Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures.

Xenobiotic exposure is a risk factor in the etiology of neurodegenerative disease. It was recently hypothesized that restricted exposure during brain development could predispose for a neurodegenerative disease later in life. As neuroinflammation contributes to progressive neurodegeneration, it is suspected that neurodevelopmental xenobiotic exposure could elicit a neuroinflammatory process, which over time may assume a detrimental character. We investigated the neurotoxic effects of paraquat (PQ) in three-dimensional whole rat brain cell cultures, exposed during an early differentiation stage, comparing immediate effects-directly post exposure-with long-term effects, 20 days after interrupted PQ-administration. Adverse effects and neuroinflammatory responses were assessed by measuring changes in gene- and protein-expression as well as by determining cell morphology changes. Differentiating neural cultures were highly susceptible to PQ and showed neuronal damage and strong astrogliosis. After the 20-day washout period, neurons partially recovered, whereas astrogliosis persisted, and was accompanied by microglial activation of a neurodegenerative phenotype. Our data shows that immediate and long-term effects of subchronic PQ-exposure differ. Also, PQ-exposure during this window of extensive neuronal differentiation led to a delayed microglial activation, of a character that could promote further pro-inflammatory signals that enable prolonged inflammation, thereby fueling further neurodegeneration.

Muscarinic receptor M1 and phosphodiesterase 1 are key determinants in pulmonary vascular dysfunction following perinatal hypoxia in mice.

Perinatal adverse events such as limitation of nutrients or oxygen supply are associated with the occurrence of diseases in adulthood, like cardiovascular diseases and diabetes. We investigated the long-term effects of perinatal hypoxia on the lung circulation, with particular attention to the nitric oxide (NO)/cGMP pathway. Mice were placed under hypoxia in utero 5 days before delivery and for 5 days after birth. Pups were then bred in normoxia until adulthood. Adults born in hypoxia displayed an altered regulation of pulmonary vascular tone with higher right ventricular pressure in normoxia and increased sensitivity to acute hypoxia compared with controls. Perinatal hypoxia dramatically decreased endothelium-dependent relaxation induced by ACh in adult pulmonary arteries (PAs) but did not influence NO-mediated endothelium-independent relaxation. The M(3) muscarinic receptor was implicated in the relaxing action of ACh and M(1) muscarinic receptor (M(1)AChR) in its vasoconstrictive effects. Pirenzepine or telenzepine, two preferential inhibitors of M(1)AChR, abolished the adverse effects of perinatal hypoxia on ACh-induced relaxation. M(1)AChR mRNA expression was increased in lungs and PAs of mice born in hypoxia. The phosphodiesterase 1 (PDE1) inhibitor vinpocetine also reversed the decrease in ACh-induced relaxation following perinatal hypoxia, suggesting that M(1)AChR-mediated alteration of ACh-induced relaxation is due to the activation of calcium-dependent PDE1. Therefore, perinatal hypoxia leads to an altered pulmonary circulation in adulthood with vascular dysfunction characterized by impaired endothelium-dependent relaxation and M(1)AChR plays a predominant role. This raises the possibility that muscarinic receptors could be key determinants in pulmonary vascular diseases in relation to "perinatal imprinting."

