Bone morphogenetic proteins: from their discoveries till their clinical applications

Since their discovery 40 years ago by Urist M., several studies have been done on the bone morphogenetic proteins (BMP). They belong to the superfamily of TGF β (Transforming Growth Factor) and are the only osteo-inductive growth factors known until now. They are nowadays up to 20. After the fixation of these molecules on their receptors, intracellular cell reactions occur, inducing bone formation by the activation of genes responsible for cartilaginous formation and osteogenesis. In experimental studies on animal species, BMP showed their efficiency on the recovery of bone defects, on the acceleration of fractures consolidation or spine arthrodesis fusion or on pseudarthrodesis treatment. To be efficient, BMP must be used at the proper dose and delivered locally for a sufficient period by a biocompatible and biodegradable matrix, whose tridimensional structure allows its invasion by new bone and vascular cells. According to these data, clinical trials have been conducted on the human. Only rhBMP-2 and rhBMP-7 uses are validated for definite clinical applications (vertebral fusion, tibial pseudarthrosis and open leg fracture) by the results of randomized multicentric studies. Other clinical applications have been reported in the literature but large-scale studies are still necessary to confirm their results. Even if the clinical results are sometimes spectacular, and if the use of BMP, currently reserved because of their cost, in difficult situations give rise to big hopes, many questions remain unsolved. These questions will probably be dealt with in the future: stability of the new bone formation, eventual long-term adverse effects.     

The radial forearm flap

Described in 1981 by the Chinese authors Yang Kuofan et al. [1] as a free flap, then in 1982 by Lu et al. [2] as a retrograde flow pedicle flap, this fasciocutaneous flap is designed at the level of the anterior and external faces of the forearm, and vascularized by the radial artery via a network of septal arteries. Prior to utilization it must be reversed on its distal pedicle. This flap allows repairing cutaneous substance loss of the whole hand and fingers. The emergence of the Chinese flap in the 1980’s resulted in a regression of the Mac Gregor groin flap that was widely used at this time [3,4]. Nevertheless, other forearm flaps, less “expensive” in terms of vascular involvement [5–9] have reduced its indications. The Chinese flap however keeps two essential indications: the multi-finger important defect that no other forearmflapmay cover; and composite substance loss of the thumb (despite the fact that the Chinese flap shares these indications with interosseous artery composite flaps).     

Increased glucose excursion in cystic fibrosis and its association with a worse clinical status

BACKGROUND: Abnormal glucose tolerance is a frequent co-morbidity in cystic fibrosis patients (CF), and is associated with a worse prognosis. The objectives are to investigate (a) the relative contribution of insulinopenia and insulin resistance (IR) for glucose tolerance and (b) the association between various glucose parameters and CF clinical status. METHODS: Oral glucose tolerance tests were performed in 114 consecutive CF patients not known to be diabetic as well as 14 controls similar for age and BMI. RESULTS: Abnormal glucose tolerance was found in 40% of patients with CF: 28% had impaired glucose tolerance (IGT) and 12% had new cystic fibrosis related diabetes (CFRD). Compared to control subjects, all CF patients were characterized by an increased glucose excursion (AUC). While reduced early insulin release characterised CF, IGT and CFRD patients also present IR thus both mechanisms significantly contribute to glucose tolerance abnormalities. Increased glucose AUC and reduced early insulin release but not glucose tolerance categories were associated with a reduced pulmonary function (FEV(1)). CONCLUSION: In CF, early insulin secretion defect but also IR contribute to glucose intolerance. Early in the course of the disease, increased glucose AUC and reduced early insulin secretion are more closely associated with a worse clinical status than conventional glucose tolerance categories.     

Determinants of liver damage associated with intravenous methylprednisolone pulse therapy in Graves' ophthalmopathy.

BACKGROUND: Intravenous methylprednisolone pulses (IVMP) are more efficacious and better tolerated than oral prednisone in Graves' ophthalmopathy (GO) patients. However, acute and severe liver damage has been reported in sporadic cases during IVMP, resulting in fatal acute liver failure in four patients so far. The mechanism causing the liver damage is incompletely understood. DESIGN: We performed a prospective observational study in 13 patients with dysthyroid optic neuropathy (group A) and in 14 patients with moderately severe GO (group B) who were treated with high-dose (group A) or low-dose (group B) IVMP; cumulative steroid doses were 8.45 g in group A and 4.5 g in group B, and follow-up time was 24 weeks. MAIN OUTCOME: Slight increases in serum aminotransferases (in alanine aminotransferase [ALAT] more than in aspartate aminotransferase [ASAT]) were observed, in seven patients exceeding the upper normal limit of 40 U/L. These changes were more prominent in group A than in group B as was also evident from a decrease in ASAT/ALAT ratio in group A but not in group B. Changes in serum aminotransferases occurred especially in the first 6 weeks of IVMP, becoming smaller thereafter with the decrease in steroid dosage. Pretreatment liver steatosis or diabetes were not related to liver damage, but preexistent viral hepatitis was. CONCLUSION: IVMP in GO patients causes dose-dependent liver damage by a direct toxic effect of glucocorticoids on hepatocytes. Nevertheless, IVMP seems to be pretty safe if cumulative doses exceeding 8 g are avoided and liver function is checked before and at regular intervals during pulse therapy.     

Comparative study of 3 therapeutic methods for Pouteau Colles' fracture. Apropos of 97 cases

Results of three therapeutic modalities used for the treatment of a homogeneous series of patients with a Pouteau Colles fracture are analyzed. Orthopedic treatment provided deceiving results. Pinning was, on the contrary, very effective, intrafocal pinning with immediate mobilization of the wrist appearing perfectly effective. Few complications were reported in contrast to plastered immobilizations. Good results were obtained in 80% of cases and functional recovery was rapid, indicating that this method represents undoubted progress when compared with conventional therapies.     

Prospective multicenter clinical trial of Uretex Sup for surgical treatment of stress urinary incontinence

AIM: To evaluate in a prospective multicenter study the efficacy and safety of the suburethral support Uretex (Sofradim, Trevoux, France) delivered by a suprapubic approach in the treatment of female stress urinary incontinence. METHODS: Between March 2002 and March 2003, 57 patients were treated for stress urinary incontinence with Uretex. Preoperative evaluation included urodynamic examination and questionnaires (symptoms and quality of life, Contilife). Forty patients had pure stress urinary incontinence and 17 mixed urinary incontinence. No associated procedure was performed. The objective cure rate was evaluated by clinical examination and pad-test, and the subjective cure rate was assessed through questionnaires at 1, 3 and 12 months. RESULTS: The mean follow-up was 13 months (range 11-24 months). During follow up, chronic urinary retention requiring a tape section occurred in one patient, and in another patient a delay of vaginal healing was followed by a sling exposure and resection at 4 months. No infection or urethral erosion was reported. The objective cure rate was 96.2%, and the subjective cure rate was 79.2%; four patients reported low leakage on stress and nine patients complained of urge incontinence (four de novo and five persistent). CONCLUSION: The suprapubic Uretex Sup procedure is a safe and effective treatment for women with stress urinary incontinence.     

NOS1 polymorphism is associated with atopy but not exhaled nitric oxide levels in healthy children

Exhaled nitric oxide (FE_NO) is raised in atopy. The mechanism for this is unclear. The aim of this study was to investigate whether the number of AAT repeats in intron 20 of the NOS1 gene, recently associated with variations in FE_NO in adults with asthma and cystic fibrosis, was associated with the raised FE_NO in healthy atopic children. Eighty-seven healthy children (44 girls, 42 atopic, age range 6–18 years) underwent measurements of FE_NO, spirometry, airway responsiveness and skin prick testing. Genotyping was carried out to determine the number of AAT repeats. There was no association between the number of AAT repeats and FE_NO in either the whole sample of healthy children (n = 87) or in the subsample of healthy atopics (n = 42). However, a greater number of atopic children had two high repeat alleles compared with non-atopic children (33.3% vs. 13.6%, respectively, p = 0.03). This suggests that variations in the NOS1 gene may contribute to atopy without this relationship being reflected by FE_NO.     

Effect of acute tyrosine depletion in using a branched chain amino-acid mixture on dopamine neurotransmission in the rat brain.

Central dopamine function is reduced by decreasing the availability of the catecholamine precursor, tyrosine, using a tyrosine-free amino acid mixture containing multiple large neutral as well as branched chain amino-acids, which compete with tyrosine for uptake into the brain. Current mixtures are cumbersome to make and administer, and unpalatable to patients and volunteers. Here, we investigate whether individual or limited amino-acid combinations could reduce brain tyrosine levels and hence dopamine function. Measurements of regional brain tyrosine levels, catecholamine and indoleamine synthesis (L-DOPA and 5-HTP accumulation, respectively) were used to identify an effective paradigm to test in neurochemical, behavioral and fos immunocytochemical models. Administration of leucine or isoleucine, or a mixture of leucine, isoleucine, and valine reduced tyrosine and 5-HTP, but not L-DOPA accumulation. A mixture of leucine, valine, and isoleucine supplemented with tryptophan reduced brain tyrosine and L-DOPA, but not 5-HTP. In microdialysis experiments this amino-acid mixture reduced basal and amphetamine-evoked striatal dopamine release, as well as amphetamine-induced hyperactivity. This mixture also reduced amphetamine-induced fos expression in striatal areas. In conclusion, the present study identified a small combination of amino acids that reduces brain tyrosine and dopamine function in a manner similar to mixtures of multiple amino acids. This minimal mixture may have use as a dopamine reducing paradigm in patient and volunteer studies.