Design of a prospective, longitudinal cohort of people living with type 1 diabetes exploring factors associated with the residual cardiovascular risk and other diabetes-related complications: The SFDT1 study.

Type 1 diabetes mellitus (T1DM) is associated with a high risk of cardiovascular (CV) complications, even after controlling for traditional CV risk factors. Therefore, determinants of the residual increased CV morbidity and mortality remain to be discovered. This prospective cohort of people living with T1DM in France (SFDT1) will include adults and children aged over six years living with T1DM, recruited throughout metropolitan France and overseas French departments and territories. The primary objective is to better understand the parameters associated with CV complications in T1DM. Clinical data and biobank samples will be collected during routine visits every three years. Data from connected tools, including continuous glucose monitoring, will be available during the 10-year active follow-up. Patient-reported outcomes, psychological and socioeconomic information will also be collected either at visits or through web questionnaires accessible via the internet. Additionally, access to the national health data system (Health Data Hub) will provide information on healthcare and a passive 20-year medico-administrative follow-up. Using Health Data Hub, SFDT1 participants will be compared to non-diabetic individuals matched on age, gender, and residency area. The cohort is sponsored by the French-speaking Foundation for Diabetes Research (FFRD) and aims to include 15,000 participants.

A cancer care electronic medical record highly integrated into clinicians' workflow: users' attitudes pre-post implementation.

The purpose was to study users' attitudes towards an electronic medical record (EMR) closely integrated into the clinicians' cancer care workflow. The EMR, implemented in an ambulatory cancer care centre, was designed as a care pathway information system providing real-time support to the coordination of shared care processes involving all the care personnel. Mixed method pre-post study design was used. The study population consisted of all care personnel. A survey measured the quality attributes of the EMR, the clinical information it produces, the perceived usefulness of the system for supporting clinical data management tasks and the perceived impacts in terms of access and quality of care. The survey shows that users' attitudes towards the EMR (response rate of 71%) measured after the go-live were positive ranging from 3.42 to 3.95 on a 5-point scale. Besides, the content analysis of 33 pre-post interviews revealed five main themes: magnitude of the changes caused by the EMR; its innovative potential; its positive benefits; an ongoing growth in users' expectancies; and the burden associated with the time required to operate the EMR. In sum, the study shows that users can largely apply innovative uses of information technologies that automate their clinical processes.

Energy disruptors: rising stars in anticancer therapy?

The metabolic features of tumor cells diverge from those of normal cells. Otto Warburg was the first to observe that cancer cells dramatically increase their glucose consumption to generate ATP. He also claimed that cancer cells do not have functional mitochondria or oxidative phosphorylation (OXPHOS) but simply rely on glycolysis to provide ATP to the cell, even in the presence of oxygen (aerobic glycolysis). Several studies have revisited this observation and demonstrated that most cancer cells contain metabolically efficient mitochondria. Indeed, to sustain high proliferation rates, cancer cells require functional mitochondria to provide ATP and intermediate metabolites, such as citrate and cofactors, for anabolic reactions. This difference in metabolism between normal and tumors cells causes the latter to be more sensitive to agents that can disrupt energy homeostasis. In this review, we focus on energy disruptors, such as biguanides, 2-deoxyglucose and 5-aminoimidazole-4-carboxamide ribonucleotide, that interfere with the main metabolic pathways of the cells, OXPHOS, glycolysis and glutamine metabolism. We discuss the preclinical data and the mechanisms of action of these disruptors at the cellular and molecular levels. Finally, we consider whether these drugs can reasonably contribute to the antitumoral therapeutic arsenal in the future.

[Epilepsy in Lao Popular Democratic Republic: difficult procurement of a first-line antiepileptic contributes to widening the treatment gap]. / Épilepsie au Laos : le difficile parcours d'un antiépileptique de première ligne contribue à la forte carence de traitement.

