The gene MAPK8IP1, encoding islet-brain-1, is a candidate for type 2 diabetes.

Type 2 diabetes is a polygenic and genetically heterogeneous disease . The age of onset of the disease is usually late and environmental factors may be required to induce the complete diabetic phenotype. Susceptibility genes for diabetes have not yet been identified. Islet-brain-1 (IB1, encoded by MAPK8IP1), a novel DNA-binding transactivator of the glucose transporter GLUT2 (encoded by SLC2A2), is the homologue of the c-Jun amino-terminal kinase-interacting protein-1 (JIP-1; refs 2-5). We evaluated the role of IBi in beta-cells by expression of a MAPK8IP1 antisense RNA in a stable insulinoma beta-cell line. A 38% decrease in IB1 protein content resulted in a 49% and a 41% reduction in SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, we detected MAPK8IP1 transcripts and IBi protein in human pancreatic islets. These data establish MAPK8IP1 as a candidate gene for human diabetes. Sibpair analyses performed on i49 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. We did, however, identify in one family a missense mutation located in the coding region of MAPK8IP1 (559N) that segregated with diabetes. In vitro, this mutation was associated with an inability of IB1 to prevent apoptosis induced by MAPK/ERK kinase kinase 1 (MEKK1) and a reduced ability to counteract the inhibitory action of the activated c-JUN amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel non-maturity onset diabetes of the young (MODY) form of diabetes demonstrates that IB1 is a key regulator of 3-cell function.

Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid.

OBJECTIVES: To determine HIV-1 RNA in cerebrospinal fluid (CSF) of successfully treated patients and to evaluate if combination antiretroviral treatments with higher central nervous system penetration-effectiveness (CPE) achieve better CSF viral suppression. METHODS: Viral loads (VLs) and drug concentrations of lopinavir, atazanavir, and efavirenz were measured in plasma and CSF. The CPE was calculated using 2 different methods. RESULTS: The authors analyzed 87 CSF samples of 60 patients. In 4 CSF samples, HIV-1 RNA was detectable with 43-82 copies per milliliter. Median CPE in patients with detectable CSF VL was significantly lower compared with individuals with undetectable VL: CPE of 1.0 (range, 1.0-1.5) versus 2.3 (range, 1.0-3.5) using the method of 2008 (P = 0.011) and CPE of 6 (range, 6-8) versus 8 (range, 5-12) using the method of 2010 (P = 0.022). The extrapolated CSF trough levels for atazanavir (n = 12) were clearly above the 50% inhibitory concentration (IC50) in only 25% of samples; both patients on atazanavir/ritonavir with detectable CSF HIV-1 RNA had trough levels in the range of the presumed IC50. The extrapolated CSF trough level for lopinavir (n = 42) and efavirenz (n = 18) were above the IC50 in 98% and 78%, respectively, of samples, including the patients with detectable CSF HIV-1 RNA. CONCLUSIONS: This study suggests that treatment regimens with high intracerebral efficacy reflected by a high CPE score are essential to achieve CSF HIV-1 RNA suppression. The CPE score including all drug components was a better predictor for treatment failure in the CSF than the sole concentrations of protease inhibitor or nonnucleoside reverse transcriptase inhibitor in plasma or CSF.

Long-term safety and effectiveness of ritonavir, nelfinavir, and lopinavir/ritonavir in antiretroviral-experienced HIV-infected children.

