Although overall results remain unsatisfactory, 33% of studied French children with type 1 diabetes had HbA1c < 8%, the value obtained in Diabetes Control and Complications Trial adolescents treated intensively. Diabetes management in specialized centers should be encouraged.

Objectives: To evaluate the long-term effects of GH therapy in early diagnosed GH-deficient patients treated before 1 year of age. Study design: We studied all 59 patients (33 males) recorded by Association France-Hypophyse and treated with GH (0.50 Ϯ 0.15 IU/kg (S.D.) per week) before 1 year of age. Clinical presentation and growth parameters under GH treatment were analyzed. Results: Neonatal manifestations of hypopituitarism were frequent: hypoglycemia (n ¼ 50), jaundice (n ¼ 25) and micropenis (n ¼ 17/33). Although birth length was moderately reduced (¹0.9 Ϯ 1.4), growth retardation at diagnosis (5.8 Ϯ 3.8 months) was severe (¹3.5 Ϯ 1.9 standard deviation scores (SDS)). Fifty patients (85%) had thyrotropin and/or corticotropin deficiency. After a mean duration of GH therapy of 8.0 Ϯ 3.6 years, change in height SDS was þ3:11 Ϯ 2:06 S.D., exceeding 4 SDS in 19 patients. Only 9 patients (15%) did not reach a height of ¹2 S.D. for chronological age and 20 patients (34%) exceeded their target height. Pretreatment height SDS was independently associated with total catch-up growth. Conclusion: Conventional doses of GH allow normalization of height in patients with early GH deficiency and treatment.

Objective: Adult height deficit seen in Turner syndrome (TS) originates, in part, from growth retardation in utero and throughout the first 3 years of life. Earlier diagnosis enables earlier therapeutic intervention, such as with recombinant human GH (r-hGH), which may help to prevent growth retardation. In this open-label, multicentre phase III study, we investigated efficacy and safety in r-hGH treatment in young girls with TS. Subjects and methods: Girls (nZ61) aged !4 years with TS receiving 0.035-0.05 mg/kg per day r-hGH for 4 years were compared with an historical control group (nZ51) comprising untreated, age-and height-matched girls with TS. The main outcome measure was change in height SDS (H-SDS). Other measures included changes in height velocity SDS, IGF1 levels and glucose metabolism. Results: After 4 years, a gain in mean H-SDS of 1.0 SDS (from K2.33G0.73 to K1.35G0.86 SDS) was observed with r-hGH treatment, in contrast to the decrease in mean H-SDS of 0.3 SDS in the control group (from K2.09G0.81 to K2.44G0.73 SDS; P!0.0001). r-hGH treatment was the main predictor of H-SDS gain and accounted for 52% of variability (multivariate analysis). r-hGH was well tolerated. As expected, IGF1 levels rose with treatment. A case of transient glucose intolerance resolved after dietary adaptation. Conclusion: Early treatment with r-hGH helps to prevent natural evolution towards short stature in most girls with TS. IGF1 levels and glucose metabolism should be monitored routinely during r-hGH therapy.

