The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma

Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.     

D-hormone analog alfacalcidol: an update on its role in post-menopausal osteoporosis and rheumatoid arthritis management

Alfacalcidol (1-alpha-hydroxyvitamin D3) is a non-endogenous analog of vitamin D which can bypass the renal and intestinal regulatory mechanisms that control the production of calcitriol (1,25-hydroxyvitamin D3, the active form of vitamin D, D-Hormone). Alfacalcidol may be metabolized into calcitriol with a limited risk of hypercalcemia. Alfacalcidol and calcitriol have been evaluated in animal and human studies assessing their effects on bone mineral density and fracture rates. More recently, they have been shown to produce beneficial effects in muscle, immune system, and autoimmune diseases, including rheumatoid arthritis. This paper discusses the therapeutic efficacy of alfacalcidol in reports in which it has been proposed as an interesting alternative to vitamin D or calcitriol. Some recent findings about general metabolism and regulation of vitamin D and its analogs are discussed. The biological and clinical effects of alfacalcidol in post-menopausal osteoporosis are reviewed, followed by critical appraisal of its efficacy in preventing bone loss and falls in the elderly. The last two sections discuss the role of D analogs in regulating the immune system, with particular regard to rheumatoid arthritis. The main results of this review show that alfacalcidol may have a wider range of therapeutic applicability, beyond simply restricting it to patients in hemodialysis or peritoneal dialysis with high serum levels of intact PTH.     

Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments

The mechanism of risk reduction obtained by blood pressure-lowering pharmacological treatment remains unclear. We explored the amount of risk reduction attributable to the apparent effect of antihypertensive medicines on blood pressure by using the capture approach. Five randomized, placebo or nil controlled trials with a total of 28,997 subjects and 1,935 cardiovascular fatal or non-fatal events from the INDANA database met the eligibility criteria. Computations were performed on the original individual records using multiple Cox's proportional hazard regression models designed for meeting the assumed treatment mode of action and comparing relevant assumptions. For coronary event, the results are inconclusive essentially because the risk reduction is mild. However, for stroke the risk reduction adjusted for baseline risk factors is 34% (P<0.0001). The part explained by the effect of treatment on systolic blood pressure is 49% of this reduction, with 95% confidence interval not including 100%. This result suggests that the apparent effect on blood pressure is not the only cause of stroke risk reduction in hypertensive subjects submitted to an antihypertensive medicine.     

Coccygectomy for instability of the coccyx

Between 1993 and 2000, 61 patients with instability-related coccygodynia were operated on by a single surgeon using the same technique. There were 49 women and 12 men, mean age 45.3 (18–72) years. Twenty-seven patients had hypermobility of the coccyx and 33 subluxation. In all cases, the unstable portion was removed through a limited incision directly over the coccyx. The outcome was assessed using a detailed questionnaire. Follow-up was between 12 months and more than 30 months. The outcome was rated excellent or good in 53 patients, fair in one, and poor in seven. There were nine patients with infection requiring reoperation.

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Résume Entre 1993 et 2000, 61 malades avec une coccygodynie lié à une instabilité ont été opérés par un seul chirurgien, en utilisant la même technique. Il y avait 49 femmes et 12 hommes, dâge moyen âge 45.3 ans (18–72). Vingt-sept malades avaient une hypermobilité du coccyx et 33 une subluxation. Dans tous les cas, la portion instable a été enlevée par une incision limitée, directement sur le coccyx. Le résultat a été apprécié en utilisant un questionnaire détaillé. Le suivi était entre 12 mois et plus de 30 mois. Le résultat a été estimé excellent ou bon pour 53 malades, moyen pour un, et mauvais pour sept. Il y avait neuf malades avec une infection qui a nécessité une réintervention.

     

Cardiac toxicity of cancer treatment regimes in children and adolescents: physiopathology, clinical data and the paediatric oncologist's point of view

Over the last 20 years, the increase in the cure rate of childhood cancer and leukemia of almost 80% has facilitated the observation of middle and long-term sequelae, particularly of cardiovascular origin; such after-effects are the consequence of cytotoxic damage to the cells of the cardiovascular system, in particular by anthracyclines and radiotherapy, and all the more so by their combined use. Such destructive lesions to myocytes greatly hinder the capacity of the cardiac muscle to hypertrophy to meet the needs of bodily growth, pregnancy and certain intense sports activities. Endothelial cells also accelerate an early arteriosclerotic process, a potential cause of sudden death in the case of ostial stenosis. All such phenomena build up over time, together with the usual adult cardio-vascular risk factors. Finally, no cardiac tissue, pericardial, valvular endocardium or autonomic nervous tissue escapes these cytotoxic effects, giving rise to pericarditis, calcification, valvular leaks and arrythmias and conduction abnormalities. The resulting excessive cardiac mortality is one of the major concerns of paediatric oncologists, along with secondary tumours and leukaemia. This article analyses physiopathological consequences that are often asymptomatic or clinical, together with diagnostic, screening and follow-up methods for these patients, encouraging lifestyle modifications where appropriate or, when possible, treatment before the appearance of cardiac failure, myocardial infarction or sudden death. Other cytotoxic drugs such as high-dose cyclophosphamide, amsacrin, 5-FU and tubulin acting agents are also mentioned as a result of their cardiac toxicity, but this is not usually dose-cumulative.     

