Atteinte osseuse axiale de la sarcoïdose.

INTRODUCTION: Sarcoidosis is a multi-systemic disease characterized by non-caseating granulomas. Bone involvement initially considered as rare and described as a peripheral osteitis of the hands and feet, has recently been reported on the axial skeleton. CASE REPORTS: We report 4 clinical observations of sarcoidosis (3 women, 1 man) with axial bone involvement located to the spine (n = 4), pelvic bone (n = 2), scapular bone (n = 2), sternum (n = 1), mandible (n = 1). Sarcoidosis was already diagnosed in 3 cases. Bone pain was the main symptom, related in 3 cases. Magnetic resonance imaging appeared to be the best imaging test Histological bone analysis revealed typical granulomatous lesions (n = 2). Treatment included corticosteroids (n = 4), hydroxychloroquine (n = 2), and methotrexate (n = 2), with a good efficacy on bone pain in symptomatic patients. CONCLUSION: These 4 cases, as well as recent literature, illustrate bone involvement of sarcoidosis on the axial skeleton. It is symptomatic in around 50% of cases but may be a source of significant disability. Differential diagnosis with neoplasm may require bone histological analysis. This condition appears to be responsive to usual treatments for sarcoidosis.

Severe acute pancreatitis in a child with phenylketonuria.

We report for the first time severe acute pancreatitis in a child treated for phenylketonuria (PKU) discovered on neonatal screening. This 2-year-old boy was first hospitalized for bilious vomiting and moderate back pain. Laboratory values included a lipase level of 1.142 U/L, a phenylalanine level of 10mg/dL, and computed tomography revealed Balthazar grade E pancreatitis. Continuous enteral feeding was started on the 3rd day after admission. We observed clinical and biological improvement. Etiologic investigations for pancreatitis returned negative. Despite the severity of the pancreatitis, we did not observe decompensation of the metabolic disease. Specific nutritional management was necessary.

IL-15 improves skeletal muscle oxidative metabolism and glucose uptake in association with increased respiratory chain supercomplex formation and AMPK pathway activation.

BACKGROUND: IL-15 is believed to play a role in the beneficial impact of exercise on muscle energy metabolism. However, previous studies have generally used supraphysiological levels of IL-15 that do not represent contraction-induced IL-15 secretion. METHODS: L6 myotubes were treated acutely (3 h) and chronically (48 h) with concentrations of IL-15 mimicking circulating (1-10 pg/ml) and muscle interstitial (100 pg/ml -20 ng/ml) IL-15 levels with the aim to better understand its autocrine/paracrine role on muscle glucose uptake and mitochondrial function. RESULTS: Acute exposure to IL-15 levels representing muscle interstitial IL-15 increased basal glucose uptake without affecting insulin sensitivity. This was accompanied by increased mitochondrial oxidative functions in association with increased AMPK pathway and formation of complex III-containing supercomplexes. Conversely, chronic IL-15 exposure resulted in a biphasic effect on mitochondrial oxidative functions and ETC supercomplex formation was increased with low IL-15 levels but decreased with higher IL-15 concentrations. The AMPK pathway was activated only by high levels of chronic IL-15 treatment. Similar results were obtained in skeletal muscle from muscle-specific IL-15 overexpressing mice that show very high circulating IL-15 levels. CONCLUSIONS: Acute IL-15 treatment that mimics local IL-15 concentrations enhances muscle glucose uptake and mitochondrial oxidative functions. That mitochondria respond differently to different levels of IL-15 during chronic treatments indicates that IL-15 might activate two different pathways in muscle depending on IL-15 concentrations. GENERAL SIGNIFICANCE: Our results suggest that IL-15 may act in an autocrine/paracrine fashion and be, at least in part, involved in the positive effect of exercise on muscle energy metabolism.

[Eosinophilia heralding the diagnosis of eosinophilic fasciitis (Shulman's disease)]. / Hyperéosinophilie isolée précédant le diagnostic d'une fasciite à éosinophiles (maladie de Shulman).

