Insulin Resistance as a Therapeutic Target for Chronic Kidney Disease.

Insulin resistance (IR) is a prevalent metabolic feature in chronic kidney disease (CKD). Postreceptor insulin-signaling defects have been observed in uremia. A decrease in the activity of phosphatidylinositol 3-kinase appears critical in the pathophysiology of CKD-associated IR. Lipotoxicity due to ectopic accumulation of lipid moieties has recently emerged as another mechanism by which CKD and/or associated metabolic disorders may lead to IR through impairment of various insulin-signaling molecules. Metabolic acidosis, anemia, excess of fat mass, inflammation, vitamin D deficiency, adipokine imbalance, physical inactivity, and the accumulation of nitrogenous compounds of uremia all contribute to CKD-associated IR. The clinical impacts of IR in this setting are numerous, including endothelial dysfunction, increased cardiovascular mortality, muscle wasting, and possibly initiation and progression of CKD. This is why IR may be a therapeutic target in the attempt to improve outcomes in CKD. General measures to improve IR are directed to counteract causal factors. The use of pharmaceutical agents such as inhibitors of the renin-angiotensin system may improve IR in hypertensive and CKD patients. Pioglitazone appears a safe and promising therapeutic agent to reduce IR and uremic-associated abnormalities. However, interventional studies are needed to test if the reduction and/or normalization of IR may actually improve outcomes in these patients.

Mechanical properties of rat cardiac skinned fibers are altered by chronic growth hormone hypersecretion.

Chronic growth hormone (GH) hypersecretion in rats leads to increased isometric force without affecting the unloaded shortening velocity of isolated cardiac papillary muscles, despite a marked isomyosin shift toward V3. To determine if alterations occurred at the level of the contractile proteins in rats bearing a GH-secreting tumor (GH rats), we examined the mechanical properties of skinned fibers to eliminate the early steps of the excitation-contraction coupling mechanism. We found that maximal active tension and stiffness at saturating calcium concentrations (pCa 4.5) were markedly higher in GH rats than in control rats (tension, 52.9 +/- 5.2 versus 38.1 +/- 4.6 mN.mm-2, p < 0.05; stiffness, 1,105 +/- 120 versus 685 +/- 88 mN.mm-2.microns-1, p < 0.01), whereas values at low calcium concentrations (pCa 9) were unchanged. In addition, the calcium sensitivity of the contractile proteins was slightly but significantly higher in GH rats than in control rats (delta pCa 0.04, p < 0.001). The crossbridge cycling rate, reflected by the response to quick length changes, was lower in GH rats than in control rats (62.0 +/- 2.6 versus 77.4 +/- 6.6 sec-1, p < 0.05), in good agreement with a decrease in the proportion of alpha-myosin heavy chains in the corresponding papillary muscles (45.5 +/- 2.0% versus 94.6 +/- 2.4%, p < 0.001). The changes in myosin heavy chain protein phenotype were paralleled by similar changes of the corresponding mRNAs, indicating that the latter occurred mainly at a pretranslational level. These results demonstrate that during chronic GH hypersecretion in rats, alterations at the myofibrillar level contribute to the increase in myocardial contractility observed in intact muscle.

The new EASL guidelines for the management of chronic hepatitis B infection adapted for Swiss physicians.

Since the arrival of several new antivirals and due to the growing molecular and clinical knowledge of hepatitis B virus (HBV) infection, therapy of hepatitis B has become complex. Clinical guidelines aim at streamlining medical attitudes: in this respect, the European Association for the Study of the Liver (EASL) recently issued clinical practice guidelines for the management of chronic hepatitis B. Guidelines made by international experts need however to be adapted to local health care systems. Here, we summarise the EASL guidelines with some minor modifications in order to be compatible with the particular Swiss situation, while discussing in more detail some aspects. Chronic hepatitis B is a complex disease with several phases where host and viral factors interact: the features of this continuous interplay need to be evaluated when choosing the most appropriate treatment. The EASL guidelines recommend, as first-line agents, using the most potent antivirals available with the optimal resistance profile, in order to abate HBV DNA as rapidly and as sustainably as possible. Once therapy has been started, the infection evolves and resistant viral strains may emerge. Rescue therapy needs to be started early with more potent agents lacking cross-resistance.

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: a comparative risk assessment.

BACKGROUND: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. METHODS: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. FINDINGS: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. INTERPRETATION: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. FUNDING: UK Medical Research Council, US National Institutes of Health.

