Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.

Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.

Induction of macrophage nitric oxide production by interferon-gamma and tumor necrosis factor-alpha is enhanced by interleukin-10.

Interleukin-10 (IL-10) has been reported to inhibit nitric oxide (NO) synthesis and microbicidal activity of interferon-gamma (IFN-gamma)-stimulated macrophages (M phi) by preventing the secretion of tumor necrosis factor-alpha (TNF-alpha) which serves as an autocrine activating signal. We have examined the effects of recombinant IL-10 on the capacity of IFN-gamma together with exogenous TNF-alpha to induce NO synthesis by bone marrow-derived M phi. Under these conditions and in contrast to its reported deactivating potential, IL-10 strongly enhanced NO synthesis measured as nitrite (NO2-) release (half maximal stimulation at approximately 10 U/ml). IL-10 further increased NO2- production by M phi stimulated in the presence of optimal concentrations of prostaglandin E2, a positive modulator of M phi activation by IFN-gamma/TNF-alpha. Increased steady state levels of NO synthase mRNA were observed in 4-h IFN-gamma/TNF-alpha cultures and enhanced NO2(-)-release was evident 24 h but not 48 h after stimulation. These results suggest that the effects of IL-10 on M phi function are more complex than previously recognized.

Concomitant administration of intravenous drugs in the ICU: evaluation of physico-chemical compatibilities

Background and objective: Patients in the ICU often get many intravenous (iv) drugs at the same time. Even with three-lumen central venous catheters, the administration of more than one drug in the same iv line (IVL) is frequently necessary. The objective of this study was to observe how nurses managed to administer these many medications and to evaluate the proportion of two-drugs associations (TDA) that are compatible or not, based on known compatibility data. Design: Observational prospective study over 4 consecutive months. All patients receiving simultaneously more than one drugs in the same IVL (Y-site injection or mixed in the same container) were included. For each patient, all iv drugs were recorded, as well as concentration, infusion solution, location on the IVL system, time, rate and duration of administration. For each association of two or more drugs, compatibility of each drug was checked with each other. Compatibilities between these pairs of drugs were assessed using published data (mainly Trissel LA. Handbook on Injectable Drugs and Trissel's Tables of Physical Compatibility) and visual tests performed in our quality control laboratory. Setting: 34 beds university hospital adult ICU. Main outcome measures: Percentage of compatibilities and incompatibilities between drugs administered in the same IVL. Results: We observed 1,913 associations of drugs administered together in the same IVL, 783 implying only two drugs. The average number of drugs per IVL was 3.1 ± 0.8 (range: 2-9). 83.2% of the drugs were given by continuous infusion, 14.3% by intermittent infusion and 2.5% in bolus. The associations observed allowed to form 8,421 pairs of drugs (71.7% drug-drug and 28.3% drug-solute). According to literature data, 80.2% of the association were considered as compatible and 4.4% incompatible. 15.4% were not interpretable because of different conditions between local practices and those described in the literature (drug concentration, solute, etc.) or because of a lack of data. After laboratory tests performed on the most used drugs (furosemide, KH2PO4, morphine HCl, etc.), the proportion of compatible TDA raised to 85.7%, the incompatible stayed at 4.6% and only 9.7% remain unknown or not interpretable. Conclusions: Nurses managed the administration of iv medications quite well, as only less than 5% of observed TDA were considered as incompatible. But the 10% of TDA with unavailable compatibility data should have been avoided too, since the consequences of their concomitant administration cannot be predictable. For practical reasons, drugs were analysed only by pairs, which constitutes the main limit of this work. The average number of drugs in the same association being three, laboratory tests are currently performed to evaluate some of the most observed three-drugs associations.

Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma.

