Genetic factors contributing to late adverse musculoskeletal effects in childhood acute lymphoblastic leukemia survivors.

BACKGROUND: A substantial number of survivors of childhood acute lymphoblastic leukemia (ALL) suffer from treatment-related late adverse effects. While multiple studies have identified the effects of chemotherapeutics and radiation therapy on musculoskeletal outcomes, few have investigated their associations with genetic factors. METHODS: Here we analyzed musculoskeletal complications in relation to common and rare genetic variants derived through whole-exome sequencing of the PETALE cohort. Top-ranking associations were further assessed through stratified and multivariate analyses. RESULTS: DUOX2 variant was associated with skeletal muscle function deficit, as defined by peak muscle power Z score ≤ -2 SD (P = 4.5 × 10-5 for genotyping model). Upon risk stratification analysis, common variants in the APOL3, COL12A1, and LY75 genes were associated with Z score ≤ -2 SD at the cross-sectional area (CSA) at 4% radial length and lumbar bone mineral density (BMD) in high-risk patients (P ≤ 0.01). The modulation of the effect by risk group was driven by the interaction of the genotype with cumulative glucocorticoid dose. Identified variants remained significant throughout multivariate analyses incorporating non-genetic factors of the studied cohort. CONCLUSION: This exploratory study identified novel genetic variants associated with long-term musculoskeletal impairments in childhood ALL survivors. Replication in an independent cohort is needed to confirm the association found in this study.

Lung function in Birt-Hogg-Dubé syndrome: a retrospective analysis of 96 patients.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD. RESULTS: Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years. CONCLUSIONS: Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.

Evaluating the risk of pneumonia with inhaled corticosteroids in COPD: Retrospective database studies have their limitations SA.

An increased risk of non-fatal pneumonia has been documented in COPD patients treated with inhaled corticosteroids (ICS) in randomized clinical trials. Retrospective database analyses have been conducted to evaluate this signal in larger populations treated in the community. To understand how methodological choices may influence results in observational studies, we compared two recent Canadian studies which used health administrative databases from Quebec and Ontario and came to opposite conclusions on the risk of pneumonia in ICS treated COPD patients. Explanations for why the results of these studies diverged are explored. The Suissa analysis used RAMQ data from Quebec and showed an increased relative risk of serious pneumonia for current users of ICS compared to non users, RR = 1.69 (95% confidence interval, 1.63-1.75). The Gershon analysis used ODB data and showed no difference for pneumonia hospitalisation, RR = 1.01 (0.93-1.08). Reasons for differences in study findings include lack of validated definitions of COPD, poor selection of relevant exposure groups, channeling and confounding biases, and failure to perform on-treatment analyses for safety. CONCLUSION: Our study identifies methodological features that need consideration to increase robustness and minimize threats to internal validity of retrospective health administrative database studies.

Asthma Control in Cities of Developing Countries: Results of a Five-City Survey

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Quality of life and control of allergic rhinitis in patients from regions beyond western Europe and the United States.

There is comparatively little information on health-related quality of life (HRQoL) in subjects with allergic rhinitis (AR) or allergic rhinoconjunctivitis (AR/C) in countries beyond western Europe and North America. The primary aim of this investigation was therefore to review and assess the information in the public domain on HRQoL in AR/C patients from diverse regions of the world, represented by different countries, including Argentina, Australia, Brazil, Russia, Singapore, South Africa and Turkey. Second, in view of the absence of a standardized definition for 'AR control', the review aimed to determine whether a working definition of AR/C can be inferred from validated tests or other instruments documented to date. Despite the comparatively low number of studies, this review demonstrated that overall the symptoms of AR/C impair the HRQoL of patients in these regions by adversely impacting sleep, daily activities, physical and mental status and social functioning, similar to that demonstrated in much larger numbers of studies of AR/C patients in Europe and the United States. Furthermore, the findings of the review suggest that 'overall' control of the disease should encompass reduction of nasal and ocular symptoms, as well as improvements in HRQoL, comorbid conditions and cognition. Although some instruments are currently available for measuring control of AR, none are capable of assessing all these aspects, emphasizing the need to develop appropriate new instruments.