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

METABOLIC EFFECTS OF DIETARY PROTEINS

SUMMARY :Non-alcoholic fatty liver disease (NAFLD) is characterized by an elevated intra- hepatocellular lipid (IHCL) concentration (> 5%). The incidence of NAFLD is frequently increased in obese patients, and is considered to be the hepatic component of the metabolic syndrome. The metabolic syndrome, also characterized by visceral obesity, altered glucose homeostasis, insulin resistance, dyslipidemia, and high blood pressure, represents actually a major public health burden. Both dietary factors and low physical activity are involved in the development of the metabolic syndrome. ln animals and healthy humans, high-fat or high-fructose diets lead to the development of several features of the metabolic syndrome including increased intrahepatic lipids and insulin resistance. ln contrast the effects of dietary protein are less well known, but an increase in protein intake has been suggested to exert beneficial effects by promoting weight loss and improving glucose homeostasis in insulin-resistant patients. Increased postprandial thermogenesis and enhanced satiety after protein ingestion may be both involved. The effects of dietary protein on hepatic lipids have been poorly investigated in humans, but preliminary studies in rodents have shown a reduction of hepatic lipids in carbohydrate fed rats and in obese rats. ln this context this work aimed at investigating the metabolic effects of dietary protein intake on hepatic lipid metabolism and glucose homeostasis in humans. The modulation by dietary proteins of exogenous lipid oxidation, net lipid oxidation, hepatic beta-oxidation, triglycerides concentrations, whole-body energy expenditure and glucose tolerance was assessed in the fasting state and in postprandial states. Measurements of IHCL were performed to quantify the amount of triglycerides in the liver. ln an attempt to cover all these metabolic aspects under different point of views, these questions were addressed by three protocols involving various feeding conditions. Study I addressed the effects of a 4-day hypercaloric high-fat high-protein diet on the accumulation of fat in the liver (IHCL) and on insulin sensitivity. Our findings indicated that a high protein intake significantly prevents intrahepatic fat deposition induced by a short- term hypercaloric high-fat diet, adverse effects of which are presumably modulated at the liver level.These encouraging results led us to conduct the second study (Study ll), as we were also interested in a more clinical approach to protein administration and especially if increased protein intakes might be of benefit for obese patients. Therefore the effects of one-month whey protein supplementation on IHCL, insulin sensitivity, lipid metabolism, glucose tolerance and renal function were assessed in obese women. Results showed that whey protein supplementation reduces hepatic steatosis and improves the plasma lipid profile in obese patients, without adverse effects on glucose tolerance or creatinine clearance. However since patients were fed ud-libitum, it remains possible that spontaneous carbohydrate and fat intakes were reduced due to the satiating effects of protein. The third study (Study lll) was designed in an attempt to deepen our comprehension about the mechanisms involved in the modulation of IHCL. We hypothesized that protein improved lipid metabolism and, therefore, we evaluated the effects of a high protein meal on postprandial lipid metabolism and glucose homeostasis after 4-day on a control or a protein diet. Our results did not sustain the hypothesis of an increased postprandial net lipid oxidation, hepatic beta oxidation and exogenous lipid oxidation. Four days on a high-protein diet rather decreased exogenous fat oxidation and enhanced postprandial triglyceride concentrations, by impairing probably chylomicron-TG clearance. Altogether the results of these three studies suggest a beneficial effect of protein intake on the reduction in lHCL, and clearly show that supplementation of proteins do not reduce IHCL by stimulating lipid metabolism, e.g. whole body fat oxidation, hepatic beta oxidation, or exogenous fat oxidation. The question of the effects of high-protein intakes on hepatic lipid metabolism is still open and will need further investigation to be elucidated. The effects of protein on increased postprandial lipemia and lipoproteins kinetics have been little investigated so far and might therefore be an interesting research question, considering the tight relationship between an elevation of plasmatic TG concentrations and the increased incidence of cardiovascular diseases.Résumé :La stéatose hépatique non alcoolique se caractérise par un taux de lipides intra-hépatiques élevé, supérieur à 5%. L'incidence de la stéatose hépatique est fortement augmentée chez les personnes obèses, ce qui mène à la définir comme étant la composante hépatique du syndrome métabolique. Ce syndrome se définit aussi par d'autres critères tels qu'obésité viscérale, altération de l'homéostasie du glucose, résistance à l'insuline, dyslipidémie et pression artérielle élevée. Le syndrome métabolique est