INTRODUCTION: In Laos, over 95% of people with epilepsy (PWE) do not receive a proper treatment. Traditional beliefs and practices have long explained this wide treatment gap. From 2008 to 2010 we evaluated the procurement process for phenobarbital, the leading first-line antiepileptic drug (AED) in Laos, and its availability at a national scale as a potential additional major cause of this treatment gap in Laos. METHODS: Data were drawn from several surveys conducted from 2008 to 2010: (i) semi structured interviews of key persons from the Ministry of Health and from pharmaceutical factories, wholesalers, pharmacists, neurologists, psychiatrists, and non-governmental organisations; (ii) retrospective survey of AED prescriptions in three main hospitals of Vientiane the capital city during two randomised weeks from June to August 2009; (iii) self-administered questionnaires of pediatricians regarding their knowledge about phenobarbital; (iv) a national survey of the AED availability in pharmacies and drug shops in 16/17 provinces, 16 districts and 96 villages (multistage randomised survey) in 2010 and a survey among the population in 2009. RESULTS: Phenobarbital is imported in Laos via a carefully controlled importation process either as raw material to be processed by factory N(o) 2 or in the form of tablets. The International Narcotics Control Board (Vienne) delivers a yearly quota of 25kg of raw phenobarbital to the Food and Drug department (FDA). This allows the production of 245000 tablets per year (around 671 annual adult treatments). The overall importation process for phenobarbital lasts 6months. Grade 1 pharmacists (mostly located in urban areas) and regional and district hospitals are authorized to deliver phenobarbital. The cost of phenobarbital ranged from 0.11 to 0.2US dollars/tablet per day (39 to 67US dollars per year). High cost of transportation and increased cost of phenobarbital (5- to 10-fold greater than the international market) contribute to reduce access to treatment. CONCLUSION: Needs for phenobarbital at delivery sites should be re-assessed by the health authorities based on the expected number of PWE. Improved training of health and pharmacist personnel and increased awareness of the population concerning effective long-term treatment for epilepsy are crucial to improve access of PWE to AED in Laos.

When to treat a diabetic patient using an external insulin pump. Expert consensus. Société francophone du diabète (ex ALFEDIAM) 2009.

For years, external insulin pumps have enjoyed proven efficacy as an intensive diabetes treatment to improve glycaemic control and reduce hypoglycaemia. Since the last ALFEDIAM guidelines in 1995, however, basal-bolus treatment using a combination of long- and short-acting insulin analogues have emerged and could challenge, at a lower cost, the efficacy of pumps using rapid-acting insulin analogues, considered the 'gold standard' of insulin treatment. Nevertheless, given its theoretical and practical advantages, some patients will derive more benefit from pump treatment. These cases have been carefully evaluated in the literature by a panel of experts appointed by ALFEDIAM to determine the indications for pump treatment. In patients with type 1 diabetes, persistent elevated HbA(1c) despite multiple daily injections (MDI), and repeated hypoglycaemia and high glycaemic variability, represent the most validated indications. In patients with type 2 diabetes, pump treatment may be indicated in cases of MDI failure to achieve HbA(1c) targets. Absolute contraindications are rare, and comprise severe psychiatric disorders, rapidly progressing ischaemic or proliferative retinopathy before laser treatment and exposure to high magnetic fields. Relative contraindications are mostly related to the patient's lack of compliance or inability to cope with the treatment, and need to be evaluated individually to clearly assess the benefit/risk ratio for the given patient. However, as these conditions are progressive, there should also be annual reassessment of the appropriateness of pump treatment. Specific education on pump treatment initially and throughout the follow-up, delivered by experienced medical and paramedical teams, are the best guarantees of treatment efficacy and safety.

Adjuvant regional irradiation after breast-conserving therapy for early stage breast cancer: a survey of canadian radiation oncologists.

