, AR showed deterioration in FPG levels due predominantly to a decline in insulin secretion index without major change in insulin resistance index. Importantly, baseline body fatness (especially central adiposity), as well as increases in fatness with time, were the major predictors of the subsequent decline of insulin secretion index and the consequent rise in FPG.