INTRODUCTION: Eosinophilic fasciitis or Shulman's disease is characterized, in its typical form, by palpable thickening of the skin and soft tissues, blood hypereosinophilia and fascia lesions. We hereby report a case of eosinophilic fasciitis in which hypereosinophilia preceded for several months the clinical signs of fasciitis. CASE REPORT: A 64-year-old woman, with a history of Little's syndrome with motor disability, was admitted in internal medicine for eosinophilia. For almost three months, no origin to the eosinophilia was found. The secondary onset of an edema and pain located on four limbs led to the diagnosis of eosinophilic fasciitis. Muscle magnetic resonance imaging was supportive and the muscle histological analysis confirmed the diagnosis of eosinophilic fasciitis. Treatment with steroids induced a rapid normalization of the eosinophilia and edema. CONCLUSION: In this case report, eosinophilia was preceding the clinical cutaneous signs that led to the diagnosis of eosinophilic fasciitis. It is likely to believe that myalgias, frequently found in the onset of eosinophilic fasciitis, may have been hidden by the history of infantile encephalopathy. The diagnosis of eosinophilic fasciitis must be kept in mind of physicians in the investigation of an eosinophilia, even though cutaneous signs are lacking.

Neonatal outcomes following planned preterm delivery in diabetic mothers.

OBJECTIVE: Women with diabetes may need elective preterm delivery due to pregnancy or diabetes related complications. The aim of this study was to describe the neonatal outcomes arising from elective preterm delivery in diabetic women. METHOD: Suitable patients were identified by the obstetric team at Hull Royal Infirmary Women and Children's Hospital and data was extracted from their case notes. 45 diabetic women with planned preterm delivery were identified within a set time frame, resulting in 48 babies. RESULTS: Of the 48 babies born, 47 survived. 36 out of 48 were delivered via caesarean section. Gestational ages ranged from 29+3 to 36+6 weeks, and 24 out of 48 (50%) had a birth weight greater than the 90th centile for gestational age.34 out of the 48 babies experienced some form of neonatal complication and were admitted to the neonatal unit. The median duration of stay in the neonatal unit was 7 days. 14 of the surviving neonates suffered from respiratory distress, although only 4 required surfactant therapy to regain respiratory function. However, the incidence of serious neonatal complications in those born after 34 weeks was shown to be low. CONCLUSIONS: Elective preterm delivery after 34 weeks had little effect on overall neonatal outcome. Therefore it could be proposed that elective preterm delivery after 34 weeks gestation may be an acceptable option in diabetic women if there are maternal or obstetric complications.

High added-value products from the hydrothermal carbonisation of olive stones.

Olive stones (OS) were submitted to hydrothermal carbonisation (HTC) in order to evaluate the possibility of producing high added-value products, mainly furfural (FU) and 5-hydroxymethylfurfural (5-HMF) on one hand and hydrochars and carbons on the other hand. Temperature (160-240 °C), residence time (1-8 h), initial pH (1-5.5) and liquid/solid ratio (4-48 w/w) were systematically varied in order to study the main products and to optimise FU production. FU production yield up to 19.9 %, based on the hemicellulose content, was obtained. Other minor, but valuable, compounds such as 5-methylfurfural (5-MF) and some phenolic compounds were also produced. The hydrochar was carbonised at 900 °C, and the resultant carbon material was highly ultramicroporous with a peak of pore size distribution centred on 0.5 nm and a surface area as high as 1065 m2 g-1, typical of most carbon molecular sieves.

Integration of Physiologically-Based Pharmacokinetic Modeling into Early Clinical Development: An Investigation of the Pharmacokinetic Nonlinearity.

BMS-911543, a promising anticancer agent, exhibited time-dependent and dose-dependent nonlinear pharmacokinetics (PKs) in its first-in-human (FIH) study. Initial physiologically based pharmacokinetic (PBPK) modeling efforts using CYP1A2-mediated clearance kinetics were unsuccessful; however, further model analysis revealed that CYP1A2 time-dependent inhibition (TDI) and perhaps other factors could be keys to the nonlinearity. Subsequent experiments in human liver microsomes showed that the compound was a time-dependent inhibitor of CYP1A2 and were used to determine the enzyme inactivation parameter values. In addition, a rat tissue distribution study was conducted and human plasma samples were profiled to support the refinement of the PBPK model. It was concluded that the interplay between four BMS-911543 properties, namely, low solubility, saturation of the metabolizing enzyme CYP1A2, CYP1A2 TDI, and CYP1A2 induction likely resulted in the time-dependent and dose-dependent nonlinear PKs. The methodology of PBPK model-guided unmasking of compound properties can serve as a general practice for mechanistic understanding of a new compound's disposition.