Asthma programmes in diverse regions of the world: challenges, successes and lessons learnt.

International surveys have demonstrated that asthma is still underdiagnosed and undertreated in many parts of the world. Despite improvements in the standard of asthma care delivered in many areas, as evidenced by improved global asthma mortality data, much information on projects and programmes undertaken in resource-limited regions of the world is not in the public domain. The aim of this report is to review projects and programmes in diverse regions around the world so that health care providers, planners and consumers may draw on the successes, failures and lessons learnt. Such real world experiences may contribute to achieving Global Initiative for Asthma goals of asthma control. Asthma projects and programmes in Argentina, Australia, Brazil, China, Japan, Mexico, Philippines, Russia, South Africa and Turkey were discussed by a group of experts in asthma care, the Advancing Asthma Care Network, from their respective countries, over a course of three satellite meetings in 2010. Collective analyses consistently identified low rates of dissemination and implementation of national and international treatment guidelines, low levels of continuing medical education and training of primary health care professionals and access and distribution of inhaled corticosteroids to be major barriers that are critical to the overall success of a national asthma management programme. In the less developed asthma programmes, under-recognition and undertreatment further limited the success of the programmes. Evidence from well-established national asthma management programmes suggests that establishment of a successful programme entails a logical progression through specific developmental stages, starting with political/stakeholder endorsement and commitment, followed by epidemiological evaluation, evaluation of disease burden, evaluation of access to care and best therapy, and finally optimisation and maintenance therapy for individual patients.

[Molecular chromosomic genetics in prenatal and perinatal diagnosis of chromosomal anomalies and genetic diseases]. / Apport de la génétique chromosomique moléculaire au diagnostic prénatal et périnatal des anomalies chromosomiques et des maladies géniques.

Prenatal and perinatal diagnosis needs a rapid, accurate and overall genome analysis. Molecular chromosomic techniques such as fluorescent in situ hybridization (FISH) with "cold" (not radioactively labeled) probes combine techniques of both conventional chromosome banding and molecular biology. FISH is a powerful tool for detecting some genetic diseases as well as microscopic or submicroscopic chromosome rearrangements, in metaphases cells or interphase nuclei.

BRCA1 can stimulate gene transcription by a unique mechanism.

Most familial breast and ovarian cancers have been linked to mutations in the BRCA1 gene. BRCA1 has been shown to affect gene transcription but how it does so remains elusive. Here we show that BRCA1 can stimulate transcription without the requirement for a DNA-tethering function in mammalian and yeast cells. Furthermore, the BRCA1 C-terminal region can stimulate transcription of the p53-responsive promoter, MDM2. Unlike many enhancer-specific activators, non-tethered BRCA1 does not require a functional TATA element to stimulate transcription. Our results suggest that BRCA1 can enhance transcription by a function additional to recruiting the transcriptional machinery to a targeted gene.

[Lower limb spasticity in adults. Clinical evaluation with motor block]. / La spasticité des membres inférieurs chez l'adulte. Evaluation clinique et blocs moteurs.

Clinical assessment of spastic lower limbs in adults requires identification of neurologic components (motor deficit, spasticity, co-contraction, sensory deficit) and non-neurological components (contracture) of the motor disorder and the intrinsic mechanism of the "spastic" gait. In order to determine the nature of a complex motor disorder, the clinical can call on different diagnostic tools such as motor blocks or gait analysis measuring time-distance parameters, kinematic, kinetics, gait dynamic electromyography and energy expenditure for gait performance. Clinical assessment is guided by the therapeutic goal (function, gait, mobility, pain relief, nursing), both to propose treatment and objectively monitor treatment results in terms of deficit (strength, flexibility, appropriate contraction, muscle activation) and handicap (gait, transfers, activities of daily living).

Clinical and functional evaluation of a gaze controlled system for the severely handicapped.

This preliminary study evaluates the suitability of a gaze controlled communication system for severely handicapped patients. The system drives a computer by movements of the patient's pupils. The capacity to communicate by producing text on a screen was assessed in 30 patients, 22 traumatic tetraplegics and 8 patients whose handicaps were due to other causes. The rate at which they learned to use the system, and the speed of their word processing were measured. Those tetraplegics who had used other communication systems found the gaze controlled system tiring, and its lack of other peripherals limiting. But its true application seems to be as the sole available interface for the most severely handicapped who can neither move nor speak. Peripherals and improved calibration systems are presently being developed.