AIMS: To document the use of adjuvant regional irradiation after breast-conserving therapy for early stage breast cancer by Canadian radiation oncologists and to identify the factors influencing their clinical decisions. MATERIALS AND METHODS: We conducted a survey to assess the above aims. In April 2008, a questionnaire was sent to 167 members of the Canadian and Quebec Associations of Radiation Oncologists with interest in breast cancer management. The answers were obtained through a dedicated website, which collected the raw data collected for analysis. RESULTS: In total, 67 radiation oncologists completed the survey, corresponding to a 40% response rate. Most respondents were experienced and high-volume providers. We identified several areas of variation in the decision-making regarding regional lymph node irradiation after breast-conserving therapy. Regarding the decision to combine regional nodal irradiation with irradiation of the breast, the number of positive nodes after axillary dissection (1-3 vs > or =4) was a crucial determinant. For patients with between one and three positive nodes and a nodal ratio of 50%, most respondents added regional irradiation. Similarly, the same nodal ratio of 50% was the main factor for inclusion of the axillary nodal region in the radiation field. However, few radiation oncologists have chosen to include the internal mammary chain in their treatment plan. The number of positive lymph nodes, the nodal ratio, the number of lymph nodes removed and the presence of extracapsular extension were the primary self-reported factors that directed the decision to offer regional radiotherapy. CONCLUSIONS: This survey showed that there is a wide variation of practices among radiation oncologists in Canada. These results support the need for treatment guidelines and provide guidance on which factors should be included in a decision-making algorithm.

Lipoprotein lipase and endothelial lipase expression in mouse brain: regional distribution and selective induction following kainic acid-induced lesion and focal cerebral ischemia.

Lipoprotein and endothelial lipases are members of the triglyceride lipase gene family. These genes are expressed in the brain, where the encoded proteins are fulfilling functions that have yet to be elucidated. In this study, we examined the distribution of their respective mRNAs in the C57BL/6 mouse brain by in situ hybridization. In control mice, we observed widespread expression of lipoprotein lipase (LPL) mRNA mainly in pyramidal cells of the hippocampus (CA1, CA2 and CA3 areas), in the striatum and in several cortical areas. Endothelial lipase (EL) mRNA expression was restricted to CA3 pyramidal cells of the hippocampus, to ependymal cells in the ventral part of the third ventricle and to some cortical cell layers. To gain insight into the role played by lipases in the brain, neurodegeneration was induced by intraperitoneal injection of kainic acid (KA) or by occlusion of the middle cerebral artery (MCA). Upon injection of KA, a rapid increase in EL mRNA expression was observed in the piriform cortex, hippocampus, thalamus and neocortex. However, the levels of LPL mRNA were unaffected by KA injection. Remarkably, after focal cerebral ischemia, the expression of EL was unaffected whereas a dramatic increase in LPL expression was observed in neocortical areas of the lesioned side of the brain. These results show that LPL and EL transcripts are selectively upregulated in function of the type of brain injury. LPL and EL could thus fulfill a function in the pathophysiological response of the brain to injury.

Uncoupling protein 2 in the brain: distribution and function.

Uncoupling protein 2 (UCP2) mRNA is expressed in a panoply of tissues, including the brain, where it is widely distributed. In the mouse brain, it is expressed in the hypothalamus (suprachiasmatic, paraventricular, dorsomedial, ventromedial and arcuate nuclei), the thalamus (submedius nucleus) and the brain-stem (dorsal motor nucleus of the vagus nerve). In the rat brain, it is also expressed in the hippocampus. The presence of UCP2 mRNA in neurons expressing corticotropin-releasing factor and arginine-vasopressin suggests a role for UCP2 in the control of neuroendocrine and behavioural functions. We have recently demonstrated that UCP2-deficient mice can resist the lethal effect of toxoplasmosis through an enhanced production of reactive oxygen species (ROS) from the macrophages. This finding provides evidence that UCP2 can be part of a mechanism preventing ROS production. UCP2 could therefore be involved in protecting the brain against oxidative stress. The involvement of UCP2 in neuroprotection is also consistent with the recent observation that kainic acid, which promotes Ca(2+) uptake in the glutamate-activated neurons in the hippocampal CA1 field, can induce the UCP2 gene in the activated CA1 cells. The role of UCP2 in neuroprotection warrants further investigation.

High neonatal leptin exposure enhances brain GR expression and feedback efficacy on the adrenocortical axis of developing rats.

