GLUT4, AMP kinase, but not the insulin receptor, are required for hepatoportal glucose sensor-stimulated muscle glucose utilization.

Recent evidence suggests the existence of a hepatoportal vein glucose sensor, whose activation leads to enhanced glucose use in skeletal muscle, heart, and brown adipose tissue. The mechanism leading to this increase in whole body glucose clearance is not known, but previous data suggest that it is insulin independent. Here, we sought to further determine the portal sensor signaling pathway by selectively evaluating its dependence on muscle GLUT4, insulin receptor, and the evolutionarily conserved sensor of metabolic stress, AMP-activated protein kinase (AMPK). We demonstrate that the increase in muscle glucose use was suppressed in mice lacking the expression of GLUT4 in the organ muscle. In contrast, glucose use was stimulated normally in mice with muscle-specific inactivation of the insulin receptor gene, confirming independence from insulin-signaling pathways. Most importantly, the muscle glucose use in response to activation of the hepatoportal vein glucose sensor was completely dependent on the activity of AMPK, because enhanced hexose disposal was prevented by expression of a dominant negative AMPK in muscle. These data demonstrate that the portal sensor induces glucose use and development of hypoglycemia independently of insulin action, but by a mechanism that requires activation of the AMPK and the presence of GLUT4.

Immunodéficience commune variable: ce qu'il faut savoir [Common variable immune deficiency: what you need to know].

Common variable immune deficiency is the most frequent primary immune deficiency, characterized mainly by a disorder of B lymphocytes differentiation and a deficit in immunoglobulins. The clinical manifestations include recurrent infections, non-infectious lung and digestive involvements, autoimmune diseases, and an increased susceptibility to cancers. Recent breakthroughs have been made in the understanding of some genetic mechanisms of the disease. Replacement therapy with intravenous immunoglobulins remains the treatment of choice, which allows significant improvement in the survival and quality of life. However progress should be made in the understanding of the pathophysiology and in the early detection of this disease, since a delay in the diagnosis may have harmful consequences in terms of morbidity and mortality.

Is pretreatment with Beta-blockers beneficial in patients with acute coronary syndrome?

OBJECTIVES: The role of beta-blockers in the treatment of hypertension is discussed controversially and the data showing a clear benefit in acute coronary syndromes (ACS) were obtained in the thrombolysis era. The goal of this study was to analyze the role of pretreatment with beta-blockers in patients with ACS. METHODS: Using data from the Acute Myocardial Infarction in Switzerland (AMIS Plus) registry, we analyzed outcomes of patients with beta-blocker pretreatment in whom they were continued during hospitalization (group A), those without beta-blocker pretreatment but with administration after admission (group B) and those who never received them (group C). Major adverse cardiac events defined as composed endpoint of re-infarction and stroke (during hospitalization) and/or in-hospital death were compared between the groups. RESULTS: A total of 24,709 patients were included in the study (6,234 in group A, 12,344 in group B, 6,131 in group C). Patients of group B were younger compared to patients of group A and C (62.5, 67.6 and 68.4, respectively). In the multivariate analysis, odds ratio for major adverse cardiac events was 0.59 (CI 0.47-0.74) for group A and 0.66 (CI 0.55-0.83) for group B, while group C was taken as a reference. CONCLUSIONS: beta-Blocker therapy is beneficial in ACS and they should be started in those who are not pretreated and continued in stable patients who had been on chronic beta-blocker therapy before.

Pré-éclampsie et troubles électrolytiques: à propos d'un cas [Electrolyte disorders in preeclampsia. A case report].

The occurrence of electrolyte disorders as hypocalcemia and/or hyponatremia is an uncommon event in preeclampsia, which can be the sign of serious situation, with potentially unfavourable consequences for the mother and her foetus. Hyponatremia in the setting of preeclampsia is an indicator of severity, and requires the understanding of the etiologic mechanisms to initiate an appropriate treatment. Indeed the often-considered fluid restriction is rarely a treatment option for pregnant women. Hypocalcemia is a complication that must be monitored when a treatment with high doses of intravenous magnesium sulphate is introduced. In this context, hypocalcemia must be sought, with the exclusion of other etiologies as vitamin D deficiency, hypoparathyroidism or renal and extrarenal loss of calcium. A replacement therapy, intravenous or oral according to circumstances, should be considered in case of severe or symptomatic hypocalcemia.