actuellement un problème de santé publique majeur.Tant une alimentation trop riche et déséquilibrée, qu'une faible activité physique, semblent être des causes pouvant expliquer le développement de ce syndrome. Chez l'animal et le volontaire sain, des alimentations enrichies en graisses ou en sucres (fructose) favorisent le développement de facteurs associés au syndrome métabolique, notamment en augmentant le taux de lipides intra-hépatiques et en induisant le développement d'une résistance à l'insuline. Par ailleurs, les effets des protéines alimentaires sont nettement moins bien connus, mais il semblerait qu'une augmentation de l'apport en protéines soit bénéfique, favorisant la perte de poids et l'homéostasie du glucose chez des patients insulino-résistants. Une augmentation de la thermogenese postprandiale ainsi que du sentiment de satiété pourraient en être à l'origine.Les effets des protéines sur les lipides intra-hépatiques chez l'homme demeurent inconnus à ce jour, cependant des études préliminaires chez les rongeurs tendent à démontrer une diminution des lipides intra hépatiques chez des rats nourris avec une alimentation riche en sucres ou chez des rats obèses.Dans un tel contexte de recherche, ce travail s'est intéressé à l'étude des effets métaboliques des protéines alimentaires sur le métabolisme lipidique du foie et sur l'homéostasie du glucose. Ce travail propose d'évaluer l'effet des protéines alimentaires sur différentes voies métaboliques impliquant graisses et sucres, en ciblant d'une part les voies de l'oxydation des graisses exogènes, de la beta-oxydation hépatique et de l'oxydation nette des lipides, et d'autre part la dépense énergétique globale et l'évolution des concentrations sanguines des triglycérides, à jeun et en régime postprandial. Des mesures des lipides intra-hépatiques ont aussi été effectuées pour permettre la quantification des graisses déposées dans le foie.Dans le but de couvrir l'ensemble de ces aspects métaboliques sous différents angles de recherche, trois protocoles, impliquant des conditions alimentaires différentes, ont été entrepris pour tenter de répondre à ces questions. La première étude (Etude I) s'est intéressée aux effets d'u.ne suralimentation de 4 jours enrichie en graisses et protéines sur la sensibilité à l'insuline et sur l'accumulation de graisses intra-hépatiques. Les résultats ont démontré que l'apport en protéines prévient l'accumulation de graisses intra-hépatiques induite par une suralimentation riche en graisses de courte durée ainsi que ses effets délétères probablement par le biais de mécanismes agissant au niveau du foie. Ces résultats encourageants nous ont conduits à entreprendre une seconde étude (Etude ll) qui s'intéressait à l'implication clinique et aux bénéfices que pouvait avoir une supplémentation en protéines sur les graisses hépatiques de patients obèses. Ainsi nous avons évalué pendant un mois de supplémentation l'effet de protéines de lactosérum sur le taux de graisses intrahépatiques, la sensibilité à l'insuline, la tolérance au glucose, le métabolisme des graisses et la fonction rénale chez des femmes obèses. Les résultats ont été encourageants; la supplémentation en lactosérum améliore la stéatose hépatique, le profil lipidique des patientes obèses sans pour autant altérer la tolérance au glucose ou la clairance de la créatinine. L'effet satiétogene des protéines pourrait aussi avoir contribué à renforcer ces effets. La troisième étude s'est intéressée aux mécanismes qui sous-tendent les effets bénéfiques des protéines observés dans les 2 études précédentes. Nous avons supposé que les protéines devaient favoriser le métabolisme des graisses. Par conséquent, nous avons cherché a évaluer les effets d'un repas riche en protéines sur la lipémie postprandiale et l'homéostasie glucidique après 4 jours d'alimentation contrôlée soit isocalorique et équilibrée, soit hypercalorique enrichie en protéines. Les résultats obtenus n'ont pas vérifié l'hypothèse initiale ; ni une augmentation de l'oxydation nette des lipides, ni celle d'une augmentation de la béta-oxydation hépatique ou de l'oxydation d'un apport exogène de graisses n'a pu étre observée. A contrario, il semblerait même plutôt que 4 jours d'a]irnentation hyperprotéinée inhibent le métabolisme des graisses et augmente les concentrations sanguines de triglycérides, probablement par le biais d'une clairance de chylornicrons altérée. Globalement, les résultats de ces trois études nous permettent d'attester que les protéines exercent un effet bénéfique en prévenant le dépot de graisses intra-hépatiques et montrent que cet effet ne peut être attribué à une stimulation du métabolisme des lipides via l'augmentation des oxydations des graisses soit totales, hépatiques, ou exogènes. La question demeure en suspens à ce jour et nécessite de diriger la recherche vers d'autres voies d'exploration. Les effets des protéines sur la lipémie postprandiale et sur le cinétique des lipoprotéines n'a que peu été traitée à ce jour. Cette question me paraît néanmoins importante, sachant que des concentrations sanguines élevées de triglycérides sont étroitement corrélées à une incidence augmentée de facteurs de risque cardiovasculaire.

