Long-Term Safety of Canakinumab in Patients with Gouty Arthritis.

Background/Purpose: Gouty arthritis (GA) is a chronic inflammatory disease. Targeting the inflammatory pathway through IL-1_ inhibition with canakinumab (CAN) may provide significant long-term benefits. CAN safety versus triamcinolone acetonide (TA) over initial 24 weeks (blinded study) for patients (pts) with history of frequent attacks (_3 in year before baseline) was reported earlier from core (_-RELIEVED [_-REL] and _-REL-II) and first extension (E1) studies1. Herein we present full 18-month long-term CAN safety data, including open-label second extension (E2) studies. Methods: GA pts completing _-REL E1 and _-REL-II E1 studies1 were enrolled in these 1-year, open-label, E2 studies. All pts entering E2, whether randomized to CAN or TA, received CAN 150 mg sc on demand upon new attack. Data are presented only for pts randomized to CAN, and are reported cumulatively, i.e. including corresponding data from previously reported core and E1 studies. Long-term safety outcomes and safety upon re-treatment are presented as incidence rate per 100 patient-years (pyr) of study participation for AEs and SAEs. Deaths are reported for all pts (randomized to CAN or TA). Selected predefined notable laboratory abnormalities are shown (neutrophils, platelets, liver and renal function tests). Long-term attack rate per year is also provided. Results: In total, 69/115 (60%) and 72/112 (64.3%) of the pts randomized to CAN in the two core studies entered the two E2 studies, of which 68 and 64 pts, respectively completed the E2 studies. The 2 study populations had differing baseline comorbidity and geographic origin. Lab data (not time adjusted) for neutropenia appears worse after retreatment in _-REL E2, and deterioration of creatinine clearance appears worse after retreatment (Table 1). The time-adjusted incidence rates for AEs were 302.4/100 pyr and 360/100 pyr, and for SAEs were 27.9/100 pyr and 13.9/100 pyr in _-REL E2 and _-REL-II E2 respectively (Table 1). The time-adjusted incidence rates of any AEs, infection AEs, any SAEs, and selected SAEs before and after re-treatment are presented in Table 1. Incidence rates for AEs and SAEs declined after re-treatment, with the exception of SAEs in _-REL-II E2, which increased from 2.9/100 pyr to 10.9/100 pyr (no infection SAEs after retreatment in _-REL-II E2, and other SAEs fit no special pattern). In the total safety population (N_454, core and all extensions), there were 4 deaths, 2 in the core studies previously reported1 and 2 during the _-REL E2 study (one patient in the CAN group died from pneumonia; one patient in the TA group who never received CAN died of pneumococcal sepsis). None of the deaths was suspected by investigators to be study drug related. The mean rates of new attacks per year on CAN were 1.21 and 1.18 in _-REL E2 and in _-REL-II E2. Conclusion: The clinical safety profile of CAN upon re-treatment was maintained long-term with no new infection concerns

Résultats anatomiques comparés à long terme de décollements de rétine avec prolifération vitréo-rétinienne opérés avec ou sans utilisation de perfluorocarbones liquides [Long-term comparative anatomic results of retinal detachment with vitreoretinal proliferation operated with or without using liquid perfluorocarbons].

PURPOSE: To investigate whether peroperative perfluorocarbon liquids (PFCL) improve the long term anatomical success of retinal detachment associated with severe proliferative vitreoretinopathy (PVR). PATIENTS AND METHODS: The charts of 62 successive patients operated on for retinal detachment associated with severe PVR were retrospectively analyzed. For one group of 39 patients PFCL were used intraoperatively to improve membrane dissection. The anatomical status of the two groups were compared one month after surgery and at least 6 months after silicone oil ablation. RESULTS: Anatomical success was observed in 84.6% in the group of patients operated with PFCL compared to 52% in the other group (P = 0.005). At the end of the follow up, anatomical success was observed in 64% of patients operated with PFCL compared to 61% in the control group (P = 0.8). However, recurrences were observed later in the group operated on with PFCL. CONCLUSION: Perfluorocarbons liquids significantly improve the initial reattachment of retinal detachment complicated with severe PVR, but they do not seem to improve their final anatomical status.