Evaluation of tumor vascularisation in two rat sarcoma models for studying isolated lung perfusion : Injection route determines the origin of tumour vessels

Résumé Introduction: La perfusion isolée cytostatique du poumon est une technique attractive qui permet l'administration des doses élevées d'un agent cytostatique tout en épargnant dans la mesure du possible la circulation systémique. Cependant, la perfusion de l'artère pulmonaire risque d'épargner le territoire pulmonaire vascularisé par l'intermédiaire des artères bronchiques, ce qui pourrait diminuer l'efficacité de ce traitement au cas où la lésion ciblée est vascularisée par les artères bronchiques. Ce travail est destiné au développement d'un modèle tumoral au niveau des poumons de rongeur (rat) porteur d'un sarcome pulmonaire afin de déterminer si la voie d'injection des cellules tumorales (intraveineuse, versus intratumorale) influencera la vascularisation des tumeurs (provenant du système artères pulmonaires ou artères bronchiques). Méthod: Des tumeurs de sarcomes pulmonaires ont été générées par injection d'une suspension cellulaire de sarcome, soit par injection intraveineuse, soit directement dans le parenchyme pulmonaire par thoracotomie. Ensuite, une perfusion isolée du poumon porteur de la tumeur à l'aide de l'encre a été effectuée, soit par l'artère pulmonaire, soit par le système des artères bronchiques. La distribution de l'encre dans les vaisseaux tumoraux ainsi que dans les vaisseaux non tumoraux du poumon adjacent a été investiguée à l'aide d'une analyse histologique des poumons perfusés. Résultat: L'administration intraveineuse et intratumorale de la suspension de cellules tumorales résulte en des tumeurs similaires sur le plan histologique. Néanmoins, l'injection intra-parenchymateuse démontre des tumeurs plus homogènes et avec un développement plus prédictible, était associée à une survie plus longue qu'après injection intraveineuse. Les analyses histologiques après perfusion isolée à l'aide de l'encre démontre que les tumeurs résultant de l'injection intraveineuse ont développé une vascularisation se basant sur le système d'artères pulmonaires tandis que les tumeurs émergeant après injection intraparenchymateuse ont développé une vascularisation provenant du système des artères bronchiques. Conclusion: Ce travail démontre pour la première fois l'importance du mode de génération de tumeurs pulmonaires en ce qui concerne leur future vascularisation, ce qui pourrait avoir un impact sur leur traitement par perfusion isolée du poumon. Abstract Isolated cytostatic lung perfusion (ILP) is an attractive technique allowing delivery of a high-dose of cytostatic agents to the lungs while limiting systemic toxicity. In developing a rat model of ILP, we have analysed the effect of the route of tumour cell injection on the source of tumour vessels. Pulmonary sarcomas were estab¬lished by injecting a sarcoma cell suspension either by the intravenous (i.v.) route or directly into the lung paren¬chyma. Ink perfusion through either pulmonary artery (PA) or bronchial arteries (BA) was performed and the characteristics of the tumour deposits defined. i.v. and direct injection methods induced pulmonary sarcoma nodules, with similar histological features. The intraparenchymal injection of tumour cells resulted in more reli¬able and reproducible tumour growth and was associat¬ed with a longer survival of the animals. i.v. injected tumours developed a PA-derived vascular tree whereas directly injected tumours developed a BA-derived vasculature.

Impact of an intervention to control risk associated with patient transfer.

QUESTION UNDER STUDY: Hospitals transferring patients retain responsibility until admission to the new health care facility. We define safe transfer conditions, based on appropriate risk assessment, and evaluate the impact of this strategy as implemented at our institution. METHODS: An algorithm defining transfer categories according to destination, equipment monitoring, and medication was developed and tested prospectively over 6 months. Conformity with algorithm criteria was assessed for every transfer and transfer category. After introduction of a transfer coordination centre with transfer nurses, the algorithm was implemented and the same survey was carried out over 1 year. RESULTS: Over the whole study period, the number of transfers increased by 40%, chiefly by ambulance from the emergency department to other hospitals and private clinics. Transfers to rehabilitation centres and nursing homes were reassigned to conventional vehicles. The percentage of patients requiring equipment during transfer, such as an intravenous line, decreased from 34% to 15%, while oxygen or i.v. drug requirement remained stable. The percentage of transfers considered below theoretical safety decreased from 6% to 4%, while 20% of transfers were considered safer than necessary. A substantial number of planned transfers could be "downgraded" by mutual agreement to a lower degree of supervision, and the system was stable on a short-term basis. CONCLUSION: A coordinated transfer system based on an algorithm determining transfer categories, developed on the basis of simple but valid medical and nursing criteria, reduced unnecessary ambulance transfers and treatment during transfer, and increased adequate supervision.