5-aminosalicylic acid (5-ASA) is an antiinflammatory drug widely used in the treatment of inflammatory bowel diseases. It is known to inhibit the production of cytokines and inflammatory mediators, but the mechanism underlying the intestinal effects of 5-ASA remains unknown. Based on the common activities of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands and 5-ASA, we hypothesized that this nuclear receptor mediates 5-ASA therapeutic action. To test this possibility, colitis was induced in heterozygous PPAR-gamma(+/-) mice and their wild-type littermates, which were then treated with 5-ASA. 5-ASA treatment had a beneficial effect on colitis only in wild-type and not in heterozygous mice. In epithelial cells, 5-ASA increased PPAR-gamma expression, promoted its translocation from the cytoplasm to the nucleus, and induced a modification of its conformation permitting the recruitment of coactivators and the activation of a peroxisome-proliferator response element-driven gene. Validation of these results was obtained with organ cultures of human colonic biopsies. These data identify PPAR-gamma as a target of 5-ASA underlying antiinflammatory effects in the colon.

Oral and intravenous methadone use: some clinical and pharmacokinetic aspects.

A sample of 15 patients participating in an injectable methadone trial and of 15 patients in an oral methadone maintenance treatment, who admitted injecting part or all of their methadone take-home doses, were compared to 20 patients in maintenance treatment who use methadone exclusively by mouth. The present study confirms the poorer general health, the higher levels of emotional, psychological or psychiatric problems, the higher use of illicit drugs, and the higher number of problems related to employment and support associated with the use of the intravenous mode of administration of methadone. As expected, due to the shunt of metabolism in the gut wall and of the liver first-pass effect, higher concentration to dose ratios of (R)-methadone, which is the active enantiomer, were measured in the intravenous group (23% increase). This difference reached an almost statistically significant value (P = 0.054). This raises the question whether the effect of a higher methadone dose could be unconsciously sought by some of the intravenous methadone users.

Intravenous thrombolysis in nonagenarians with ischemic stroke.

Background and Purpose-Demographic changes will result in a rapid increase of patients age >= 90 years (nonagenarians), but little is known about outcomes in these patients after intravenous thrombolysis (IVT) for acute ischemic stroke. We aimed to assess safety and functional outcome in nonagenarians treated with IVT and to compare the outcomes with those of patients age 80 to 89 years (octogenarians).Methods-We analyzed prospectively collected data of 284 consecutive stroke patients age >= 80 years treated with IVT in 7 Swiss stroke units. Presenting characteristics, favorable outcome (modified Rankin scale [mRS] 0 or 1), mortality at 3 months, and symptomatic intracranial hemorrhage (SICH) using the National Institute of Neurological Disorders and Stroke (NINDS) and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) criteria were compared between nonagenarians and octogenarians.Results-As compared with octogenarians (n=238; mean age, 83 years), nonagenarians (n=46; mean age, 92 years) were more often women (70% versus 54%; P=0.046) and had lower systolic blood pressure (161 mm Hg versus 172 mm Hg; P=0.035). Patients age >= 90 years less often had a favorable outcome and had a higher incidence of mortality than did patients age 80 to 89 years (14.3% versus 30.2%; P=0.034; and 45.2% versus 22.1%; P=0.002; respectively), while more nonagenarians than octogenarians experienced a SICH (SICHNINDS, 13.3% versus 5.9%; P=0.106; SICHSITS-MOST, 13.3% versus 4.7%; P=0.037). Multivariate adjustment identified age >= 90 years as an independent predictor of mortality (P=0.017).Conclusions-Our study suggests less favorable outcomes in nonagenarians as compared with octogenarians after IVT for ischemic stroke, and it demands a careful selection for treatment, unless randomized controlled trials yield more evidence for IVT in very old stroke patients. (Stroke. 2011; 42: 1967-1970.)

Determination of radionuclide levels in rainwater using ion exchange resin and gamma-spectrometry.

The evaluation of radioactivity accidentally released into the atmosphere involves determining the radioactivity levels of rainwater samples. Rainwater scavenges atmospheric airborne radioactivity in such a way that surface contamination can be deduced from rainfall rate and rainwater radioactivity content. For this purpose, rainwater is usually collected in large surface collectors and then measured by gamma-spectrometry after such treatments as evaporation or iron hydroxide precipitation. We found that collectors can be adapted to accept large surface (diameter 47mm) cartridges containing a strongly acidic resin (Dowex AG 88) which is able to quantitatively extract radioactivity from rainwater, even during heavy rainfall. The resin can then be measured by gamma-spectrometry. The detection limit is 0.1Bq per sample of resin (80g) for (137)Cs. Natural (7)Be and (210)Pb can also be measured and the activity ratio of both radionuclides is comparable with those obtained through iron hydroxide precipitation and air filter measurements. Occasionally (22)Na has also been measured above the detection limit. A comparison between the evaporation method and the resin method demonstrated that 2/3 of (7)Be can be lost during the evaporation process. The resin method is simple and highly efficient at extracting radioactivity. Because of these great advantages, we anticipate it could replace former rainwater determination methods. Moreover, it does not necessitate the transportation of large rainwater volumes to the laboratory.

The role of the radiotherapy technologist in gamma knife radiosurgery within a multidisciplinary team: the Lausanne experience

Objective: Integration of the radiotherapy technologist "know-how" in the Gamma Knife treatment processMaterials and Methods: Gamma Knife (GK) treatments started in July 2010 at the GK Center in C.H.U.V. with the Leksell Gamma KnifeR Perfexion?(Elekta AB, Sweden). The multidisciplinary GK team involves neurosurgeons, radio-oncologists, physicists, neuroradiologists, nurses and technologists, aiming at a full integration for optimal patient management.Results: Between July and December 2010, 60 patients have been treated. Required stereotactic imaging involves IRM, CT scan (and angiography for AVM). All the steps in the treatment process (Leksell coordinate frame fixation, imaging, planning, treatment) are supervised by the members of the multidisciplinary team. In our experience, radiotherapy technologist (RTT) have acquired an important role in the multidisciplinary team communication and integration. Specifically, the RTT are responsible of: supervision of the image acquisition, performing the Gamma Knife unit control tests, patient setup, and patient surveillance during treatment.Conclusion: RTT have a fundamental role in the communication within the team, between the team and the patient and also to assure the patient security. Our experience shows that it is possible and required to involve RTT in all steps of the GK treatment process, to guarantee the best GK treatment possible.

A Mendelian randomization approach to assess the causal relationship of gamma-glutamyl transferase with blood pressure and insulin

Background: Elevated levels of g-glutamyl transferase (GGT) have been associated with subsequent risk of elevated blood pressure (BP), hypertension and diabetes. However, the causality of these relationships has not been addressed. Mendelian randomization refers to the random allocation of alleles at the time of gamete formation. Such allocation is expected to be independent of any behavioural and environmental factors (known or unknown), allowing the analysis of largely unconfounded risk associations that are not due to reverse causation. Methods: We performed a cross-sectional analysis among 4361 participants to the population based CoLaus study. Associations of sex-specific GGT quartiles with systolic BP, diastolic BP and insulin levels were assessed using multivariable linear regression analyses. The rs2017869 GGT1 variant, which explained 1.6% of the variance in GGT levels, was used as an instrument to perform a Mendelian randomization analysis. Results: Median age of the study population was 53 years. After age and sex adjustment, GGT quartiles were strongly associated with systolic and diastolic BP (all p for linear trend <0.0001). After multivariable adjustment, these relationships were significantly attenuated, but remained significant for systolic (b(95%CI)¼1.30 (0.32;2.03), p¼0.007) and diastolic BP (b (95%CI)¼0.57 (0.02;1.13), p¼0.04). Using Mendelian randomization, we observed no positive association of GGT with either systolic BP (b (95%CI)¼-5.68 (-11.51-0.16), p¼0.06) or diastolic BP (b (95%CI)¼ -2.24 (-5.98;1.49) p¼0.24). The association of GGT with insulin was also attenuated after multivariable adjustment. Nevertheless, a strong linear trend persisted in the fully adjusted model (b (95%CI)¼0.07 (0.04;0.09), p<0.0001). Using Mendelian randomization, we observed a similar positive association of GGT with insulin (b (95%CI)¼0.19 (0.01-0.37), p¼0.04). Conclusion: In this study, we found evidence for a direct causal relationship between GGT and insulin, suggesting that oxidative stress may be causally implicated in the pathogenesis of type 2 diabetes mellitus.