Syndrome douloureux de la fosse iliaque droite et laparoscopie: appendicectomie de routine ou non? [Pain syndrome in the right iliac fossa and laparoscopy: routine appendectomy or not?]

Diagnostic laparoscopy is useful in the evaluation of patients with lower right quadrant pain when the diagnosis is uncertain. The object of this study was to determine whether a normal appendix should be routinely removed at laparoscopy. We have decided to do this in children, men under the age of 30 and women of childbearing age. However we do not perform appendectomy in men over the age of 30, women over 50 and in immunodeficient patients. This is a working hypothesis and is the basis of an on-going prospective study in our unit

Proportion of out-of-hospital adult non-traumatic cardiac or respiratory arrest among calls for seizure.

OBJECTIVES: To measure the proportion of adult non-traumatic cardiac or respiratory arrest among calls for seizure to an emergency medical dispatch centre and to record whether known epileptic patients present cardiac or respiratory arrest together with seizure. METHODS: This 2-year prospective observational investigation involved the collection of tape recordings of all incoming calls to the emergency medical dispatch centre, in which an out-of-hospital non-traumatic seizure was the chief complaint in patients >18 years, in addition to the paramedics' records of all patients who presented with respiratory or cardiac arrest. The authors also recorded whether the bystander spontaneously mentioned to the dispatcher that the victim was known to have epilepsy. RESULTS: During the 24-month period, the call centre received 561 incoming calls for an out-of-hospital non-traumatic seizure in an adult. Twelve cases were classified as cardiac or respiratory arrest by paramedics. In one case, the caller spontaneously mentioned that the victim had a history of epilepsy. The proportion of cardiac or respiratory arrest among calls for seizure was 2.1%. CONCLUSION: Although these cases are rare, dispatchers should closely monitor seizure patients with the help of bystanders to exclude an out-of-hospital cardiac or respiratory arrest, in which case the dispatcher can offer telephone cardiopulmonary resuscitation advice until the paramedics arrive. Whenever the activity of the centre allows it and no new incoming call is on hold, this can be achieved by staying on the line with the caller or by calling back. A history of epilepsy should not modify the type of monitoring performed by the dispatcher as those patients may also have an arrest together with seizure.

Inhibition of the renin-angiotensin system does not reduce platelet activity at rest or during stress in hypertension.

OBJECTIVES: We investigated the influence of angiotensin receptor blockade and angiotensin-converting enzyme inhibition on stress-induced platelet activation in hypertensive patients. Secondary aims were effects on inflammation, coagulation, and endothelial function. METHODS: Following a 4-week placebo period, 25 hypertensive patients entered a double-blind, crossover study comparing enalapril (20 mg once daily) and losartan (100 mg once daily) treatment (each for 8 weeks). Patients were studied at rest and after a standardized exercise test. RESULTS: Mean arterial pressure was reduced from 119 ± 2 to 104 ± 2 (enalapril) and 106 ± 2 (losartan) mmHg (both P <0.001). Plasma angiotensin II decreased from 2.4 ± 0.4 to 0.5 ± 0.1 pmol/l with enalapril, and increased to 7.2 ± 1.3 pmol/l with losartan (both P <0.001). Exercise-evoked platelet activation, as evidenced by increased numbers of P-selectin-positive platelets (P <0.01), elevated circulating platelet-platelet aggregates (P <0.01) and soluble P-selectin levels (P <0.001), and increased platelet responsiveness to adenosine diphosphate and thrombin (both P <0.05). Neither drug influenced these markers of platelet activation at rest or following exercise. Markers of inflammation (high-sensitivity C reactive protein, interleukin-6, tissue necrosis factor-α), coagulation (tissue plasminogen activator antigen, prothrombin fragment F1+2), and endothelial function (von Willebrand factor, soluble vascular cellular adhesion molecule-1, and intercellular adhesion molecule-1) were also uninfluenced by treatment. CONCLUSION: Enalapril and losartan failed to reduce platelet activity both at rest and during exercise in hypertensive patients. Markers of inflammation, coagulation, and endothelial function were similarly unaffected. Inhibition of the renin-angiotensin system promotes its beneficial effects in hypertension through mechanisms other than platelet inhibition.

Factors favoring a degradation or an improvement in activities of daily living (ADL) performance among nursing home (NH) residents: A survival analysis.

Different factors influence ADL performance among nursing home (NH) residents in long term care. The aim was to investigate which factors were associated with a significant change of ADL performance in NH residents, and whether or not these factors were gender-specific. The design was a survival analysis. The 10,199 participants resided in ninety Swiss NHs. Their ADL performance had been assessed by the Resident Assessment Instrument Minimum Data Set (RAI-MDS) in the period from 1997 to 2007. Relevant change in ADL performance was defined as 2 levels of change on the ADL scale between two successive assessments. The occurrence of either an improvement or a degradation of the ADL status) was analyzed using the Cox proportional hazard model. The analysis included a total of 10,199 NH residents. Each resident received between 2 and 23 assessments. Poor balance, incontinence, impaired cognition, a low BMI, impaired vision, no daily contact with proxies, impaired hearing and the presence of depression were, by hierarchical order, significant risk factors for NH residents to experience a degradation of ADL performance. Residents, who were incontinent, cognitively impaired or had a high BMI were significantly less likely to improve their ADL abilities. Male residents with cancer were prone to see their ADL improve. The year of NH entry was significantly associated with either degradation or improvement of ADL performance. Measures aiming at improving balance and continence, promoting physical activity, providing appropriate nourishment and cognitive enhancement are important for ADL performance in NH residents.

Combining blockers of the renin-angiotensin system or increasing the dose of an angiotensin II receptor antagonist in proteinuric patients: a randomized triple-crossover study.

Objective The goal of this study was to investigate whether increasing the dose of an angiotensin II receptor blocker (ARB) provides as much benefits as combining the ARB with an angiotensin-converting enzyme inhibitor (ACEI) in terms of blood pressure (BP) control and urinary albumin excretion (UAE) in hypertensive patients with a proteinuria.Methods We enrolled 20 hypertensive patients with proteinuric nephropathies and a reduced renal function in a randomized, 12-month, triple-crossover, prospective, open-label study to compare the effects of a regular dose of losartan (Los 100mg q.d., LOS100) vs. a high dose of losartan (Los 100mg b.i.d., LOS200) vs. losartan 100mg q.d. associated with lisinopril 20 mg q.d. (LOS100 + LIS20). Each treatment was given for 8 weeks with a 4-week initial run-in period and 2 weeks of washout between each treatment phases. 24 h UAE and ambulatory BP were measured during the running phase and at the end of each treatment period.Results Compared to pretreatment, 24 h SBP and DBP were reduced by 10/5 +/- 7/4 mmHg with LOS100 (P=0.023 vs. baseline) and, respectively, 13/6 +/- 12/5 mmHg with LOS200 (P=0.011) and 19/9 +/- 15/8 mmHg with LOS100+LIS20 (P < 0.01). UAE decreased significantly with LOS100 and to an even greater degree with LOS200 and LOS100+LIS20 (P < 0.01 vs. baseline for both and P=0.032, LOS100+LIS20 vs. LOS200). The combination had a greater impact in patients with a high baseline proteinuria as suggested by a nonparallel leftward shift of the relationship between the changes in UAE induced by the combination and those induced by LOS200. The high dose of losartan was better tolerated than the combination.Conclusion Increasing the dose of losartan from 100mg once daily to 100mg twice a day enables to obtain a greater decrease in BP and proteinuria and is better tolerated than combining the ARB with lisinopril, though the high dose appears to be slightly less effective than the combination in patients with a marked proteinuria. J Hypertens 29: 1228-1235 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

The effect of exercise, alcohol or both combined on health and physical performance.

Alcohol (ethanol) is consumed on a daily basis by a large fraction of the population, and in many countries, light-to-moderate alcohol consumption is considered as an integral part of the diet. Although the relationship between alcohol intake and obesity is controversial, regular consumption of alcohol, through its effects in suppressing fat oxidation, is regarded as a risk factor for weight gain, increased abdominal obesity and hypertriglyceridemia. Indeed, alcohol taken with a meal leads to an increase in postprandial lipemia-an effect on postprandial metabolism that is opposite to that observed with exercise. Furthermore, although regular exercise training and/or a preprandial exercise session reduce postprandial lipemia independently of alcohol ingestion, the exercise-induced reduction in postprandial lipemia is nonetheless less pronounced when alcohol is also consumed with the meal. Whether or not alcohol influences exercise and sport performance remains contradictory. It is believed that alcohol has deleterious effects on the performance, although it may contribute to reduce pain and anxiety. The alcohol effects on sports performance depend on the type and dosage of alcohol, acute vs chronic administration, the alcohol elimination rate as well as the type of exercise.

Influence from friends to drink more or drink less: a cross-national comparison.

Drinking habits are socially patterned and social networks influence individuals' drinking behaviors. Previous studies have focused primarily upon the influence from family members to drink less. Those studies that have focused upon peer influence have been largely confined to social norms among adolescent and college-age drinkers. By contrast, based in adult populations, this article examines exhortations from friends not only to reduce alcohol consumption but also to increase it. Survey data in 15 countries that participate in the Gender, Alcohol and Culture: An International Study project (GENACIS) were used to test whether there were country and gender differences concerning the influence to drink less or to drink more by friends and examine if this was affected by the drinking behavior. The findings revealed that those influenced to drink less had more heavy episodic drinking (HED) occasions than those who did not report such influence. By contrast, influence to drink more, originating mainly from same-sex friends, may be more the result of social situations that encourage all drinkers, regardless of their frequency of HED occasions. At the country level, influence to drink less for both sexes decreased with the proportion of drinkers in a country. Similarly, influence to drink less for both sexes also decreased in countries where gender roles were more egalitarian. Thus, in countries where alcohol use is more widespread and fewer differences are observed between male and female gender role expectations, fewer people were influenced to drink less. These findings have implications for social and behavioral strategies designed to reduce alcohol-related harm across a wide range of cultures.

Effects of a short-term overfeeding with fructose or glucose in healthy young males.

Consumption of simple carbohydrates has markedly increased over the past decades, and may be involved in the increased prevalence in metabolic diseases. Whether an increased intake of fructose is specifically related to a dysregulation of glucose and lipid metabolism remains controversial. We therefore compared the effects of hypercaloric diets enriched with fructose (HFrD) or glucose (HGlcD) in healthy men. Eleven subjects were studied in a randomised order after 7 d of the following diets: (1) weight maintenance, control diet; (2) HFrD (3.5 g fructose/kg fat-free mass (ffm) per d, +35 % energy intake); (3) HGlcD (3.5 g glucose/kg ffm per d, +35 % energy intake). Fasting hepatic glucose output (HGO) was measured with 6,6-2H2-glucose. Intrahepatocellular lipids (IHCL) and intramyocellular lipids (IMCL) were measured by 1H magnetic resonance spectroscopy. Both fructose and glucose increased fasting VLDL-TAG (HFrD: +59 %, P < 0.05; HGlcD: +31 %, P = 0.11) and IHCL (HFrD: +52 %, P < 0.05; HGlcD: +58 %, P = 0.06). HGO increased after both diets (HFrD: +5 %, P < 0.05; HGlcD: +5 %, P = 0.05). No change was observed in fasting glycaemia, insulin and alanine aminotransferase concentrations. IMCL increased significantly only after the HGlcD (HFrD: +24 %, NS; HGlcD: +59 %, P < 0.05). IHCL and VLDL-TAG were not different between hypercaloric HFrD and HGlcD, but were increased compared to values observed with a weight maintenance diet. However, glucose led to a higher increase in IMCL than fructose.

Cilengitide modulates attachment and viability of human glioma cells, but not sensitivity to irradiation or temozolomide in vitro.

Cilengitide is a cyclic peptide antagonist of integrins alphavbeta3 and alphavbeta5 that is currently being evaluated as a novel therapeutic agent for recurrent and newly diagnosed glioblastoma. Its mode of action is thought to be mainly antiangiogenic but may include direct effects on tumor cells, notably on attachment, migration, invasion, and viability. In this study we found that, at clinically relevant concentrations, cilengitide (1-100 microM) induces detachment in some but not all glioma cell lines, while the effect on cell viability is modest. Detachment induced by cilengitide could not be predicted by the level of expression of the cilengitide target molecules, alphavbeta3 and alphavbeta5, at the cell surface. Glioma cell death induced by cilengitide was associated with the generation of caspase activity, but caspase activity was not required for cell death since ectopic expression of cytokine response modifier (crm)-A or coexposure to the broad-spectrum caspase inhibitor zVAD-fmk was not protective. Moreover, forced expression of the antiapoptotic protein marker Bcl-X(L) or altering the p53 status did not modulate cilengitide-induced cell death. No consistent effects of cilengitide on glioma cell migration or invasiveness were observed in vitro. Preliminary clinical results indicate a preferential benefit from cilengitide added to temozolomide-based radiochemotherapy in patients with O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter methylation. Accordingly, we also examined whether the MGMT status determines glioma cell responses to cilengitide alone or in combination with temozolomide. Neither ectopic expression of MGMT in MGMT-negative cells nor silencing the MGMT gene in MGMT-positive cells altered glioma cell responses to cilengitide alone or to cilengitide in combination with temozolomide. These data suggest that the beneficial clinical effects derived from cilengitide in vivo may arise from altered perfusion, which promotes temozolomide delivery to glioma cells.

Aβ1-42 monomers or oligomers have different effects on autophagy and apoptosis.

The role of autophagy and its relationship with apoptosis in Alzheimer disease (AD) pathogenesis is poorly understood. Disruption of autophagy leads to buildup of incompletely digested substrates, amyloid-β (Aβ) peptide accumulation in vacuoles and cell death. Aβ, in turn, has been found to affect autophagy. Thus, Aβ might be part of a loop in which it is both the substrate of altered autophagy and its cause. Given the relevance of different soluble forms of Aβ1-42 in AD, we have investigated whether monomers and oligomers of the peptide have a differential role in causing altered autophagy and cell death. Using differentiated SK-N-BE neuroblastoma cells, we found that monomers hamper the formation of the autophagic BCL2-BECN1/Beclin 1 complex and activate the MAPK8/JNK1-MAPK9/JNK2 pathway phosphorylating BCL2. Monomers also inhibit apoptosis and allow autophagy with intracellular accumulation of autophagosomes and elevation of levels of BECN1 and LC3-II, resulting in an inhibition of substrate degradation due to an inhibitory action on lysosomal activity. Oligomers, in turn, favor the formation of the BCL2-BECN1 complex favoring apoptosis. In addition, they cause a less profound increase in BECN1 and LC3-II levels than monomers without affecting the autophagic flux. Thus, data presented in this work show a link for autophagy and apoptosis with monomers and oligomers, respectively. These studies are likely to help the design of novel disease modifying therapies.

Differential effects of pro- and anti-inflammatory cytokines alone or in combinations on the metabolic profile of astrocytes.