Leptin modifies the activity of the hypothalamic-pituitary-adrenal axis in adult rodents and inhibits the production of glucocorticoids from human and rat adrenals in vitro. During development, high levels of circulating leptin and low levels of corticosterone secretion are observed together with adrenal hyporesponsiveness to stress. As chronic neonatal leptin administration reduced stress-induced corticotropin-releasing factor mRNA expression and ACTH secretion in pups, we determined whether elevated leptin levels enhanced the feedback effect of glucocorticoids on the hypothalamic-pituitary-adrenal axis. In naive pups we found a highly significant inverse relationship between plasma levels of leptin and corticosterone (P < 0.01) during postnatal d 6-20. We tested the ability of dexamethasone (1 or 10 microg/kg BW, ip, -3 h before stress) to suppress ether-induced ACTH secretion in 10-d-old pups that were treated during the neonatal period (d 2-9) with either vehicle or leptin (1 or 3 mg/kg BW, ip, daily). The expressions of brain GR and MR in vehicle- or leptin-treated neonates were determined by in situ hybridization and Western blotting. Chronic leptin treatment enhanced the ability of dexamethasone to suppress ACTH secretion after stress, and the low dose of dexamethasone was discriminant. Leptin treatment increased GR mRNA levels in the hypothalamic paraventricular nucleus (P < 0.05) and in the dentate gyrus of the hippocampus in a dose-dependent fashion. Hippocampal GR protein concentrations were increased by leptin treatment (P < 0.05). Expression of MR mRNA was not modified. Thus, the ability of leptin to enhance glucocorticoid feedback in pups is mediated in part by changes in brain GR. The high circulating leptin concentrations found in developing pups might be critical to regulate glucocorticoid production, GR levels, and stress responses. As leptin levels in pups vary with maternal diet, leptin might represent an important mediator of the maternal environment on the infant.

Anti TSH-receptor antibodies in pregnant patients with autoimmune thyroid disorder.

The study was designed to test further the usefulness of the radioreceptor assay of thyroid stimulating hormone (TSH) binding inhibitory immunoglobulins (TBII) and the bioassay of thyroid stimulating antibodies (TSAb) or TSH stimulated cAMP response inhibitory antibodies (TBkAb) in the prediction of neonatal thyroid dysfunction. Of 63 pregnant women with a current or past history of autoimmune thyroid disorder, 11 (one with active and six with a past history of Graves' disease and four with autoimmune thyroiditis) gave birth to a baby with transient hyper or hypo-thyroidism. Only high maternal titres (which could persist after partial thyroidectomy) of anti TSH-receptor antibodies (TRAb) led to neonatal hyperthyroidism. Both types of assay were able to detect the antibodies responsible for transitory neonatal autoimmune thyroid disease. TBII values reflected TSAb titres so that there was a significant correlation between the results of both assays in women with Graves' disease and in neonatal sera. Positive TBII and TBkAb activities were present in 5 of the 28 women with autoimmune thyroiditis. Therefore, when TBII is positive, the functional characterization of the antibodies warrants the use of the bioassay.

Additional factors associated with plantar ulcers in diabetic neuropathy.

Patients can only examine and handle their own feet if they have adequate visual acuity and joint mobility. We therefore studied the physical capacity of patients with neuropathy to perform the preventive footcare measures previously taught. The study included three groups of diabetic outpatients, comparable for age and duration of diabetes: (1) 38 patients with neuropathic ulcers; (2) 21 patients with neuropathy, but no ulcers; (3) 30 patients without neuropathy. Visual acuity and joint mobility, expressed as minimum eye-metatarsum and heel-buttock distances, did not differ between uncomplicated neuropathic and non-neuropathic patients: visual acuity was sufficient in 95% of neuropathic patients without ulceration and in 87% of non-neuropathic patients; joint mobility was in the normal range in both groups. However, 71% of complicated neuropathic patients had insufficient visual acuity for correct foot examination, and their joint mobility was reduced compared with uncomplicated neuropathic and non-neuropathic patients.

Blocking anti-thyrotropin receptor antibodies desensitize cultured human thyroid cells.