Family doctors' consultations with people suffering from chronic pain without objective findings: Which protective practices might they develop in these challenging medical encounters?

Introduction: Consultations with patients suffering from chronic pain without objective findings represent a challenge fo r family doctors (FDs). A mutual lack of understanding may arise, which threatens the doctor-patient relationship and may lead to dissatisfaction of both patient and doctor and to a breakdown of the therapeutic alliance. Objectives: This study aims to investigate FDs' potential protective practices to preserve the doctor-patient relationship during this type of consultation. Method: In the first step of this qualitative research, I carried out a range of 10 se- mi-structured interviews with FDs to explore their reported practices and repre- sentations during consultations with people suffering from chronic pain without objective findings. The interviews' transcripts were integrally analysed with computer-assisted thematic content analysis (QSR NVivo ® ) to highlight the main themes related to the topic in the participants' talk. Results: At this point of the research, two types of FDs' protective practices can be identified: first the use of complementary sources of knowledge in addition to the medical model to provide explanations to patients, second the collaboration with multidisciplinary teams or support gr oups that allow them to share profes- sional expertise and emotional experiences. Conclusion: The findings could be useful to develop ways to improve the follow- up of patients suffering from chronic pain without objective findings and conse- quently the FDs' work satisfaction.

Poor reward sensitivity and apathy after stroke: implication of basal ganglia.

OBJECTIVE: To examine the relationship between reward sensitivity and self-reported apathy in stroke patients and to investigate the neuroanatomical correlates of both reward sensitivity and apathy. METHODS: In this prospective study, 55 chronic stroke patients were administered a questionnaire to assess apathy and a laboratory task to examine reward sensitivity by measuring motivationally driven behavior ("reinforcement-related speeding"). Fifteen participants without brain damage served as controls for the laboratory task. Negative mood, working memory, and global cognitive functioning were also measured to determine whether reward insensitivity and apathy were secondary to cognitive impairments or negative mood. Voxel-based lesion-symptom mapping was used to explore the neuroanatomical substrates of reward sensitivity and apathy. RESULTS: Participants showed reinforcement-related speeding in the highly reinforced condition of the laboratory task. However, this effect was significant for the controls only. For patients, poorer reward sensitivity was associated with greater self-reported apathy (p < 0.05) beyond negative mood and after lesion size was controlled for. Neither apathy nor reward sensitivity was related to working memory or global cognitive functioning. Voxel-based lesion-symptom mapping showed that damage to the ventral putamen and globus pallidus, dorsal thalamus, and left insula and prefrontal cortex was associated with poorer reward sensitivity. The putamen and thalamus were also involved in self-reported apathy. CONCLUSIONS: Poor reward sensitivity in stroke patients with damage to the ventral basal ganglia, dorsal thalamus, insula, or prefrontal cortex constitutes a core feature of apathy. These results provide valuable insight into the neural mechanisms and brain substrate underlying apathy.

Insufficient coping behavior under chronic stress and vulnerability to psychiatric disorders

Epidemiological data indicate that 75% of subjects with major psychiatric disorders have their onset in the age range of 17-24 years. An estimated 35-50% of college and university students drop out prematurely due to insufficient coping skills under chronic stress, while 85% of students receiving a psychiatric diagnosis withdraw from college/university prior to the completion of their education. In this study we aimed at developing standardized means for identifying students with insufficient coping skills under chronic stress and at risk for mental health problems. A sample of 1,217 college students from 3 different sites in the U.S. and Switzerland completed 2 self-report questionnaires: the Coping Strategies Inventory "COPE" and the Zurich Health Questionnaire "ZHQ" which assesses "regular exercises", "consumption behavior", "impaired physical health", "psychosomatic disturbances", and "impaired mental health". The data were subjected to structure analyses by means of a Neural Network approach. We found 2 highly stable and reproducible COPE scales that explained the observed inter-individual variation in coping behavior sufficiently well and in a socio-culturally independent way. The scales reflected basic coping behavior in terms of "activity-passivity" and "defeatism-resilience", and in the sense of stable, socio-culturally independent personality traits. Correlation analyses carried out for external validation revealed a close relationship between high scores on the defeatism scale and impaired physical and mental health. This underlined the role of insufficient coping behavior as a risk factor for physical and mental health problems. The combined COPE and ZHQ instruments appear to constitute powerful screening tools for insufficient coping skills under chronic stress and for risks of mental health problems.

Evolution of foraging behaviour in response to chronic malnutrition in Drosophila melanogaster.