Ätiologie und Management der Gicht [The etiology and management of gout].

Gout is an inflammatory arthritis caused by monosodium urate (MSU) crystal deposits in and around the joint. The formation of urinary calculi can also occur in gout, but are less common than arthritis. Gout usually presents with recurrent episodes of joint inflammation, which over time lead to tophus formation and joint destruction. In the last decade, significant advances have been made regarding not only the epidemiology and genetics of gout and hyperuricemia but also the mechanisms of inflammation and treatment of gout. In addition, knowledge concerning the key role of interleukin 1 (IL-1) has provided new therapeutic perspectives. However, the current management of gout is often suboptimal, with many Patienten either not receiving adequate treatment or being unable to tolerate existing treatments. New therapeutic agents provide interesting new options for Patienten with difficult-to-treat gouty arthritis.The English full-text version of this is available at SpringerLink (under "Supplemental").

One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation.

No consensus exists on whether acyclovir prophylaxis should be given for varicella-zoster virus (VZV) prophylaxis after hematopoietic cell transplantation because of the concern of "rebound" VZV disease after discontinuation of prophylaxis. To determine whether rebound VZV disease is an important clinical problem and whether prolonging prophylaxis beyond 1 year is beneficial, we examined 3 sequential cohorts receiving acyclovir from day of transplantation until engraftment for prevention of herpes simplex virus reactivation (n = 932); acyclovir or valacyclovir 1 year (n = 1117); or acyclovir/valacyclovir for at least 1 year or longer if patients remained on immunosuppressive drugs (n = 586). In multivariable statistical models, prophylaxis given for 1 year significantly reduced VZV disease (P < .001) without evidence of rebound VZV disease. Continuation of prophylaxis beyond 1 year in allogeneic recipients who remained on immunosuppressive drugs led to a further reduction in VZV disease (P = .01) but VZV disease developed in 6.1% during the second year while receiving this strategy. In conclusion, acyclovir/valacyclovir prophylaxis given for 1 year led to a persistent benefit after drug discontinuation and no evidence of a rebound effect. To effectively prevent VZV disease in long-term hematopoietic cell transplantation survivors, additional approaches such as vaccination will probably be required.

A multicenter, cross-sectional study on the prevalence and risk factors for nasal colonization with Staphylococcus aureus in patients admitted to children's hospitals in Switzerland.

The rate of nasal carriage of Staphylococcus aureus and associated risk factors were determined in a cross-sectional study involving Swiss children's hospitals. S. aureus was isolated in 562 of 1363 cases. In a stepwise multivariate analysis, the variables age, duration of antibiotic use, and hospitalization of a household member were independently associated with carriage of S. aureus.

Gériatrie [Review in geriatric medicine 2011].

In 2011, new tools to evaluate life expectancy are available. Controversy about PSA-based screening for prostate cancer is still going on, with new data from the US Preventive services task force. A brief behavioral treatment for insomnia can be efficient and durable. Gliptines are be useful to avoid treatment-induced hypoglycemia in diabetic patients. New Alzheimer diagnostic criteria, including biomarkers, have been published.

Behavior of nuclear matrix proteins during camptothecin-induced apoptosis in HL-60 human leukemia cells.