Methadone maintenance treatment (MMT) in general practice or in specialized centers: profile of patients in the Swiss Canton of Vaud.

We studied profile of patients (n=1782) treated in specialized centers and general practice (GP) enrolled in methadone maintenance treatment (MMT) programs during 2001 in the Swiss Canton of Vaud. We found that GPs treated the majority of patients (76%). Specialized centers treated a higher proportion of patients with uncontrolled intravenous use of cocaine and heroin, and prescribed neuroleptics as concomitant medication three times more frequently than GPs. Patients treated in specialized centers were more likely to undergo screening for HIV, HBV, HCV, and receive complete HBV immunization. In conclusion, specialized centers are more likely to treat severely addicted patients and patients with a poor global assessment (physical, psychiatric, and social).

Treatment of symphysitis pubis with one unique iv injection of Ibandronate: report of two cases

Objective: Osteitis pubis is a noninfectious painful inflammatorydisorder of the symphysis pubis. Etiologic factors are numerous, themost common are: osseous extension of adductor, enthesis due tosport overuse, irritation after urological and abdominal procedures,and systemic inflammatory disorders in particularspondylarthropathies. Many cases are idiopathic. The symptomsconsist of regional chronic mechanical and sometime nocturnal pain.Diagnosis is usually confirmed by either bone scintigraphy or by MRI.There are no standard treatments but conservative approachesincluding rest and NSAIDS are generally recommended. In 2001, agood clinical and radiological response of three refractory cases with3 to 6 monthly perfusions of pamidronate was reported [1].Ibandronate is a much more powerful and long-lasting bisphosphonatethan pamidronate, and has not yet been reported in literature to ourknowledge in this indication.Patients and Methods: We present two cases of idiopathic origin:one woman (63 years old) and one man (36 years old).The symptomswere present >3 months in the first patient and one year in the second.The diagnosis was confirmed by MRI which showed bone edemaon both sizes of symphysis and in the second case bony erosionsadjacent to the joint were seen. Both cases failed to respond toconservative measures. Both patients received one single direct ivInjection of 3 mg of Ibandronate.Results: The injections resulted in a rapid (within a few days)resolution of pain that lasted more than 6 months in both patients.No side effects were observed. In the first case, an isotope bone scanperformed 4 months after the injection showed no residual uptake. Thesecond patient had a repeated MRI after 6 months. It demonstrated anattenuation of bone edema compared to the first MRI.Conclusion: IV Ibandronate may constitute a safe and effectivetreatment option for patients with refractory osteitis pubis.References1 Maksymowych WP, Aaron SL, Russell AS. Treatment of refractorysymphysitis pubis with intravenous pamidronate. J Rheumatol.2001;28(12):2754, 2001.

Eculizumab to treat antibody-mediated rejection in a 7-year-old kidney transplant recipient.

We report on successful early eculizumab administration to treat acute antibody-mediated rejection (ABMR) in a highly sensitized kidney transplant recipient. The recipient is a 7-year-old boy who received, 6 months after a desensitization protocol with monthly intravenous immunoglobulin infusion, a second kidney transplant in the presence of low donor-specific antibodies (DSAs). Both pretransplant lymphocytotoxic and flow cytometric crossmatch were negative. Allograft function recovered promptly, with excellent initial function. On postoperative day (POD) 4, the child developed significant proteinuria with an acute rise in serum creatinine. Allograft biopsy showed severe acute ABMR. Intravenous eculizumab (600 mg), preceded by a single session of plasmapheresis, was administered on POD 5 and 12 along with a 4-day thymoglobulin course. After the first dose of eculizumab, a strikingly rapid normalization of allograft function with a decrease in proteinuria occurred. However, because circulating DSA levels remained elevated, the child received 3 doses of intravenous immunoglobulin (POD 15, 16, and 17), with a significant subsequent decrease in DSA levels. At 9 months after transplant, the child continues to maintain excellent allograft function with undetectable circulating DSA levels. This unique case highlights the potential efficacy of using early eculizumab to rapidly reverse severe ABMR in pediatric transplantation, and therefore it suggests a novel therapeutic approach to treat acute ABMR.

The Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+): rationale and methodology.

Venous thromboembolism (VTE) is common and has a high impact on morbidity, mortality, and costs of care. Although most of the patients with VTE are aged ≥65 years, there is little data about the medical outcomes in the elderly with VTE. The Swiss Cohort of Elderly Patients with VTE (SWITCO65+) is a prospective multicenter cohort study of in- and outpatients aged ≥65 years with acute VTE from all five Swiss university and four high-volume non-university hospitals. The goal is to examine which clinical and biological factors and processes of care drive short- and long-term medical outcomes, health-related quality of life, and medical resource utilization in elderly patients with acute VTE. The cohort also includes a large biobank with biological material from each participant. From September 2009 to March 2012, 1,863 elderly patients with VTE were screened and 1003 (53.8 %) were enrolled in the cohort. Overall, 51.7 % of patients were aged ≥75 years and 52.7 % were men. By October 16, 2012, after an average follow-up time of 512 days, 799 (79.7 %) patients were still actively participating. SWITCO65+ is a unique opportunity to study short- and long-term outcomes in elderly patients with VTE. The Steering Committee encourages national and international collaborative research projects related to SWITCO65+, including sharing anonymized data and biological samples.

Persistent human parvovirus B19 infection in children under maintenance chemotherapy for acute lymphocytic leukemia.

OBJECTIVE: To report on B19 infection management and chemotherapy schedule consequences in five children treated for acute lymphocytic leukemia (ALL). PATIENTS AND METHODS: Between May 2001 and February 2002, five patients between 4 and 12 years of age, receiving maintenance chemotherapy for ALL, presented with symptoms suggesting B19 infection (pallor, fatigue, petechiae and pancytopenia in four patients; generalized rash in two patients; acute hepatitis in one patient). Qualitative polymerase chain reaction (PCR) on peripheral blood was used for diagnosis and follow-up of infection; quantitative PCR was used for viral load measurement. Intravenous nonspecific high-dose immunoglobulin therapy was administered until PCR was negative. RESULTS: Qualitative B19 DNA was found in the peripheral blood of all patients, confirming the infection. Viral load at diagnosis ranged from 10 to 10 particles/mL blood. B19 DNA was detectable in four patients at 45, 21, 40, and 44 weeks, respectively. Chemotherapy was delayed in all patients. No clear benefit of intravenous immunoglobulin was noted. CONCLUSIONS: Infection with B19 is rarely reported in patients with ALL, but it should be suspected when unexplained pancytopenia occurs during chemotherapy. Persistent B19 infection remains a challenge in the management of patients receiving maintenance chemotherapy for ALL, as no specific therapy such as a specific immunoglobulin or vaccine exists. The role of viral load measurement needs to be established in terms of its use in follow-up and evaluation of the therapeutic response.

Mapping HIV-related behavioural surveillance among injecting drug users in Europe, 2008.

The systematic collection of behavioural information is an important component of second-generation HIV surveillance. The extent of behavioural surveillance among injecting drug users (IDUs) in Europe was examined using data collected through a questionnaire sent to all 31 countries of the European Union and European Free Trade Association as part of a European-wide behavioural surveillance mapping study on HIV and other sexually transmitted infections. The questionnaire was returned by 28 countries during August to September 2008: 16 reported behavioural surveillance studies (two provided no further details). A total of 12 countries used repeated surveys for behavioural surveillance and five used their Treatment Demand Indicator system (three used both approaches). The data collected focused on drug use, injecting practices, testing for HIV and hepatitis C virus and access to healthcare. Eight countries had set national indicators: three indicators were each reported by five countries: the sharing any injecting equipment, uptake of HIV testing and uptake of hepatitis C virus testing. The recall periods used varied. Seven countries reported conducting one-off behavioural surveys (in one country without a repeated survey, these resulted an informal surveillance structure). All countries used convenience sampling, with service-based recruitment being the most common approach. Four countries had used respondent-driven sampling. Three fifths of the countries responding (18/28) reported behavioural surveillance activities among IDUs; however, harmonisation of behavioural surveillance indicators is needed.