O-GlcNAc modification, insulin signaling and diabetic complications.

O-GlcNAc glycosylation (O-GlcNAcylation) corresponds to the addition of N-acetylglucosamine on serine and threonine residues of cytosolic and nuclear proteins. O-GlcNAcylation is a dynamic post-translational modification, analogous to phosphorylation, that regulates the stability, the activity or the subcellular localisation of target proteins. This reversible modification depends on the availability of glucose and therefore constitutes a powerful mechanism by which cellular activities are regulated according to the nutritional environment of the cell. O-GlcNAcylation has been implicated in important human pathologies including Alzheimer disease and type-2 diabetes. Only two enzymes, OGT and O-GlcNAcase, control the O-GlcNAc level on proteins. Therefore, O-GlcNAcylations cannot organize in signaling cascades as observed for phosphorylations. O-GlcNAcylations should rather be considered as a "rheostat" that controls the intensity of the signals traveling through different pathways according to the nutritional status of the cell. Thus, OGT attenuates insulin signal by O-GlcNAcylation of proteins involved in proximal and distal steps in the PI-3 kinase signaling pathway. This negative feedback may be exacerbated when cells are chronically exposed to elevated glucose concentrations and could thereby contribute to alterations in insulin signaling observed in diabetic patients. O-GlcNAcylation also appears to contribute to the deleterious effects of hyperglycaemia on excessive glucose production by the liver and deterioration of ß-cell pancreatic function, resulting in worsening of hyperglycaemia (glucotoxicity). Moreover, O-GlcNAcylations directly participate in several diabetic complications. O-GlcNAcylation of eNOS in endothelial cells have been involved in micro- and macrovascular complications. In addition, O-GlcNAcylations activate the expression of profibrotic and antifibrinolytic factors, contributing to vascular and renal dysfunctions.

Randomised controlled trial of the use of three dressing preparations in the management of chronic ulceration of the foot in diabetes.

OBJECTIVES: To determine the comparative effectiveness and cost-effectiveness of three dressing products, N-A, Inadine and Aquacel, for patients with diabetic foot ulcers, as well as the feasibility and consequences of less frequent dressing changes by health-care professionals. DESIGN: A multicentre, prospective, observer-blinded, parallel group, randomised controlled trial, with three arms. SETTING: Established expert multidisciplinary clinics for the management of diabetic foot ulcers across the UK. PARTICIPANTS: Patients over age 18 with type 1 or type 2 diabetes with a chronic (present for at least 6 weeks) full-thickness foot ulcer (on or below the malleoli) not penetrating to tendon, periosteum or bone, and with a cross-sectional area between 25 and 2500 mm(2). INTERVENTIONS: Participants were randomised 1:1:1 to treatment with one of N-A (a non-adherent, knitted, viscose filament gauze), Inadine (an iodine-impregnated dressing), both traditional dressings, or Aquacel, a newer product. MAIN OUTCOME MEASURES: The primary outcome measure was the number of ulcers healed in each group at week 24. Secondary measures included time to healing, new ulcerations, major and minor amputations, and episodes of secondary infection. RESULTS: A total of 317 patients were randomised. After 88 withdrawals, 229 remained evaluable. A greater proportion of smaller (25-100 mm(2) ulcers healed within the specified time (48.3% versus 37.3%; p = 0.048). There was, however, no difference between the three dressings in terms of percentage healed by 24 weeks, or in the mean time to healing, whether analysed on the basis of intention to treat (Inadine 44.4%, N-A 38.7%, Aquacel 44.7%; not significant) or per protocol (Inadine 55.2%, N-A 59.4%, Aquacel 63.0%; not significant). There was no difference in the quality of healing, as reflected in the incidence of recurrence within 12 weeks. Likewise, there was no difference in the incidence of adverse events, although a greater proportion of those randomised to the non-adherent dressings were withdrawn from the study (34.9% versus 29.1% Aquacel and 19.4% Inadine; p = 0.038). The only statistically significant difference found in the health economic analysis was the cost associated with the provision of dressings (mean cost per patient: N-A 14.85 pounds, Inadine 17.48 pounds, Aquacel 43.60 pounds). The higher cost of Aquacel was not offset by the fewer dressings required. There was no difference in measures of either generic or condition-specific measures of quality of life. However, there was a significant difference in the change in pain associated with dressing changes between the first and second visits, with least pain reported by those receiving non-adherent dressings (p = 0.012). There was no difference in the costs of professional time, and this may relate to the number of dressing changes undertaken by non-professionals. Fifty-one per cent of all participants had at least one dressing change undertaken by themselves or a non-professional carer, although this ranged from 22% to 82% between the different centres. CONCLUSIONS: As there was no difference in effectiveness, there is no reason why the least costly of the three dressings could not be used more widely across the UK National Health Service, thus generating potentially substantial savings. The option of involving patients and non-professional carers in changing dressings needs to be assessed more formally and could be associated with further significant reductions in health-care costs. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78366977.