Energy consumption of paraplegic locomotion using reciprocating gait orthosis.

The energy cost of walking using a reciprocating gait orthosis (RGOII) with functional electrical stimulation (FES) was assessed in 14 patients with spastic complete paraplegia from six rehabilitation centres. Before and after training asing RGOII with FES, the subjects performed a progressive maximal test on an arm-crank ergometer to obtain their laboratory peak oxygen uptake (LVO2peak), heart rate (HR) and blood lactate concentration changes. At the end of the training session, oxygen uptake (VO2) was measured during a walking test with orthosis at different speeds (6 min steady state at 0.1 m.s-1, followed by 2-min stages at progressively increasing speeds up to exhaustion). Of the subjects 4 repeated this test using orthosis without FES. At a speed of 0.1 m.s-1, VO2 represented 47 (SD 23)% of LVO2peak, mean HR was 137 (SD 21) beats.min-1 and mean blood lactate concentration 2.4. (SD 1.4) mmol.l-1. Maximal speed ranged from 0.23 to 0.5 m.s-1. At maximal speed, VO2 was 91 (SD 18)% of LVO2peak, mean HR reached 96 (SD 7)% and mean blood lactate concentration only 52 (SD 19)% of the maximal values measured during the laboratory test. Walking without electrical stimulation induced an increase in HR but there was no difference in VO2 and blood lactate compared to walking with stimulation. The training period did not result in any improvement in maximal physiological data. We concluded that the free cadence walking speed with orthosis remains much lower than that of able-bodied people or wheelchair users. The metabolic cost at a given speed is much higher even if, using a stimulation device, the cardiovascular stress is reduced.

Restoration of functional gait in paraplegic patients with the RGO-II hybrid orthosis. A multicentre controlled study. I. Clinical evaluation.

By means of a multicentric study in six rehabilitation centres, we assessed the RGO-II orthosis to restore functional gait in patients with spinal cord injuries. The 26 subjects participating in the study had spastic complete paraplegia. Twenty one had progressed to the training programme and 19 were able to stand up alone. The trained subject's walking distance ranged from 200 to 1400 m, while their walking speed ranged from 0.15 to 0.45 ms-1. A 2-month follow-up study revealed that, out of 15 patients using the hybrid orthosis, 11 were home users. Modalities and adverse effects of training are reported. The place of gait restoration with a hybrid orthosis in a rehabilitation programme is discussed.

Hypnosis and Hypnotism in Family Medicine: How are they used in a clinical setting?

This article attempts to define and demystify hypnosis and to present the range of its applications in family medicine. The author reviews definitions and describes hypnotic phenomena, suggestibility, and the use of suggestion, as well as traditional, semitraditional, and Ericksonian induction methods, precautions, and dangers. Clinical uses are then presented for the family physician to apply to surgery, obstetrics, pain treatment, psychosomatic disorders, and psychotherapy.

Purification and properties of the cytosolic and mitochondrial forms of aspartate aminotransferase and malate dehydrogenase from rat heart.

The present work describes the purification from rat heart of the mitochondrial and cytosolic forms of the enzymes of the malate--aspartate shuttle, aspartate aminotransferase (EC 2.6.1.1) and malate dehydrogenase (EC 1.1.1.37), by a single procedure after the preparation of the original crude extract. In 10 purification steps, the four enzymes were obtained electrophoretically pure in yields ranging from 6 to 54% of their respective isoenzyme levels in the crude extract. Apoenzymes were formed from the aminotransferases by reacting them with cysteine sulfinate and dialyzing. Complete reconstitution was obtained after a brief incubation with pyridoxal phosphate. All four enzymes are dimers. The mitochondrial isoenzymes are of slightly lower molecular weight than their respective cytosolic forms. Michaelis constants and maximal velocities were derived by the use of primary and secondary plots. In general, the properties of the enzymes from rat heart are similar to the properties of the enzymes from other animal sources.