AIM: To evaluate the long-term safety and effectiveness of ritonavir, nelfinavir, and lopinavir/ritonavir in antiretroviral-experienced, initially protease inhibitor (PI)-naive, human immunodeficiency virus (HIV)-1-infected children. METHODS: HIV-1-infected children enrolled in the Swiss Mother and Child HIV Cohort Study were eligible for this observational cohort study if they received at least 1 PI of interest between March 1996 and October 2003: ritonavir, nelfinavir, or lopinavir/ritonavir. Data regarding demographics, clinical disease and antiretroviral treatment history, HIV-1 RNA copies/mL, CD4 T-cell counts [absolute (cells/microL) and percentages (%)], adverse events, clinical laboratory values, reasons for discontinuation of PIs, and concomitant medications were extracted from the database for PI-naive (first-line) and PI-experienced (second- or higher-line) PI use. RESULTS: The total duration of ritonavir, nelfinavir, and lopinavir/ritonavir use for 133 HIV-1-infected children was 163.8, 235.0, and 46.1 patient-years, respectively. In an on-treatment analysis, first-line therapy with any of the PIs significantly reduced HIV-1 concentrations and increased CD4 T-cell counts and percentages from baseline throughout the 288-week study (P <or= 0.05) for ritonavir and nelfinavir and throughout 84 weeks of use for lopinavir/ritonavir, which was introduced into treatment more recently. All PIs investigated were most effective in PI-naive children. Thirteen PI-associated toxicities occurred requiring treatment changes or interruptions (neurologic symptoms, n = 2; pancreatitis, n = 1; allergic reactions, n = 4; visual symptoms, n = 3; and hyperlipidemia, n = 3). CONCLUSIONS: Long-term PI-based therapy seems to be safe and to result in durable virologic and immunologic effectiveness in HIV-1-infected antiretroviral-experienced children.

Pharmacogenetic Study on Risperidone Long-Acting Injection: Influence of Cytochrome P450 2D6 and Pregnane X Receptor on Risperidone Exposure and Drug-Induced Side-Effects.

Risperidone is metabolized by polymorphic enzymes, and a large variability in plasma concentration and therapeutic response is observed. Risperidone long-acting injection (RLAI) avoids the first-pass effect, and little is known about the influence of gene polymorphisms involved in its pharmacokinetics. The influence on plasma concentrations of risperidone (RIS), its metabolite 9-hydroxy-risperidone, and on adverse effects were investigated for polymorphisms of cytochrome P450 2D6 (CYP2D6) (*3, *4, *5, *6), CYP3A (CYP3A4*1B, CYP3A4 rs4646437, CYP3A5*3, CYP3A7*1C), ABCB1 (1236C>T, 2677G>T, 3435C>T), NR1/2 coding for pregnane X receptor (rs1523130, rs2472677, rs7643645), and for CYP3A activity measured by a phenotyping test. Forty-two patients with at least 4 consecutive unchanged doses of RLAI were included in a multicenter cross-sectional study. A 55% lower dose-adjusted plasma levels of RIS were observed for CYP2D6 ultrarapid metabolizers (n = 5) as compared with CYP2D6 intermediate metabolizers (P < 0.007). NR1/2 polymorphism (rs7643645A>G) influenced RIS exposure with a 2.8-fold lower active moiety (P = 0.031) in GG compared with the AA genotype. This was confirmed in a second independent cohort (n = 16). Furthermore, high-density lipoprotein cholesterol was positively correlated with CYP3A activity (P = 0.01), and the NR1/2 (rs2472677) polymorphism was associated with different adverse effects including prolactin plasma levels adjusted for age and sex. In conclusion, our results confirmed the influence of CYP2D6 genotype on plasma levels of RIS. This is the first report on the influence of NR1/2 polymorphisms on RLAI exposure and on drug-induced adverse effects. These results should be validated in larger cohorts.

Exploring the connection between the stellar wind and the non-thermal emission in LS 5039