Stimulating anti-TSH receptor antibodies (TSAb) mimic TSH in the induction of refractoriness in cultured thyroid cells; TSAb and TSH desensitize one another. We investigated whether blocking anti-TSH receptor antibodies (TBkAb) have the same desensitizing effects in cultured human thyroid cells. Prolonged exposure of cells (20 h) to TBkAb followed by antigen-antibody dissociation by an acid wash step was required to induce refractoriness to subsequent stimulation of cAMP accumulation with TSH and TSAb. Cycloheximide prevented this desensitization effect. The cAMP response to forskolin was not reduced in cells pretreated by TBkAb and was increased in cells desensitized by TSH or TSAb. The pattern of the TSH dose-response curves suggested that desensitization by TSH or TSAb involved only a postreceptor mechanism but both receptor and postreceptor phenomena in the case of TBkAb. In conclusion, like TSH or TSAb, TBkAb may induce a homologous desensitization in human thyroid cells which is not mediated by cAMP.

[Extrarenal synthesis of calcitriol in sarcoidosis]. / Synthèse extra-rénale du calcitriol dans la sarcoïdose.

Mean plasma calcitriol was significantly increased in a patient with sarcoidosis and hypercalcemia without elevation of PTH. Recent studies provided evidence for an extrarenal production of calcitriol. To investigate this possibility, the conversion of calcidiol by a sarcoid lymph node homogenate was studied. After 2-hour incubation, a product was present in the incubation, which comigrated with synthetic calcitriol on two high performance liquid chromatography systems, was detected by ultraviolet absorption spectrometry and was bound with high affinity by the chick intestinal receptor for calcitriol. These results provide further evidence for an extrarenal synthesis of calcitriol, contributing to the excessive amounts of this metabolite found in the plasma of patients with sarcoidosis.

[Transient neonatal hypothyroidism in a neonate born of a mother with Hashimoto's thyroiditis]. / Hypothyroïdie transitoire néonatale chez un nouveau-né de mère présentant une thyroïdite de Hashimoto.

Transient neonatal hypothyroidism was found in a boy whose mother was treated for hypothyroidism due to Hashimoto's thyroiditis. During the neonatal period the infant had antithyroid microsomal and antithyroglobulin antibodies and immunoglobulins inhibiting cyclic AMP production by thyroid cells in vitro. After one year of treatment, all antibodies disappeared. Thyroid scintiscan and fixation in the neonatal period was negative and became positive 2 months after stopping treatment with normal fixation and cervical thyroid picture. The mother's serum contained the same antibodies: they crossed the placental barrier and were responsible for neonatal pathological manifestations.

Adsorption of mycobacteriophages on Mycobacterium leprae: taxonomic significance.

The following bacteriophages were shown to adsorb on Mycobacterium leprae: BK1, Clark, Sedge, Baits, Watson and D29. Bacteriophages that did not adsorb on the leprosy bacilli were Bg1, Legendre, Marshall, Panetti, Leo and Wiseman. The taxonomic significance of these findings and some prospective consequences of these investigations are discussed.

[Lipidic constituents of "Mycobacterium leprae" isolated from experimentally infected armadillo (author's transl)]. / Constituants lipidiques de Mycobacterium leprae isolé de tatou infecté expérimentalement.

Mycobacterium leprae (obtained from experimentally infected armadillo) was submitted to saponification. The liposoluble part was methylated and fractionated by chromatographic methods. Each fraction was studied by gas-liquid chromatography. Cholesterol (from the infected host) and the main fatty acids were identified. Mycolic acids were isolated, and their structures determined, using mass spectrometry. These structures are useful to make a comparison of M. leprae with some other mycobacteria. Some of these comparisons are discussed here. The absence-or, at least, the very low level-of tuberculostearate suggests comparative studies of M. leprae and M. gordonae.

Paracrystalline inclusions in Mycobacterium leprae.

The occurrence of paracrystalline inclusions of Mycobacterium leprae infected with the mycobacteriophage D29 or treated with mitomycin C was reported before [5, 6]. In pursuing these studies we have now documented by electron micrography a number of paracrystals we thought sufficient to further describe these inclusions, and to show that they appeared to be formed in association with the intracellular membranous structures of the leprosy bacilli.