In this study we focused our attention on the behavior of four nuclear matrix proteins during the various stages of apoptosis in the HL-60 cell line exposed to the DNA topoisomerase I inhibitor, camptothecin. We have examined the following antigens by immunocytochemical techniques: (i) the 180-kDa nucleolar isoform of DNA topoisomerase II; (ii) a 126-kDa polypeptide of nuclear bodies; (iii) a 125-kDa protein; and (iv) a 160-kDa polypeptide which are known to be components of the matrix inner network. Indirect immunofluorescence experiments were performed to follow these nuclear matrix antigens during apoptosis. Moreover, the ultrastructural localization of both 125- and 160-kDa proteins was investigated by electron microscope immunocytochemistry with gold-conjugated secondary antibodies. While the antibody to the nucleolar isoform of DNA topoisomerase II gave a fluorescent pattern that was well-maintained until the late phases of apoptosis, the other three nuclear antigens showed marked modifications in their distribution. A common feature, particularly evident for 125- and 160-kDa proteins, was their absence from cap-shaped chromatin marginations, whereas they were present in the areas of remaining decondensed chromatin. The 126-kDa polypeptide concentrated progressively in an irregular mass at the opposite side of the crescentic caps and then broke up in fine spots. The 125- and 160-kDa proteins localized in the nucleolus and precisely within certain granules which are known to appear in the nucleolar area after camptothecin administration. These results show that, in addition to the well-known chromatin changes, nuclear organization undergoes other rearrangements during the apoptotic process.

Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis.

BACKGROUND: Interleukin-1 is pivotal in the pathogenesis of systemic juvenile idiopathic arthritis (JIA). We assessed the efficacy and safety of canakinumab, a selective, fully human, anti-interleukin-1β monoclonal antibody, in two trials. METHODS: In trial 1, we randomly assigned patients, 2 to 19 years of age, with systemic JIA and active systemic features (fever; ≥2 active joints; C-reactive protein, >30 mg per liter; and glucocorticoid dose, ≤1.0 mg per kilogram of body weight per day), in a double-blind fashion, to a single subcutaneous dose of canakinumab (4 mg per kilogram) or placebo. The primary outcome, termed adapted JIA ACR 30 response, was defined as improvement of 30% or more in at least three of the six core criteria for JIA, worsening of more than 30% in no more than one of the criteria, and resolution of fever. In trial 2, after 32 weeks of open-label treatment with canakinumab, patients who had a response and underwent glucocorticoid tapering were randomly assigned to continued treatment with canakinumab or to placebo. The primary outcome was time to flare of systemic JIA. RESULTS: At day 15 in trial 1, more patients in the canakinumab group had an adapted JIA ACR 30 response (36 of 43 [84%], vs. 4 of 41 [10%] in the placebo group; P<0.001). In trial 2, among the 100 patients (of 177 in the open-label phase) who underwent randomization in the withdrawal phase, the risk of flare was lower among patients who continued to receive canakinumab than among those who were switched to placebo (74% of patients in the canakinumab group had no flare, vs. 25% in the placebo group, according to Kaplan-Meier estimates; hazard ratio, 0.36; P=0.003). The average glucocorticoid dose was reduced from 0.34 to 0.05 mg per kilogram per day, and glucocorticoids were discontinued in 42 of 128 patients (33%). The macrophage activation syndrome occurred in 7 patients; infections were more frequent with canakinumab than with placebo. CONCLUSIONS: These two phase 3 studies show the efficacy of canakinumab in systemic JIA with active systemic features. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT00889863 and NCT00886769.).

A phase I pharmacokinetic study of hypoxic abdominal stop-flow perfusion with gemcitabine in patients with advanced pancreatic cancer and refractory malignant ascites