Copy number variations in chronic pancreatitis.

In 1996, shortly after a locus for hereditary pancreatitis had been mapped to chromosome 7q35, an apparent gain-of-function missense mutation, p.R122H, in the cationic trypsinogen gene (PRSS1) was identified. Thereafter, the search for chronic pancreatitis-associated genetic factors has been largely focused on one form of genetic variation, namely, single nucleotide substitutions (SNSs). Only very recently has another type of genetic variation - copy number variations (CNVs) - been found to cause the disease. First, we identified duplication and triplication of an approximately 605 kb segment on chromosome 7q35 in French white patients with hereditary or idiopathic chronic pancreatitis. These alterations increased the copy number of PRSS1 as well as PRSS2, which encodes anionic trypsinogen. Second, we characterized a hybrid trypsinogen gene, in which exons 1 and 2 were derived from PRSS2 and exons 3 to 5 from PRSS1. Interestingly, this hybrid gene had two independent gain-of-function effects: increased trypsinogen gene copy number and it contained the p.N29I pancreatitis-causing missense mutation. Lastly, we identified two loss-of-function copy number mutations (deletions) in the SPINK1 gene, which encodes pancreatic secretory trypsin inhibitor (PSTI). Particularly, in one family with chronic pancreatitis, deletion of the complete SPINK1 gene was co-inherited with a CFTR missense mutation (p.L997F), revealing another layer of complexity between CNV and SNS interactions in the determination of a given disease phenotype. These findings represent a further demonstration of how studies of CNVs have altered the landscape of genetic research in the past few years and offer a fresh glimpse into the exciting realm of human CNVs.

Comparison of two methods of measuring wood pyrolysis tar.

Two methods for the sampling and analysis of tar produced from wood pyrolysis were compared. The first method used a conventional cold-trapping technique in solvent-filled impingers followed by liquid injection. The second one is a new application of multibed solid-phase adsorbent (SPA) tubes followed by thermal desorption (TD). Both methods are based on gas chromatography (GC) coupled with mass spectrometry (MS). Quantification was performed with a well reproducible GC-MS method with three internal deuterated standards. The SPA/TD method offers several advantages. No solvent is required, the detection levels are improved, and gas chromatography separation is easier. Moreover, sampling time is reduced from about 1h (for the conventional cold-trapping technique in impingers) to a few seconds. No discrimination was observed between the two sampling methods for the 10 quantified compounds (aromatic compounds from benzene to phenanthrene and phenols) except for benzene.

A phase IB, open-label dose-escalating study of the oral angiogenesis inhibitor PTK787/ZK 222584 (PTK/ZK), in combination with FOLFOX4 chemotherapy in patients with advanced colorectal cancer.

BACKGROUND: This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity. PATIENTS AND METHODS: Thirty-five patients received escalating doses of PTK/ZK (range 500-2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage. RESULTS: Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months. CONCLUSION: The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions.