Torasemide is an effective diuretic in the newborn rabbit.

The effect of intravenous (i.v.) torasemide on diuresis and renal function was evaluated in three groups of normoxemic, 5- to 10-day-old, newborn New Zealand White rabbits. The animals of group 1 received 0.2 mg/kg of torasemide i.v., whereas in group 2 an i.v. dose of 1.0 mg/kg was given. The third group of animals received a bolus i.v. dose of 1.0 mg/kg torasemide with continuous i.v. replacement of estimated urinary fluid and electrolyte losses. Torasemide proved to be an effective, potassium-sparing diuretic, without significant effect on glomerular filtration rate (GFR). Renal blood flow (RBF) fell and the renal vascular resistance (RVR) rose in all three groups of animals, although the rise in RVR in group 3 was not significant. These changes in renal hemodynamics were most pronounced in the animals of group 2 and are probably secondary to torasemide-induced hypovolemia (2.8% loss of body weight) and accompanying humoral reactions, such as an increase in angiotensin II (not measured). When the latter is prevented by simultaneous re-infusion of an electrolyte solution (group 3), replacing urinary losses, GFR increases and the changes in RBF and RVR are blunted. We conclude that torasemide is an effective, potassium-sparing diuretic in newborn rabbits. No evidence was found for a vasodilatory action of the drug.

Which anesthetic should be used in the treatment of refractory status epilepticus?

While the treatment of refractory status epilepticus (SE) relies on the use of anesthetic agents, mostly barbiturates, propofol, or midazolam, the study of the available literature discloses that the evidence level is low. Therapeutic coma induction appears straightforward for generalized convulsive or subtle SE, but this approach is debated for complex partial SE. Each anesthetic has its own advocates, and specific advantages and risks; furthermore, several different protocols have been reported regarding the duration and depth of sedation. However, it seems that the biological background of the patient (especially the etiology) remains the main prognostic determinant in SE. There is a clear need of controlled trials regarding this topic.

Ageing with HIV: medication use and risk for potential drug-drug interactions.

OBJECTIVES: To compare the use of co-medication, the potential drug-drug interactions (PDDIs) and the effect on antiretroviral therapy (ART) tolerability and efficacy in HIV-infected individuals according to age, ≥ 50 years or <50 years. METHODS: All ART-treated participants were prospectively included once during a follow-up visit of the Swiss HIV Cohort Study. Information on any current medication was obtained by participant self-report and medical prescription history. The complete treatment was subsequently screened for PDDIs using a customized version of the Liverpool drug interaction database. RESULTS: Drug prescriptions were analysed for 1497 HIV-infected individuals: 477 age ≥ 50 and 1020 age <50. Older patients were more likely to receive one or more co-medications compared with younger patients (82% versus 61%; P < 0.001) and thus had more frequent PDDIs (51% versus 35%; P < 0.001). Furthermore, older patients tended to use a higher number of co-medications and certain therapeutic drug classes more often, such as cardiovascular drugs (53% versus 19%; P < 0.001), gastrointestinal medications (10% versus 6%; P = 0.004) and hormonal agents (6% versus 3%; P = 0.04). PDDIs with ART occurred mainly with cardiovascular drugs (27%), CNS agents (22%) and methadone (6%) in older patients and with CNS agents (27%), methadone (15%) and cardiovascular drugs (11%) in younger patients. The response to ART did not differ between the two groups. CONCLUSIONS: The risk for PDDIs with ART increased in older patients who take more drugs than their younger HIV-infected counterparts. However, medication use in older and younger patients did not differ in terms of effect on antiretroviral tolerability and response.

The PPARgamma agonist pioglitazone modifies the vascular sodium-angiotensin II relationship in insulin-resistant rats.

Glitazones are efficient insulin sensitizers that blunt the effects of angiotensin II (ANG II) in the rat. Sodium chloride is another important modulator of the systemic and renal effects of ANG II. Whether glitazones interfere with the interaction between sodium and the response to ANG II is not known. Therefore, we investigated the effects of pioglitazone on the relationship between sodium and the systemic and renal effects of ANG II in rats. Pioglitazone, or vehicle, was administered for 4 wk to 8-wk-old obese Zucker rats. Animals were fed a normal-sodium (NS) or a high-sodium (HS) diet. Intravenous glucose tolerance tests, systemic and renal hemodynamic responses to ANG II, and the renal ANG II binding and expression of ANG II type 1 (AT(1)) receptors were measured. The results of our study were that food intake and body weight increased, whereas blood pressure, heart rate, filtration fraction, and insulin levels decreased significantly with pioglitazone in obese rats on both diets. Pioglitazone blunted the systemic response to ANG II and abolished the increased responsiveness to ANG II induced by a HS diet. Pioglitazone modified the renal hemodynamic response to changes in salt intake while maintaining a lower filtration fraction with ANG II perfusion. These effects were associated with a decrease in the number and expression of the AT(1) receptor in the kidney. In conclusion, these data demonstrate that the peroxisome proliferator-activated receptor-gamma agonist pioglitazone modifies the physiological relationship between sodium chloride and the response to ANG II in insulin-resistant rats.

Adult native septic arthritis: 10 years in review in order to establish local guidelines on empiric antibiotic therapy.

Objective: Antibiotic stewardship includes development of practice guidelines incorporating local microbiology and resistance patterns. In case of septic arthritis (SA), addition of vancomycin to the empiric therapy and broad-spectrum antibiotherapy in some clinical settings are subjects of discussion. Our objective was to review the local epidemiology of native septic arthritis in adults, in order to establish local guidelines for empiric therapy. Methods: Retrospective study based on positive synovial fluid cultures and hospital discharge diagnoses of SA obtained from 1999 to 2008 in patients _16 years. Medical records were reviewed to assess the diagnosis and complete relevant clinical information. Results: During this ten-year period, we identified 233 SA on native joints in 231 patients. 107 episodes (46%) were obtained through positive synovial fluid cultures, and 126 episodes (54%) through the discharge diagnosis. 147 SA (63%) were large joint infections (LJI). 35 SA (15%) occurred in intravenous drug users. Preexisting arthropathy was present in 51% of cases. 42% of patients with small joint infection (SJI) were diabetic, vs. 23% with LJI (p = 0.003). When available, synovial fluid direct examination was positive in 35% of cases. Etiologic agents are reported in the table. Five of the 11 MRSA SA (45%) occurred in known carriers. SJI were more frequently polymicrobial (24% vs. 1%, p<0.001). For LJI, an empiric treatment with amoxicillin/clavulanate (A/C) would have been appropriate in 85% of cases. MRSA (8 cases) and tuberculous (7 cases) arthritis would have been the most frequently untreated pathogens. Addition of vancomycin to A/C in MRSA carriers would rise the adequacy to 87%. In contrast, A/C would cover only 75% of SJI (82% if restricted to non-diabetic patients). MRSA (3 cases) and P. aeruginosa (9 cases, 7 monomicrobial) would be the main untreated pathogens. An anti-pseudomonal penicillin would have been appropriate in 94% of cases of SJI (P = 0.002 vs. A/C, p = 0.19 if diabetic patients not included). Conclusions: Treatment with A/C seems adequate for empiric coverage of LJI in our setting. Broad-spectrum antibiotherapy was significantly superior for SJI in diabetic patients, due to different causative bacteria. In an area of low MRSA incidence, our results do not justify a systematic empiric therapy for MRSA, which should be considered in a known carrier.

Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients.

INTRODUCTION: Oxidative stress is involved in the development of secondary tissue damage and organ failure. Micronutrients contributing to the antioxidant (AOX) defense exhibit low plasma levels during critical illness. The aim of this study was to investigate the impact of early AOX micronutrients on clinical outcome in intensive care unit (ICU) patients with conditions characterized by oxidative stress. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, single-center trial in patients admitted to a university hospital ICU with organ failure after complicated cardiac surgery, major trauma, or subarachnoid hemorrhage. Stratification by diagnosis was performed before randomization. The intervention was intravenous supplements for 5 days (selenium 270 microg, zinc 30 mg, vitamin C 1.1 g, and vitamin B1 100 mg) with a double-loading dose on days 1 and 2 or placebo. RESULTS: Two hundred patients were included (102 AOX and 98 placebo). While age and gender did not differ, brain injury was more severe in the AOX trauma group (P = 0.019). Organ function endpoints did not differ: incidence of acute kidney failure and sequential organ failure assessment score decrease were similar (-3.2 +/- 3.2 versus -4.2 +/- 2.3 over the course of 5 days). Plasma concentrations of selenium, zinc, and glutathione peroxidase, low on admission, increased significantly to within normal values in the AOX group. C-reactive protein decreased faster in the AOX group (P = 0.039). Infectious complications did not differ. Length of hospital stay did not differ (16.5 versus 20 days), being shorter only in surviving AOX trauma patients (-10 days; P = 0.045). CONCLUSION: The AOX intervention did not reduce early organ dysfunction but significantly reduced the inflammatory response in cardiac surgery and trauma patients, which may prove beneficial in conditions with an intense inflammation. TRIALS REGISTRATION: Clinical Trials.gov RCT Register: NCT00515736.

Common Variable Immunodeficiency: molecular pathways and clinical manifestations

Common variable immunodeficiency (CVID), is a disease that is characterized by hypogammaglobulinemia as well as a defect in T, B and dendritic cells. This leads to recurrent bacterial infection mainly caused by Streptococcus pneumoniae, Klebsiella pneumoniae and Haemophilus influenzae, as well as inflammatory manifestations, i.e. granulomateous disease, gastro-intestinal disorders and chronic lung disease. Intravenous Immunoglobulin (IVIg) therapy reduces CVID susceptibility to bacterial infections to some extend. We analyzed clinical aspects of patients from our database. We recently showed that bacteria-specific CD4 T cells of CVID patients were impaired. We therefor postulated that CVID patients may harbor an acquired T-cell deficiency also called exhaustion. To test this hypothesis, we performed a comprehensive investigation of the functional profiles of bacteria-specific CD4 T cells isolated from 31 healthy individuals and 30 CVID patients. In the present study, we demonstrated that bacteria-specific but not virus-specific CD4 T cells in CVID patients harbored reduced proliferation capacity and expressed high level of PD-1. Interestingly, the blockade of PD-1/PD-1 ligands interactions restored partially bacteria but not virus-specific CD4 T-cell proliferation. Finally, we showed that 1) the level of endotoxins inversely correlates with IgG concentration, 2) IVIG treated CVID patients harbored reduced endotoxemia and 3) IgG concentration exceeding 7 mg/mL strongly reduces both the proportion of CVID patients with detectable endotoxemia and the concentration of endotoxins in plasma. Taken together our observations, suggest that primary B-cell defect(s) in CVID patients leads to recurrent bacterial infections that are associated to an acquired (secondary) impairment of CD4 T cells which may in turn exacerbate the lack of protection against extracellular bacteria.

Prevalence of methadone injection in three Swiss cities.

OBJECTIVE: Intravenous methadone is associated with increased risk of morbidity and mortality. A previous report from a methadone center in Fribourg, Switzerland, found a high prevalence (43%) of patients who injected oral methadone. We therefore wished to assess the prevalence of methadone injection among patients in oral methadone programs in 3 other Swiss cities--Lausanne, Geneva, and La Chaux-de-Fonds. METHOD: Subjects were randomly selected and interviewed by assistant psychologists who were not on the staff of the study centers. Participation was voluntary and anonymous. RESULTS: 164 patients participated in the study (n = 58 in Lausanne, 52 in Geneva, and 54 in La Chaux-de-Fonds). The prevalence of methadone injection was low (5%) and did not differ significantly between the cities. DISCUSSION: Less liberal policies cannot explain the lower prevalence of methadone injection in these three centers than in Fribourg. The high prevalence of methadone injection there is probably related to its separate methadone injection program: patients in oral methadone programs may be more likely to injection methadone when other patients authorized to do so. IN CONCLUSION: Although the 5% prevalence of methadone injection found in the 3 cities surveyed is low, it is not negligible. These results suggest that information on the risks associated with injection of methadone syrup should be provided to all methadone maintenance. This information is especially necessary when maintenance therapy is provided in the same center, or city as injectable methadone maintenance.

Outpatient treatment of pulmonary embolism

Pulmonary embolism (PE) is traditionally treated in hospital. Growing evidence from non randomized prospective studies suggests that a substantial proportion of patients with non-massive PE might be safely treated in the outpatient setting using low molecular weight heparins. Based on this evidence, professional societies started to recommend outpatient care for selected patients with non-massive PE. Despite these recommendations, outpatient treatment of non-massive PE appears to be uncommon in clinical practice. The major barriers to PE outpatient care are, firstly, the uncertainty as how to identify low risk patients with PE who are candidates for outpatient care and secondly the lack of high quality evidence from randomized trials demonstrating the safety of PE outpatient care compared to traditional inpatient management. Also, although clinical prognostic models, echocardiography and cardiac biomarkers accurately identify low risk patients with PE in prospective studies, the benefit of risk stratification strategies based on these instruments should be demonstrated in prospective management studies and clinical trials before they can be implemented as decision aids to guide PE outpatient treatment. Before high quality evidence documenting the safety of an outpatient treatment approach is published, outpatient management of non-massive PE cannot be generally recommended.

Cytochromes P450: génotypage et /ou phénotypage pour l'individualisation du traitement médicamenteux

La réponse aux traitements médicamenteux est affectée par de nombreux facteurs environnementaux et génétiques, dont une part importante est causée par les polymorphismes des cytochromes P450 (CYP). Ces derniers sont responsables, principalement au niveau du foie, du métabolisme de nombreux médicaments. Pour certains CYP, notamment les CYP2D6 et CYP2C19, des phénotypes de mauvais métaboliseurs et de métaboliseurs ultrarapides ont été décrits avec une influence sur la toxicité et/ou la réponse thérapeutique induites par certains médicaments tels que la codéine, le tramadol, le tamoxifen et le clopidogrel. Quelques exemples parmi les plus significatifs sont décrits ici, démontrant que le génotypage et/ou phénotypage des différents CYPs permet d'individualiser et d'améliorer la prescription médicamenteuse par sélection du principe actif et des doses les plus appropriés.

Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis.

OBJECTIVES: Rescue therapy with either cyclosporine (CYS) or infliximab (IFX) is an effective option in patients with intravenous steroid-refractory attacks of ulcerative colitis (UC). In patients who fail, colectomy is usually recommended, but a second-line rescue therapy with IFX or CYS is an alternative. The aims of this study were to investigate the efficacy and tolerance of IFX and CYS as a second-line rescue therapy in steroid-refractory UC or indeterminate colitis (IC) unsuccessfully treated with CYS or IFX.METHODS: This was a retrospective survey of patients seen during the period 2000-2008 in the GETAID centers. Inclusion criteria included a delay of <1 month between CYS withdrawal (when used first) and IFX, or a delay of <2 months between IFX (when used first) and CYS, and a follow-up of at least 3 months after inclusion. Time-to-colectomy, clinical response, and occurrence of serious adverse events were analyzed.RESULTS: A total of 86 patients (median age 34 years; 49 males; 71 UC and 15 IC) were successively treated with CYS and IFX. The median (+/-s.e.) follow-up time was 22.6 (7.0) months. During the study period, 49 patients failed to respond to the second-line rescue therapy and underwent a colectomy. The probability of colectomy-free survival (+/-s.e.) was 61.3 +/- 5.3% at 3 months and 41.3 +/- 5.6% at 12 months. A case of fatal pulmonary embolism occurred at 1 day after surgery in a 45-year-old man. Also, nine infectious complications were observed during the second-line rescue therapy.CONCLUSIONS: In patients with intravenous steroid-refractory UC and who fail to respond to CYS or IFX, a second-line rescue therapy may be effective in carefully selected patients, avoiding colectomy within 2 months in two-thirds of them. The risk/benefit ratio should still be considered individually.

High prevalence of severe vitamin D deficiency in combined antiretroviral therapy-naive and successfully treated Swiss HIV patients.

OBJECTIVES: To evaluate the prevalence of 25-hydroxyvitamin D [25(OH)D] deficiency in HIV-positive patients, a population at risk for osteoporosis. DESIGN: Retrospective assessment of vitamin D levels by season and initiation of combined antiretroviral therapy (cART). METHODS: 25(OH)D was measured in 211 HIV-positive patients: samples were taken before initiation of cART from February to April or from August to October as well as 12 (same season) and 18 months (alternate season) after starting cART. 1,25-Dihydroxyvitamin D [1,25(OH)2D] was measured in a subset of 74 patients. Multivariable analyses included season, sex, age, ethnicity, BMI, intravenous drug use (IDU), renal function, time since HIV diagnosis, previous AIDS, CD4 cell count and cART, in particular nonnucleoside reverse transcriptase inhibitor (NNRTI) and tenofovir (TDF) use. RESULTS: At baseline, median 25(OH)D levels were 37 (interquartile range 20-49) nmol/l in spring and 57 (39-74) nmol/l in the fall; 25(OH)D deficiency less than 30 nmol/l was more prevalent in spring (42%) than in fall (14%), but remained unchanged regardless of cART exposure. In multivariable analysis, 25(OH)D levels were higher in white patients and those with a longer time since HIV diagnosis and lower in springtime measurements and in those with active IDU and NNRTI use. 1-Hydroxylation rates were significantly higher in patients with low 25(OH)D. Hepatitis C seropositivity, previous AIDS and higher CD4 cell counts correlated with lower 1,25(OH)2D levels, whereas BMI and TDF use were associated with higher levels. In TDF-treated patients, higher 1,25(OH)2D correlated with increases in serum alkaline phosphatase. CONCLUSION: Based on the high rate of vitamin D deficiency in HIV-positive patients, systematic screening with consideration of seasonality is warranted. The impact of NNRTIs on 25(OH)D and TDF on 1,25(OH)2D needs further attention.

Vaccinia immune globulin: current policies, preparedness, and product safety and efficacy.

In 1980 the World Health Organization declared that smallpox was eradicated from the world, and routine smallpox vaccination was discontinued. Nevertheless, samples of the smallpox virus (variola virus) were retained for research purposes, not least because of fears that terrorist groups or rogue states might also have kept samples in order to develop a bioweapon. Variola virus represents an effective bioweapon because it is associated with high morbidity and mortality and is highly contagious. Since September 11, 2001, countries around the world have begun to develop policies and preparedness programs to deal with a bioterror attack, including stockpiling of smallpox vaccine. Smallpox vaccine itself may be associated with a number of serious adverse events, which can often be managed with vaccinia immune globulin (VIG). VIG may also be needed as prophylaxis in patients for whom pre-exposure smallpox vaccine is contraindicated (such as those with eczema or pregnant women), although it is currently not licensed in these cases. Two intravenous formulations of VIG (VIGIV Cangene and VIGIV Dynport) have been licensed by the FDA for the management of patients with progressive vaccinia, eczema vaccinatum, severe generalized vaccinia, and extensive body surface involvement or periocular implantation following inadvertent inoculation.

Effects of fructose on hepatic glucose metabolism in humans.

Hepatic and extrahepatic insulin sensitivity was assessed in six healthy humans from the insulin infusion required to maintain an 8 mmol/l glucose concentration during hyperglycemic pancreatic clamp with or without infusion of 16.7 micromol. kg(-1). min(-1) fructose. Glucose rate of disappearance (GR(d)), net endogenous glucose production (NEGP), total glucose output (TGO), and glucose cycling (GC) were measured with [6,6-(2)H(2)]- and [2-(2)H(1)]glucose. Hepatic glycogen synthesis was estimated from uridine diphosphoglucose (UDPG) kinetics as assessed with [1-(13)C]galactose and acetaminophen. Fructose infusion increased insulin requirements 2.3-fold to maintain blood glucose. Fructose infusion doubled UDPG turnover, but there was no effect on TGO, GC, NEGP, or GR(d) under hyperglycemic pancreatic clamp protocol conditions. When insulin concentrations were matched during a second hyperglycemic pancreatic clamp protocol, fructose administration was associated with an 11.1 micromol. kg(-1). min(-1) increase in TGO, a 7.8 micromol. kg(-1). min(-1) increase in NEGP, a 2.2 micromol. kg(-1). min(-1) increase in GC, and a 7.2 micromol. kg(-1). min(-1) decrease in GR(d) (P < 0. 05). These results indicate that fructose infusion induces hepatic and extrahepatic insulin resistance in humans.

Validation of the DRAGON Score in 12 Stroke Centers in Anterior and Posterior Circulation.

BACKGROUND AND PURPOSE: The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. METHODS: Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. RESULTS: Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). CONCLUSIONS: The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).