Chronic exposure to food of low quality may exert conflicting selection pressures on foraging behaviour. On the one hand, more active search behaviour may allow the animal to find patches with slightly better, or more, food; on the other hand, such active foraging is energetically costly, and thus may be opposed by selection for energetic efficiency. Here, we test these alternative hypotheses in Drosophila larvae. We show that populations which experimentally evolved improved tolerance to larval chronic malnutrition have shorter foraging path length than unselected control populations. A behavioural polymorphism in foraging path length (the rover-sitter polymorphism) exists in nature and is attributed to the foraging locus (for). We show that a sitter strain (for(s2)) survives better on the poor food than the rover strain (for(R)), confirming that the sitter foraging strategy is advantageous under malnutrition. Larvae of the selected and control populations did not differ in global for expression. However, a quantitative complementation test suggests that the for locus may have contributed to the adaptation to poor food in one of the selected populations, either through a change in for allele frequencies, or by interacting epistatically with alleles at other loci. Irrespective of its genetic basis, our results provide two independent lines of evidence that sitter-like foraging behaviour is favoured under chronic larval malnutrition.

Anévrismes de l'artère poplitée: quelle prise en charge en 2013 ? [Popliteal artery aneurysms: management in 2013].

Although rare, popliteal artery aneurysms are the most common peripheral aneurysms and are frequently associated with abdominal aorta aneurysms. They are often bilateral. One third of patients are asymptomatic at diagnosis, with an insidious evolution. Symptomatic patients may present with symptoms of either acute ischemia or chronic ischemia, or rarely compression or rupture. Surgical exclusion of aneurysm followed by venous bypass remains the treatment of choice. Endovascular treatment is an attractive alternative currently reserved for patients at high risk, with good anatomical criteria. Elective treatment before symptoms onset is preferable given the best results in terms of patency and complications. A conservative approach is allowed for small aneurysms without major embolic risk provided careful monitoring by ultrasound.

Treatment of chronic hepatitis c in 3 patients with hcv-induced severe thrombocytopenia

BACKGROUND: Thrombocytopenia has been described in HCV infection even in the absence of cirrhosis and splenomegaly. Different mechanisms have been proposed, including immunemediated platelet (plt) destruction. Here, we report on the treatment of 3 patients with HCV-HIV coinfection and HCVinduced severe thrombocytopenia. PATIENTS AND TREATMENT: All patients had an infection with HCV genotype 3, an intermediate fibrosis stage (Metavir F2 or F3), HIV infection controlled by antiretroviral combination therapy, and severe, steroid-refractory thrombocytopenia. Pegylated interferon-α2a (PEG-IFN-α2a) was started at 45 or 90 μg per week and doses were rapidly increased in the following, while ribavirin (RBV) was prescribed at standard doses. Treatment was pursued for 48 weeks. Two patients received intravenous immunoglobulins (IVIG) during the first weeks of PEG-IFN-α2a and RBV combination therapy. RESULTS: A significant increase in plt counts (from 17, 39 and 37 G/l, respectively, to > 100 G/l) was observed in the 3 patients while they experienced a virological response. Thrombocytopenia relapsed in one patient together with a relapse of chronic hepatitis C. The other 2 patients achieved a sustained virological response (SVR), with normal plt counts at follow-up in one and persistent mild thrombocytopenia in the other. CONCLUSIONS: Carefully titrated PEG-IFN-α2a and RBV combination therapy may be performed safely in this difficult-totreat patient population, with close monitoring and eventually concomitant IVIG during the first weeks. SVR can lead to normalization or significant improvement of plt counts, suggesting a causative role of HCV in this condition.

Squamous cell carcinoma in 6 patients with chronic discharging osteomyelitis: Is it really rare?