Context.LS 5039 has been observed with several X-ray instruments so far showing quite steady emission in the long term and no signatures of accretion disk. The source also presents X-ray variability at orbital timescales in flux and photon index. The system harbors an O-type main sequence star with moderate mass-loss. At present, the link between the X-rays and the stellar wind is unclear. Aims.We study the X-ray fluxes, spectra, and absorption properties of LS 5039 at apastron and periastron passages during an epoch of enhanced stellar mass-loss, and the long term evolution of the latter in connection with the X-ray fluxes. Methods.New XMM-Newton observations were performed around periastron and apastron passages in September 2005, when the stellar wind activity was apparently higher. April 2005 Chandra observations on LS 5039 were revisited. Moreover, a compilation of H EW data obtained since 1992, from which the stellar mass-loss evolution can be approximately inferred, was carried out. Results.XMM-Newton observations show higher and harder emission around apastron than around periastron. No signatures of thermal emission or a reflection iron line indicating the presence of an accretion disk are found in the spectrum, and the hydrogen column density () is compatible with being the same in both observations and consistent with the interstellar value. 2005 Chandra observations show a hard X-ray spectrum, and possibly high fluxes, although pileup effects preclude conclusive results from being obtained. The H EW shows yearly variations of 10%, and does not seem to be correlated with X-ray fluxes obtained at similar phases, unlike what is expected in the wind accretion scenario. Conclusions.2005 XMM-Newton and Chandra observations are consistent with 2003 RXTE/PCA results, namely moderate flux and spectral variability at different orbital phases. The constancy of the seems to imply that either the X-ray emitter is located at 1012 cm from the compact object, or the density in the system is 3 to 27 times smaller than that predicted by a spherical symmetric wind model. We suggest that the multiwavelength non-thermal emission of LS 5039 is related to the observed extended radio jets and is unlikely to be produced inside the binary system.

A Novel Acute Retroviral Syndrome Severity Score Predicts the Key Surrogate Markers for HIV-1 Disease Progression.

OBJECTIVE: Best long-term practice in primary HIV-1 infection (PHI) remains unknown for the individual. A risk-based scoring system associated with surrogate markers of HIV-1 disease progression could be helpful to stratify patients with PHI at highest risk for HIV-1 disease progression. METHODS: We prospectively enrolled 290 individuals with well-documented PHI in the Zurich Primary HIV-1 Infection Study, an open-label, non-randomized, observational, single-center study. Patients could choose to undergo early antiretroviral treatment (eART) and stop it after one year of undetectable viremia, to go on with treatment indefinitely, or to defer treatment. For each patient we calculated an a priori defined "Acute Retroviral Syndrome Severity Score" (ARSSS), consisting of clinical and basic laboratory variables, ranging from zero to ten points. We used linear regression models to assess the association between ARSSS and log baseline viral load (VL), baseline CD4+ cell count, and log viral setpoint (sVL) (i.e. VL measured ≥90 days after infection or treatment interruption). RESULTS: Mean ARSSS was 2.89. CD4+ cell count at baseline was negatively correlated with ARSSS (p = 0.03, n = 289), whereas HIV-RNA levels at baseline showed a strong positive correlation with ARSSS (p<0.001, n = 290). In the regression models, a 1-point increase in the score corresponded to a 0.10 log increase in baseline VL and a CD4+cell count decline of 12/µl, respectively. In patients with PHI and not undergoing eART, higher ARSSS were significantly associated with higher sVL (p = 0.029, n = 64). In contrast, in patients undergoing eART with subsequent structured treatment interruption, no correlation was found between sVL and ARSSS (p = 0.28, n = 40). CONCLUSION: The ARSSS is a simple clinical score that correlates with the best-validated surrogate markers of HIV-1 disease progression. In regions where ART is not universally available and eART is not standard this score may help identifying patients who will profit the most from early antiretroviral therapy.

Pseudarthroses aseptiques des os longs [Pseudarthrosis of the long bones].

5 to 10% of all fractures present with a delayed union, whereas 1 to 5% progress to a nonunion, which can be defined as a fracture older than 6 months and lacks any potential to heal without any further intervention. Different fracture and patient related risk factors exist, and the management of a nonunion needs a thorough clinical, radiological and biological workup to classify them in one of the two main categories, the viable nonunions that need essentially more stability, usually by a more rigid fixation, and the non-viable nonunions that need essentially a biological stimulation by decortication and bone grafting. This treatment still remains the first choice with bony healing obtained in 85 to 95% of cases, but it also comes along with certain risks, and some valuable alternatives exist if chosen on the basis of rigid criteria.