C olorectal cancer (CRC) is the third most common cancer diagnosed in both men and women, and the second most common cause of cancer deaths in the United States. There were approximately 150 000 new cases resulting in 57 000 deaths in 2002.1 CRC is one of the most studied cancer types and its underlying aetiology best elucidated. Colorectal tumorigenesis involves a multistep process including genetic and epigenetic alterations of numerous CRC related genes that may act as either oncogenes or tumour suppressor genes. [2][3][4][5] The majority of sporadic CRCs are characterised by deletions of large chromosomal segments, which are thought to represent the loss of wild type tumour suppressor genes.6 7 About 15% of sporadic CRCs, on the other hand, show microsatellite instability (MSI), characterised by the insertion and/or deletion of simple repeat sequences and indicative of the involvement of defective mismatch repair. Birt-Hogg-Dubé syndrome (BHD, OMIM 135150) is an inherited autosomal dominant syndrome characterised by a triad of cutaneous lesions consisting of fibrofolliculomas, trichodiscomas, and acrochordons. 10 A wide spectrum of neoplastic and non-neoplastic features has been described in BHD patients, 11 including diverse types of kidney tumours 12-17 and spontaneous pneumothorax.12-16 18 BHD has also been reported to be associated with colonic polyposis and colorectal neoplasia, 13 19-22 although a large study of 223 patients from 33 BHD families could not establish such a relation. 23 We recently reported a high incidence of colorectal polyps and carcinomas in patients with confirmed BHD germline mutations, indicating that the BHD gene may be involved in colorectal tumorigenesis. 13 The BHD gene has been mapped to chromosome subband 17p11.2 12 14 and recently identified to encode a novel protein named follicullin. 15 Based on the presence of inactivating BHD mutations in BHD patients, and the detection of LOH in a significant proportion of BHD related tumours, the BHD gene was considered to be a tumour suppressor gene. A 44% frequency of frameshift mutations within a mononucleotide (C) 8 tract (nt 1733-1740) has been detected in BHD patients, 15 and this repeat tract represents a BHD mutational hot spot.13 15 Other studies have reported the presence of frameshift mutations within intragenic mononucleotide tracts of the TGFBR2 and BAX genes in CRC cell lines and tumours with high level MSI.24 25 The poly C tract of the BHD gene may therefore be a potential site of mutation in CRC characterised by MSI.We have evaluated the role of the BHD gene in 47 unselected colorectal tumours (10 polyps and 37 carcinomas) by screening all coding exons of the BHD gene for mutations and analysing 46 of the tumours for LOH in the chromosome region surrounding the BHD locus. Furthermore, alterations in BHD promoter methylation profiles were determined in 23 cases of matched normal/carcinoma tissues where a sufficient quantity of DNA was available. We report the detection of two novel somatic missense mutations of ...

Background The INNODIA consortium has established a pan-European infrastructure using validated centres to prospectively evaluate clinical data from individuals with newly diagnosed type 1 diabetes combined with centralised collection of clinical samples to determine rates of decline in beta-cell function and identify novel biomarkers, which could be used for future stratification of phase 2 clinical trials. Methods In this context, we have developed a Master Protocol, based on the “backbone” of the INNODIA natural history study, which we believe could improve the delivery of phase 2 studies exploring the use of single or combinations of Investigational Medicinal Products (IMPs), designed to prevent or reverse declines in beta-cell function in individuals with newly diagnosed type 1 diabetes. Although many IMPs have demonstrated potential efficacy in phase 2 studies, few subsequent phase 3 studies have confirmed these benefits. Currently, phase 2 drug development for this indication is limited by poor evaluation of drug dosage and lack of mechanistic data to understand variable responses to the IMPs. Identification of biomarkers which might permit more robust stratification of participants at baseline has been slow. Discussion The Master Protocol provides (1) standardised assessment of efficacy and safety, (2) comparable collection of mechanistic data, (3) the opportunity to include adaptive designs and the use of shared control groups in the evaluation of combination therapies, and (4) benefits of greater understanding of endpoint variation to ensure more robust sample size calculations and future baseline stratification using existing and novel biomarkers.

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Administration of insulin by a variety of routes can prevent the onset of diabetes and the destruction of pancreatic β-cells in prediabetic animals. Moreover, intensive insulin therapy improves β-cell function in patients with recent-onset type 1 diabetes. Preliminary trials have suggested that treatment of high-risk prediabetic patients with insulin can prevent the onset of diabetes. In addition, long-term insulin treatment appears to have no significant side-effects in non-diabetics. However, the mechanism of the protective action of insulin is not yet understood. Several large-scale controlled trials have been organized (e.g. the Diabetes Prevention Trial 1, DPT-1, and the European Paediatric Prediabetes Subcutaneous Insulin Trial, EPP-SCIT), to evaluate the effect of prophylactic insulin therapy in the prevention or delay of diabetes in high-risk paediatric individuals.

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