PURPOSE: As no curative treatment for advanced pancreatic and biliary cancer with malignant ascites exists, new modalities possibly improving the response to available chemotherapies must be explored. This phase I study assesses the feasibility, tolerability and pharmacokinetics of a regional treatment of gemcitabine administered in escalating doses by the stop-flow approach to patients with advanced abdominal malignancies (adenocarcinoma of the pancreas, n = 8, and cholangiocarcinoma of the liver, n = 1). EXPERIMENTAL DESIGN: Gemcitabine at 500, 750 and 1,125 mg/m(2) was administered to three patients at each dose level by loco-regional chemotherapy, using hypoxic abdominal stop-flow perfusion. This was achieved by an aorto-caval occlusion by balloon catheters connected to an extracorporeal circuit. Gemcitabine and its main metabolite 2',2'-difluorodeoxyuridine (dFdU) concentrations were measured by high performance liquid chromatography with UV detection in the extracorporeal circuit during the 20 min of stop-flow perfusion, and in peripheral plasma for 420 min. Blood gases were monitored during the stop-flow perfusion and hypoxia was considered stringent if two of the following endpoints were met: pH </= 7.2, pO(2) nadir ratio </=0.70 or pCO(2) peak ratio >/=1.35. The tolerability of this procedure was also assessed. RESULTS: Stringent hypoxia was achieved in four patients. Very high levels of gemcitabine were rapidly reached in the extracorporeal circuit during the 20 min of stop-flow perfusion, with C (max) levels in the abdominal circuit of 246 (+/-37%), 2,039 (+/-77%) and 4,780 (+/-7.3%) mug/ml for the three dose levels 500, 750 and 1,125 mg/m(2), respectively. These C (max) were between 13 (+/-51%) and 290 (+/-12%) times higher than those measured in the peripheral plasma. Similarly, the abdominal exposure to gemcitabine, calculated as AUC(t0-20), was between 5.5 (+/-43%) and 200 (+/-66%)-fold higher than the systemic exposure. Loco-regional exposure to gemcitabine was statistically higher in presence of stringent hypoxia (P < 0.01 for C (max) and AUC(t0-20), both normalised to the gemcitabine dose). Toxicities were acceptable considering the complexity of the procedure and were mostly hepatic; it was not possible to differentiate the respective contributions of systemic and regional exposures. A significant correlation (P < 0.05) was found between systemic C (max) of gemcitabine and the nadir of both leucocytes and neutrophils. CONCLUSIONS: Regional exposure to gemcitabine-the current standard drug for advanced adenocarcinoma of the pancreas-can be markedly enhanced using an optimised hypoxic stop-flow perfusion technique, with acceptable toxicities up to a dose of 1,125 mg/m(2). However, the activity of gemcitabine under hypoxic conditions is not as firmly established as that of other drugs such as mitomycin C, melphalan or tirapazamine. Further studies of this investigational modality, but with bioreductive drugs, are therefore warranted first to evaluate the tolerance in a phase I study and later on to assess whether it does improve the response to chemotherapy.

Official Positions for FRAX® clinical regarding rheumatoid arthritis from Joint Official Positions Development Conference of the International Society for Clinical Densitometry and International Osteoporosis Foundation on FRAX®.

Rheumatoid arthritis is the only secondary cause of osteoporosis that is considered independent of bone density in the FRAX(®) algorithm. Although input for rheumatoid arthritis in FRAX(®) is a dichotomous variable, intuitively, one would expect that more severe or active disease would be associated with a greater risk for fracture. We reviewed the literature to determine if specific disease parameters or medication use could be used to better characterize fracture risk in individuals with rheumatoid arthritis. Although many studies document a correlation between various parameters of disease activity or severity and decreased bone density, fewer have associated these variables with fracture risk. We reviewed these studies in detail and concluded that disability measures such as HAQ (Health Assessment Questionnaire) and functional class do correlate with clinical fractures but not morphometric vertebral fractures. One large study found a strong correlation with duration of disease and fracture risk but additional studies are needed to confirm this. There was little evidence to correlate other measures of disease such as DAS (disease activity score), VAS (visual analogue scale), acute phase reactants, use of non-glucocorticoid medications and increased fracture risk. We concluded that FRAX(®) calculations may underestimate fracture probability in patients with impaired functional status from rheumatoid arthritis but that this could not be quantified at this time. At this time, other disease measures cannot be used for fracture prediction. However only a few, mostly small studies addressed other disease parameters and further research is needed. Additional questions for future research are suggested.

Schizophrénie, diabète et nouveaux neuroleptiques [Schizophrenia, diabetes and new neuroleptics].

Diabetes mellitus occurs more frequently in schizophrenic patients. The use of a novel antipsychotic drug seems to be concomitant to a further increase in imbalance of blood glucose homeostasis. Such cases have already been reported in the literature indicating that diabetes mellitus might be a real side effect of this novel class of neuroleptics. In conclusion, it seems that schizophrenic patients under such treatment would greatly benefit from a closer clinical and biological follow up regarding glucose metabolism. Further randomised studies would be needed.