Complete and long-lasting regression of disseminated multiple skin melanoma metastases under treatment with cyclooxygenase-2 inhibitor.

Experimental and clinical evidence indicates that non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors may have anti-cancer activities. Here we report on a patient with a metastatic melanoma of the leg who experienced a complete and sustained regression of skin metastases upon continuous single treatment with the cyclooxygenase-2 inhibitor rofecoxib. Our observations indicate that the inhibition of cyclooxygenase-2 can lead to the regression of disseminated skin melanoma metastases, even after failure of chemotherapy.

Non integrative lentiviral vactors for gene transfer in the retina

Purpose:Lentiviral vectors are among the most efficient gene transfer tools for both dividing and non dividing cells, including pigmented epithelial cells of the retina. One of the latest developments in the field, which represents a significant advance in biosafety, consists in the use of non integrative lentiviral vectors (NILVs). These newly described tools were already shown to be efficient in various tissues, such as the retina. They allow prolonged transgene expression as long as the transduced cells do not divide or divide slowly. However, they were also shown to induce transgene expression less efficiently than their integrative counterparts. Further investigations are thus needed to improve their potential. To this aim, different strategies are under evaluation. In this study, we focused on using different integrase mutations. Methods:We considered different integrase mutations, including modifications in the catalytic site and in the C-terminal domain of the enzyme. Lentiviral vectors bearing these mutant integrases and allowing expression of various transgenes were produced and characterized in vitro and in vivo. In particular, we evaluated their transgene expression capability. Influence of integrase mutation on the residual integration activity was also investigated. Results:In line with the fact that the lentiviral integrase is involved in several steps of the replication cycle of lentiviruses, we observed that integrase mutations can modify lentiviral vector features, resulting in different transduction efficiencies as well as modulation of the integration activity. Conclusions:NILVs appear as suitable tools for gene transfer in the retina, particularly to transduce RPE cells. They can be advantageously used, for instance, to develop neuroprotective strategies aimed at rescuing photoreceptors from death in various retinal diseases.

Soil phosphorus fractions in sandy soils amended with cattle manure for long periods

Phosphorus fractions were determined in soil samples from areas fertilized or not with farmyard cattle manure (FYM) and in samples of FYM used in the semi-arid region of Paraiba state, Brazil. Soil samples were taken from the 0-20; 20-40 and 40-60 cm layers of 18 cultivated areas, which, according to interviews with farmers, had been treated with 12 to 20 t ha-1 FYM annually, for the past 2 to 40 years. Soil samples were also collected from four unfertilized pasture areas as controls. Phosphorus in the soil samples was sequentially extracted with water (Pw), resin (Pres), NaHCO3 (Pi bic and Po bic), NaOH (Pi hid and Po hid), H2SO4 (Pacid) and, finally, by digestion with H2SO4/H2O2 (Presd). Nine FYM samples were extracted with water, resin, Mehlich-1, H2SO4, NaOH or digestion with H2SO4/H2O2, not sequentially, and the extracts analyzed for P. The sampled areas had homogeneous, sandy and P-deficient soils; increases in total soil P (Pt) above the mean value of the control areas (up to 274 mg kg-1 in the 0-20 cm layer of the most P-enriched samples) were therefore attributed to FYM applications, which was the only external P input in the region. Regression analysis was used to study the relationship between soil P fractions and Pt. The Pacid fraction, related to Ca-P forms, showed the greatest increases (p < 0.01) as a result of FYM applications, rising from 8.4 mg kg-1 in a non-fertilized sample to 43.8 mg kg-1 in the sample with the highest Pt content. The sum of Pw, Pres and Pi bic, considered as labile P, showed comparable increases with Pacid, while Pi hid showed the smallest increase due to FYM applications. Organic P forms also increased, more so the fraction Po hid, considered less labile, than the more labile one, Po bic. The residual P fraction was practically half of Pt, independently of the Pt value. Increases in labile P, Pacid and organic P were justified by the high average concentration of Pw (36 %), Pacid (34 %), and Po hid (30 %) in the FYM. Significant changes in the proportion of P forms among soil layers indicated the downward movement of P in organic forms.

Characterization of soil structure and porosity under long-term conventional tillage and no-tillage systems

Different management systems tend to modify soil structure and porosity over the years. The aim of this study was to study modifications in the morphostructure and porosity of dystroferric Red Latosol (Oxisol) under conventional tillage and no-tillage over a 31- year period. The study began with the description of soil profiles based on the cropping profile method, to identify the most compact structures, define sample collection points for physical and chemical analysis, and determine the water retention curve. A forest soil profile was described and used as reference. The results showed that, under conventional tillage, the microaggregate structure of the Oxisol was fragmented between 0 and 0.20 m, and compact (bulk density = 1.52 Mg m-3) in the sub-surface layer between 0.20 and 0.50 m. Under no-tillage, the structure became compacted (bulk density = 1.40 Mg m-3) between 0 and 0.60 m, but contained fissures and biopores. The volume of the class with a pore diameter of > 100 µm under no-tillage was limited, but practically non-existent in the conventional management system. On the other hand, the classes with a pore diameter of < 100 µm were not affected by the type of soil management system.

Long-term anticoagulation treatment for acute venous thromboembolism in patients with and without cancer. The SWIss Venous ThromboEmbolism Registry (SWIVTER) II.

In patients with acute cancer-associated thrombosis, current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Among 1,247 patients with acute venous thromboembolism (VTE) enrolled in the prospective Swiss Venous Thromboembolism Registry (SWIVTER) II from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, 83 (26%) prior cancer surgery, and 63 (20%) recurrent VTE. Long-term anticoagulation treatment for >12 months was more often planned in patients with versus without cancer (47% vs. 19%; p<0.001), with recurrent cancer-associated versus first cancer-associated VTE (70% vs. 41%; p<0.001), and with metastatic versus non-metastatic cancer (59% vs. 31%; p<0.001). In patients with cancer, recurrent VTE (OR 3.46; 95%CI 1.83-6.53), metastatic disease (OR 3.04; 95%CI 1.86-4.97), and the absence of an acute infection (OR 3.55; 95%CI 1.65-7.65) were independently associated with the intention to maintain anticoagulation for >12 months. In conclusion, long-term anticoagulation treatment for more than 12 months was planned in less than half of the cancer patients with acute VTE. The low rates of long-term anticoagulation in cancer patients with a first episode of VTE and in patients with non-metastatic cancer require particular attention.

Potassium availability in a hapludalf soil under long term fertilization

In a system in which fertilization is recommended, diagnosis of soil K availability and the establishment of critical levels are made difficult by the possibility of a contribution of non-exchangeable forms of K for plant nutrition. Due to its magnitude, this contribution is well diagnosed in long term experiments and in those which compare fertilization systems with positive and negative balances in terms of replacement of the K extracted by plants. The objective of this study was to evaluate K availability in a Hapludalf under fertilization for sixteen years with the addition of K doses. The study was undertaken in an experiment set up in 1991 and carried out until 2007 in the experimental area of the Soil Department of the Federal University of Santa Maria (Universidade Federal de Santa Maria - UFSM), in Santa Maria (RS), Brazil. The soil was a Typic Hapludalf submitted to four doses of K (0, 60, 120 and 180 kg ha-1 K2O) and subdivided in the second year, when 60 kg ha-1 of K2O were reapplied in the subplots in 0, 1, 2 and 3 times. As of the fifth year, the procedure was repeated. Grain yield above ground dry matter and total K content contained in the plant tissue were evaluated. Soil samples were collected, oven dried, ground, passed through a sieve and submitted to exchangeable K analysis by the Mehlich-1 extractor; non-exchangeable K by boiling HNO3 1 mol L-1 and total K by HF digestion. Potassium fertilization guidelines should foresee the establishment of a critical level as of which the recommended dose should accompany crop needs, which coincides with the quantity exported by the grain, without there being the need for the creation of broad ranges of K availability to predict K fertilization. In adopting the K fertilization recommendations proposed in this manner, there will not be K translocation in the soil profile.