We have previously reported that the pro-inflammatory cytokines tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) induce profound modifications of the metabolic profile of astrocytes. The present study was undertaken to further characterize the effects of cytokines in astrocytes and to determine whether similar effects could also be observed in neurons. To do so, selected pro-inflammatory (IL-6 and interferon-γ, in addition to the above-mentioned TNFα and IL-1β) and anti-inflammatory cytokines (IL-4, IL-10, transforming growth factor-β1 and interferon-β) were applied to primary neuronal and astrocytic cultures, and key metabolic parameters were assessed. As a general pattern, we observed that pro-inflammatory cytokines increased glucose utilization in astrocytes while the anti-inflammatory cytokines IL-4 and IL-10 decreased astrocytic glucose utilization. In contrast, no significant change could be observed in neurons. When pairs of pro-inflammatory cytokines were co-applied in astrocytes, several additive or synergistic modifications could be observed. In contrast, IL-10 partially attenuated the effects of pro-inflammatory cytokines. Finally, the modifications of the astrocytic metabolism induced by TNFα + IL-1β and interferon-γ modulated neuronal susceptibility to an excitotoxic insult in neuron-astrocyte co-cultures. Together, these results suggest that pro- and anti-inflammatory cytokines differentially affect the metabolic profile of astrocytes, and that these changes have functional consequences for surrounding neurons.

Youths carrying a weapon or using a weapon in a fight: what makes the difference?

The objective of this study was to characterize weapon-carrying adolescents and to assess whether weapon carriers differ from weapon users. Data were drawn from a cross-sectional school-based survey of 7548 adolescents aged 16-20 years in Switzerland. Youths carrying a weapon were compared with those who do not. Subsequently, weapon carriers were divided into those who had used it in a fight and those who had not. Individual, family, school and social factors were analyzed using bivariate and stepwise multivariate analysis. For both genders, delinquent behavior and being victim of physical violence were associated with weapon carrying. For males, quarreling while intoxicated, being an apprentice, being sensation seekers, having a tattoo, having a poor relationship with parents and practicing unsafe sex were also related to weapon carrying. Compared with weapon carriers, female weapon users were more likely to be regular smokers. Male weapon users were foreign born, urban and apprentices; had poor school connectedness; practiced unsafe sex and quarreled while intoxicated. Carrying a weapon is a relatively frequent behavior among youths in Switzerland and a sizeable proportion of weapon carriers have used it in a fight. Weapon carrying should be part of the clinical assessment and preventive counseling of adolescents. Preventive programs specific for at-risk youth groups need to be developed.

No interactions between previously associated 2-hour glucose gene variants and physical activity or BMI on 2-hour glucose levels.

Gene-lifestyle interactions have been suggested to contribute to the development of type 2 diabetes. Glucose levels 2 h after a standard 75-g glucose challenge are used to diagnose diabetes and are associated with both genetic and lifestyle factors. However, whether these factors interact to determine 2-h glucose levels is unknown. We meta-analyzed single nucleotide polymorphism (SNP) × BMI and SNP × physical activity (PA) interaction regression models for five SNPs previously associated with 2-h glucose levels from up to 22 studies comprising 54,884 individuals without diabetes. PA levels were dichotomized, with individuals below the first quintile classified as inactive (20%) and the remainder as active (80%). BMI was considered a continuous trait. Inactive individuals had higher 2-h glucose levels than active individuals (β = 0.22 mmol/L [95% CI 0.13-0.31], P = 1.63 × 10(-6)). All SNPs were associated with 2-h glucose (β = 0.06-0.12 mmol/allele, P ≤ 1.53 × 10(-7)), but no significant interactions were found with PA (P > 0.18) or BMI (P ≥ 0.04). In this large study of gene-lifestyle interaction, we observed no interactions between genetic and lifestyle factors, both of which were associated with 2-h glucose. It is perhaps unlikely that top loci from genome-wide association studies will exhibit strong subgroup-specific effects, and may not, therefore, make the best candidates for the study of interactions.