Introduction: Development of a squamous cell carcinoma (Marjolin's ulcer) is a rare but well-known complication of chronic discharging osteomyelitis. A high index of suspicion and highquality of histopathological examination are paramount in order to make the correct diagnosis. Methods: During a 15-year period (1993 and 2008), patients with long-standing chronic osteomyelitis with clinical symptoms of >1 year of duration, were retrospectively reviewed. Included were patients with histologically confirmed squamous-cell carcinoma associated with chronic wound overlying the site of chronic osteomyelitis. Clinical features and treatment approaches of these patients were analyzed. Results: During the study period, 6 patients were identified (2 women and 4 men) aged 52 to 67 years (mean 59 years). All patients had a long history of chronic discharging osteomyelitis (12, 19, 21, 30, 39 and 40 years), localized in the lower (5 patients) or upper extremitiy (1 patient). All tumors were histologically highly-differentiated squamous-cell carcinomas involving the deep soft tissues and the bone. 5 of 6 patients were initially misdiagnosed as chronic bone infection since bacteria were isolated in wound swabs, including Staphylococcus aureus (n = 3), Escherichia coli (n = 1) and Staphylococcus epidermidis (n = 1). Treatment consisted of major amputation in 4 patients and radical surgical excision in 2 patients refusing amputation. 4 patients were lost to follow-up due to return to their country of origin, the remaining 2 patients were without signs of tumor recurrence (both after major amputation). Conclusion: Malignant transformation of is a rare, but serious complication of long-standing discharging chronic osteomyelitis. All 6 patients were diagnosed after >10 years of persistent or recurrent wounds. It should be particularly suspected in case of a pathological fracture, development of exophytic mass and changes in local pattern of the ulcers itself. Multiple biopsies, including deep soft tissues and bone, are recommended to distinguish between chronic osteomyelitis, pseudoepitheliomatous hyperplasia and highly-differentiated squamous cell carcinoma. Early diagnosis and a team approach (orthopaedic and plastic surgeon) are crucial for optimal management of the patient

Anti-TNF Therapy in the Treatment of Psoriasis in a Patient with Acute-on-Chronic Pancreatitis.

Background: Psoriasis is accepted as a multisystemic disease with several important systemic manifestations. Thus, underlying comorbidities have to be taken into account in the choice of treatment. Objective: To explore the role of anti-TNF therapy in the treatment of psoriasis in a patient with acute-on-chronic pancreatitis. Methods: Here, we present the case of a 75-year-old patient with severe psoriasis also suffering from chronic alcohol-induced pancreatitis with recurrent acute flares. A recent life-threatening episode of acute pancreatitis and ischemic liver precluded the reintroduction of methotrexate. Cyclosporine was also excluded as it has been reported to induce acute pancreatitis. Thus, an anti-TNF treatment was initiated in close collaboration with a gastroenterologist. Results: A year after starting anti-TNF therapy the patient continues to show complete clinical remission of his psoriasis. No side effects, particularly no bacterial infections, were reported. No relapses of the patient's underlying chronic pancreatitis were observed throughout the entire treatment with regular clinical and laboratory monitoring, suggesting that chronic pancreatitis is not per se a contraindication for anti-TNF therapy. Conclusion: This case study opens the way for further questioning on the role of TNF in the pathogenesis of chronic and acute pancreatitis and the use of anti-TNF therapy in its treatment. © 2013 S. Karger AG, Basel.

Fièvre à répétition chez l'enfant: penser au syndrome de PFAPA [Periodic fever in children: keep in mind the PFAPA syndrome]

Les maladies autoinflammatoires font partie du diagnostic différentiel de l'état fébrile à répétition chez l’enfant. Ces maladies sont caractérisées par des poussées inflammatoires sans cause évidente. Certaines de ces maladies, comme la Fièvre méditerranéenne familiale, ont une origine génétique et nécessitent un traitement régulier pour éviter des conséquences graves à long terme. Le syndrome de PFAPA est la plus fréquente des fièvres récurrentes et son diagnostic se base sur des critères diagnostiques peu précis. Son traitement reste controversé. La prednisone en dose unique permet d'interrompre la poussée et l'amygdalectomie peut induire une rémission dans une majorité des cas. The autoinflammatory diseases should be considered in the differential diagnosis of recurrent fever in childhood. These diseases are characterized by inflammatory episodes without an evident cause. Some of these diseases, like the Familial Mediterranean Fever, have a genetic origin and need a chronic treatment to avoid severe complications on the long term. PFAPA syndrome is the most frequent cause of recurrent fever and is diagnosed based on unspecific criteria. The treatment is still controversial. One dose of Prednisone is able to interrupt the flare and tonsillectomy may induce a remission in the majority of the cases

Effect of acute and chronic exercise on fat oxidation and hormonal and plasma metabolite kinetics in obese and severely obese men