Does 99mTc-sestamibi uptake discriminate breast tumors?

The aim of this work was to investigate 99mTc-sestamibi uptake and histopathological characteristics of breast tumors. Static 99mTc-sestamibi scintimammography (SMM) has been performed in 101 breast tumors (98 patients). SMM were scored from 0 to 4 according to intensity of 99mTc-sestamibi uptake and classified in two groups: SMM with absence or low tumor uptake (0, 1, 2) and SMM with high tumor uptake (3, 4). Tumor histopathological characteristics have been determined on core or excisional biopsy. The 99mTc-sestamibi uptake (low vs. high) correlated to classical prognostic factors: positively with Scarff-Bloom and Richardson (SBR) grade (p < 0.0005), axillary involvement (p < 0.0005), and tumor size (p < 0.0005) and negatively with estrogen receptors (p < 0.001). Fixation of 99mTc-sestamibi in invasive lobular carcinoma was lower than in invasive ductal carcinoma (p < 0.01) despite a similar mean tumor size (28 +/- 14 mm vs. 24 +/- 14 mm). Relations between 99mTc-sestamibi uptake and tumor size, histologic type, and axillary involvement were independent variables also significant in multivariate analysis (p < 0.0005, p < 0.005, p < 0.05, respectively). Moreover, the five-year survival rate was higher when 99mTc-sestamibi breast tumor uptake was low (p < 0.005). This difference is also significant using the Cox model (p < 0.05). Uptake of 99mTc-sestamibi (low vs. high) discriminates breast tumors with different histopathological characteristics and prognosis.     

Automatically parcellating the human cerebral cortex

We present a technique for automatically assigning a neuroanatomical label to each location on a cortical surface model based on probabilistic information estimated from a manually labeled training set. This procedure incorporates both geometric information derived from the cortical model, and neuroanatomical convention, as found in the training set. The result is a complete labeling of cortical sulci and gyri. Examples are given from two different training sets generated using different neuroanatomical conventions, illustrating the flexibility of the algorithm. The technique is shown to be comparable in accuracy to manual labeling.     

Alteration in the behavior of a colon carcinoma cell line by extracellular matrix components

It was previously demonstrated that substrata derived from well differentiated colon carcinoma cell lines induced a more benign program in a separate malignant colon cell line, MOSERsf. This study attempts to define a role for extracellular matrix components in the biological events of MOSERsf cells. Alterations in morphology, secreted carcinoembryonic antigen (CEA) and urokinase brought about by individual components were determined. Laminin induced similar changes to colon-derived substrata in that there was increased cell attachment and spreading, a 4-fold elevation in CEA and a 45% reduction in urokinase. Fibronectin stimulated cell attachment without altered morphology and reduced the amount of plasminogen activator. CEA values, however, remained unchanged. Growth of MOSERsf cells on all types of collagen failed to elicit any change in cell shape or CEA. However, type I/III collagen raised urokinase levels by 40%. Transforming growth factor beta (TGF-beta) induces cellular laminin and fibronectin, promotes cell attachment, and spreading, elevates CEA and diminishes urokinase. These data argue for a role for laminin and possibly fibronectin in the governing of biological events culminating in a more mature colon cell.     

Development and validation of the ORACLE score to predict risk of osteoporosis

OBJECTIVE: To develop and validate a composite index, the Osteoporosis Risk Assessment by Composite Linear Estimate (ORACLE), that includes risk factors and ultrasonometric outcomes to screen for osteoporosis. SUBJECTS AND METHODS: Two cohorts of postmenopausal women aged 45 years and older participated in the development (n = 407) and the validation (n = 202) of ORACLE. Their bone mineral density was determined by dual energy x-ray absorptiometry and quantitative ultrasonometry (QUS), and their historical and clinical risk factors were assessed (January to June 2003). Logistic regression analysis was used to select significant predictors of bone mineral density, whereas receiver operating characteristic (ROC) analysis was used to assess the discriminatory performance of ORACLE. RESULTS: The final logistic regression model retained 4 biometric or historical variables and 1 ultrasonometric outcome. The ROC areas under the curves (AUCs) for ORACLE were 84% for the prediction of osteoporosis and 78% for low bone mass. A sensitivity of 90% corresponded to a specificity of 50% for identification of women at risk of developing osteoporosis. The corresponding positive and negative predictive values were 86% and 54%, respectively, in the development cohort. In the validation cohort, the AUCs for identification of osteoporosis and low bone mass were 81% and 76% for ORACLE, 69% and 64% for QUS T score, 71% and 68% for QUS ultrasonometric bone profile index, and 76% and 75% for Osteoporosis Self-assessment Tool, respectively. ORACLE had the best discriminatory performance in identifying osteoporosis compared with the other approaches (P < .05). CONCLUSION: ORACLE exhibited the highest discriminatory properties compared with ultrasonography alone or other previously validated risk indices. It may be helpful to enhance the predictive value of QUS.