Anti-TNF-alpha therapy in patients with chronic non-infectious uveitis: the experience of Jules Gonin Eye Hospital.

BACKGROUND: The purpose of this study is to describe the experience of Jules Gonin Eye Hospital on the long-term outcome of anti-TNF-alpha therapy in chronic non-infectious uveitis. PATIENTS AND METHODS: We identified and followed those patients with chronic non-infectious uveitis who received systemic anti-TNF-alpha therapy. Anti-TNF-alpha therapy was administered when no response had been obtained with classical immunosuppressive therapies or in the presence of severe rheumatoid disease. RESULTS: Fifteen patients (28 eyes), 7 male and 8 female (mean age, 43 years; range: 7 to 70 years) were identified. Diagnoses included HLA-B27-associated anterior uveitis (n = 4), sarcoidosis (n = 2), juvenile idiopathic arthritis (n = 2), idiopathic retinal vasculitis with uveitis (n = 2), pars planitis (n = 2), Adamantiades-Behçet disease (n = 1), birdshot retinochoroidopathy (n = 1), and Crohn's disease (n = 1). Mean duration of ocular disease was 8 years (range: 1 to 29 years). Treatment with infliximab (n = 11), etanercept (n = 2), or adalimumab (n = 2) was initiated. One patient with etanercept was switched to infliximab due to lack of clinical response. Clinical and angiographic regression of uveitis was observed within the first two months of therapy in all patients, and was maintained throughout the entire follow-up period (mean 18 months; range: 3 - 72 months). Recurrence was observed in 3 patients, and resolved after adjustment of therapy. Adverse events were recorded in only one patient (arterial hypotension). CONCLUSIONS: In this series of patients with chronic non-infectious uveitis, anti-TNF-alpha therapy was effective and safe. Further clinical studies are needed to determine an adequate duration of therapy.

Virtual anthropology: A comparison between the performance of conventional X-ray and MDCT in investigating the trabecular structure of long bones.

Recently, modern cross-sectional imaging techniques such as multi-detector computed tomography (MDCT) have pioneered post mortem investigations, especially in forensic medicine. Such approaches can also be used to investigate bones non-invasively for anthropological purposes. Long bones are often examined in forensic cases because they are frequently discovered and transferred to medico-legal departments for investigation. To estimate their age, the trabecular structure must be examined. This study aimed to compare the performance of MDCT with conventional X-rays to investigate the trabecular structure of long bones. Fifty-two dry bones (24 humeri and 28 femora) from anthropological collections were first examined by conventional X-ray, and then by MDCT. Trabecular structure was evaluated by seven observers (two experienced and five inexperienced in anthropology) who analyzed images obtained by radiological methods. Analyses contained the measurement of one quantitative parameter (caput diameter of humerus and femur) and staging the trabecular structure of each bone. Preciseness of each technique was indicated by describing areas of trabecular destruction and particularities of the bones, such as pathological changes. Concerning quantitative parameters, the measurements demonstrate comparable results for the MDCT and conventional X-ray techniques. In contrast, the overall inter-observer reliability of the staging was low with MDCT and conventional X-ray. Reliability increased significantly when only the results of the staging performed by the two experienced observers were compared, particularly regarding the MDCT analysis. Our results also indicate that MDCT appears to be better suited to a detailed examination of the trabecular structure. In our opinion, MDCT is an adequate tool with which to examine the trabecular structure of long bones. However, adequate methods should be developed or existing methods should be adapted to MDCT.