Is intracerebral hemorrhage a time-dependent phenomenon after successful combined intravenous and intra-arterial therapy?

BACKGROUND AND PURPOSE: Onset-to-reperfusion time (ORT) has recently emerged as an essential prognostic factor in acute ischemic stroke therapy. Although favorable outcome is associated with reduced ORT, it remains unclear whether intracranial bleeding depends on ORT. We therefore sought to determine whether ORT influenced the risk and volume of intracerebral hemorrhage (ICH) after combined intravenous and intra-arterial therapy. METHODS: Based on our prospective registry, we included 157 consecutive acute ischemic stroke patients successfully recanalized with combined intravenous and intra-arterial therapy between April 2007 and October 2011. Primary outcome was any ICH within 24 hours posttreatment. Secondary outcomes included occurrence of symptomatic ICH (sICH) and ICH volume measured with the ABC/2. RESULTS: Any ICH occurred in 26% of the study sample (n=33). sICH occurred in 5.5% (n=7). Median ICH volume was 0.8 mL. ORT was increased in patients with ICH (median=260 minutes; interquartile range=230-306) compared with patients without ICH (median=226 minutes; interquartile range=200-281; P=0.008). In the setting of sICH, ORT reached a median of 300 minutes (interquartile range=276-401; P=0.004). The difference remained significant after adjustment for potential confounding factors (adjusted P=0.045 for ICH; adjusted P=0.002 for sICH). There was no correlation between ICH volume and ORT (r=0.16; P=0.33). CONCLUSIONS: ORT influences the rate but not the volume of ICH and appears to be a critical predictor of symptomatic hemorrhage after successful combined intravenous and intra-arterial therapy. To minimize the risk of bleeding, revascularization should be achieved within 4.5 hours of stroke onset.

Molecular genetics and treatment of narcolepsy.

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis.

The hypothesis was tested that oral antibiotic treatment in children with acute pyelonephritis and scintigraphy-documented lesions is equally as efficacious as sequential intravenous/oral therapy with respect to the incidence of renal scarring. A randomised multi-centre trial was conducted in 365 children aged 6 months to 16 years with bacterial growth in cultures from urine collected by catheter. The children were assigned to receive either oral ceftibuten (9 mg/kg once daily) for 14 days or intravenous ceftriaxone (50 mg/kg once daily) for 3 days followed by oral ceftibuten for 11 days. Only patients with lesions detected on acute-phase dimercaptosuccinic acid (DMSA) scintigraphy underwent follow-up scintigraphy. Efficacy was evaluated by the rate of renal scarring after 6 months on follow-up scintigraphy. Of 219 children with lesions on acute-phase scintigraphy, 152 completed the study; 80 (72 females, median age 2.2 years) were given ceftibuten and 72 (62 females, median age 1.6 years) were given ceftriaxone/ceftibuten. Patients in the intravenous/oral group had significantly higher C-reactive protein (CRP) concentrations at baseline and larger lesion(s) on acute-phase scintigraphy. Follow-up scintigraphy showed renal scarring in 21/80 children treated with ceftibuten and 33/72 with ceftriaxone/ceftibuten (p = 0.01). However, after adjustment for the confounding variables (CRP and size of acute-phase lesion), no significant difference was observed for renal scarring between the two groups (p = 0.2). Renal scarring correlated with the extent of the acute-phase lesion (r = 0.60, p < 0.0001) and the grade of vesico-ureteric reflux (r = 0.31, p = 0.03), and was more frequent in refluxing renal units (p = 0.04). The majority of patients, i.e. 44 in the oral group and 47 in the intravenous/oral group, were managed as out-patients. Side effects were not observed. From this study, we can conclude that once-daily oral ceftibuten for 14 days yielded comparable results to sequential ceftriaxone/ceftibuten treatment in children aged 6 months to 16 years with DMSA-documented acute pyelonephritis and it allowed out-patient management in the majority of these children.