Acute exercise increases energy expenditure (EE) during exercise and post-exercise recovery [excess post-exercise oxygen consumption (EPOC)] and therefore may be recommended as part of the multidisciplinary management of obesity. Moreover, chronic exercise (training) effectively promotes an increase in insulin sensitivity, which seems to be associated with increased fat oxidation rates (FORs). The main purpose of this thesis is to investigate 1) FORs and extra-muscular factors (hormones and plasma metabolites) that regulate fat metabolism during acute and chronic exercise; and 2) EPOC during acute post-exercise recovery in obese and severely obese men (class II and III). In the first study, we showed that obese and severely obese men present a lower exercise intensity (Fatmax) eliciting maximal fat oxidation and a lower reliance on fat oxidation at high, but not at low and moderate, exercise intensities compared to lean men. This was most likely related to an impaired muscular capacity to oxidize non-esterified fatty acids (NEFA) rather than decreased plasma NEFA availability or a change in the hormonal milieu during exercise. In the second study, we developed an accurate maximal incremental test to correctly and simultaneously evaluate aerobic fitness and fat oxidation kinetics during exercise in this population. This test may be used for the prescription of an appropriate exercise training intensity. In the third study, we demonstrated that only 2 wk of exercise training [continuous training at Fatmax and adapted high-intensity interval training (HIIT)], matched with respect to mechanical work, may be effective to improve aerobic fitness, FORs during exercise and insulin sensitivity, which suggest that FORs might be rapidly improved and that adapted HIIT is feasible in this population. The increased FORs concomitant with the lack of changes in lipolysis during exercise suggest an improvement in the mismatching between NEFA availability and oxidation, highlighting the importance of muscular (oxidative capacity) rather than extra-muscular (hormones and plasma metabolites) factors in the regulation of fat metabolism after a training program. In the fourth study, we observed a positive correlation between EE during exercise and EPOC, suggesting that a chronic increase in the volume or intensity of exercise may increase EE during exercise and during recovery. This may have an impact in weight management in obesity. In conclusion, these findings might have practical implications for exercise training prescriptions in order to improve the therapeutic approaches in obesity and severe obesity. -- L'exercice aigu augmente la dépense énergétique (DE) pendant l'exercice et la récupération post-exercice [excès de consommation d'oxygène post-exercise (EPOC)] et peut être utilisé dans la gestion multidisciplinaire de l'obésité. Quant à l'exercice chronique (entraînement), il est efficace pour augmenter la sensibilité à l'insuline, ce qui semble être associé à une amélioration du débit d'oxydation lipidique (DOL). Le but de cette thèse est d'étudier 1) le DOL et les facteurs extra-musculaires (hormones et métabolites plasmatiques) qui régulent le métabolisme lipidique pendant l'exercice aigu et chronique et 2) l'EPOC lors de la récupération aiguë post-exercice chez des hommes obèses et sévèrement obèses (classe II et III). Dans la première étude nous avons montré que les hommes obèses et sévèrement obèses présentent une plus basse intensité d'exercice (Fatmax) correspondant au débit d'oxydation lipidique maximale et un plus bas DOL à hautes, mais pas à faibles et modérées, intensités d'exercice comparé aux sujets normo-poids, ce qui est probablement lié à une incapacité musculaire à oxyder les acides gras non-estérifiés (AGNE) plutôt qu'à une diminution de leur disponibilité ou à un changement du milieu hormonal pendant l'exercice. Dans la deuxième étude nous avons développé un test maximal incrémental pour évaluer simultanément l'aptitude physique aérobie et la cinétique d'oxydation des lipides pendant l'exercice chez cette population. Dans la troisième étude nous avons montré que seulement deux semaines d'entraînement (continu à Fatmax et intermittent à haute intensité), appariés par la charge de travail, sont efficaces pour améliorer l'aptitude physique aérobie, le DOL pendant l'exercice et la sensibilité à l'insuline, ce qui suggère que le DOL peut être rapidement amélioré chez cette population. Ceci, en absence de changements de la lipolyse pendant l'exercice, suggère une amélioration de la balance entre la disponibilité et l'oxydation des AGNE, ce qui souligne l'importance des facteurs musculaires (capacité oxydative) plutôt que extra-musculaires (hormones et métabolites plasmatiques) dans la régulation du métabolisme lipidique après un entraînement. Dans la quatrième étude nous avons observé une corrélation positive entre la DE pendant l'exercice et l'EPOC, ce qui suggère qu'une augmentation chronique du volume ou de l'intensité de l'exercice pourrait augmenter la DE lors de l'exercice et lors de la récupération post-exercice. Ceci pourrait avoir un impact sur la gestion du poids chez cette population. En conclusion, ces résultats pourraient avoir des implications pratiques lors de la prescription des entraînements dans le but d'améliorer les approches thérapeutiques de l'obésité et de l'obésité sévère.