Gender differences in HIV progression to AIDS and death in industrialized countries: slower disease progression following HIV seroconversion in women.

To evaluate sex differences in human immunodeficiency virus (HIV) disease progression before (pre-1997) and after (1997-2006) introduction of highly active antiretroviral therapy, the authors used data from a collaboration of 23 HIV seroconverter cohort studies from Europe, Australia, and Canada restricted to the 6,923 seroconverters infected through injecting drug use and sex between men and women. Within a competing risk framework, they used Cox proportional hazards models allowing for late entry to evaluate sex differences in time from HIV seroconversion to death, to acquired immunodeficiency syndrome (AIDS), and to each first AIDS-defining disease and death without AIDS. While no significant sex differences were found before 1997, from 1997 onward, women had a lower risk of AIDS (adjusted cumulative relative risk (aCRR) = 0.76, 95% confidence interval (CI): 0.63, 0.90) and death (adjusted hazard ratio = 0.68, 95% CI: 0.56, 0.82) than men did. Compared with men, women also had lower risks of AIDS dementia complex (aCRR = 0.23, 95% CI: 0.07, 0.74), tuberculosis (aCRR = 0.60, 95% CI: 0.39, 0.92), Kaposi's sarcoma (aCRR = 0.27, 95% CI: 0.07, 0.99), lymphomas (aCRR = 0.47, 95% CI: 0.23, 0.96), and death without AIDS (aCRR = 0.74, 95% CI: 0.56, 0.98). Sex differences in HIV disease progression have become larger and statistically significant in the era of highly active antiretroviral therapy, supporting a stronger impact of health interventions among women.

Simulation of amoxicillin pharmacokinetics in humans for the prevention of streptococcal endocarditis in rats.

The pharmacokinetic determinants of successful antibiotic prophylaxis of endocarditis are not precisely known. Differences in half-lives of antibiotics between animals and humans preclude extrapolation of animal results to human situations. To overcome this limitation, we have mimicked in rats the amoxicillin kinetics in humans following a 3-g oral dose (as often used for prophylaxis of endocarditis) by delivering the drug through a computerized pump. Rats with catheter-induced vegetations were challenged with either of two strains of antibiotic-tolerant viridans group streptococci. Antibiotics were given either through the pump (to simulate the whole kinetic profile during prophylaxis in humans) or as an intravenous bolus which imitated only the peak level of amoxicillin (18 mg/liter) in human serum. Prophylaxis by intravenous bolus was inoculum dependent and afforded a limited protection only in rats challenged with the minimum inoculum size infecting > or = 90% of untreated controls. In contrast, simulation of kinetics in humans significantly protected animals challenged with 10 to 100 times the inoculum of either of the test organisms infecting > or = 90% of untreated controls. Thus, simulation of the profiles of amoxicillin prophylaxis in human serum was more efficacious than mere imitation of the transient peak level in rats. This confirms previous studies suggesting that the duration for which the serum amoxicillin level remained detectable (not only the magnitude of the peak) was an important parameter in successful prophylaxis of endocarditis. The results also suggest that single-dose prophylaxis with 3 g of amoxicillin in humans might be more effective than predicted by conventional animal models in which only peak levels of antibiotic in human serum were stimulated.

Acute hemodynamic effect of a vascular antagonist of vasopressin in patients with congestive heart failure.

To assess the role of arginine vasopressin (AVP) in congestive heart failure (CHF), 10 patients with CHF refractory to conventional treatment were studied before and 60 minutes after intravenous administration of 5 micrograms/kg of d(CH2)5Tyr(Me)AVP, a specific antagonist of AVP at the vascular receptor level. Heart rate, systemic arterial pressure, pulmonary arterial pressure, pulmonary capillary wedge pressure, cardiac index by thermodilution and cutaneous blood flow by laser-Doppler technique were measured. In 9 patients with no significant hemodynamic and cutaneous blood flow response to the AVP antagonist, baseline values (mean +/- standard deviation) were: heart rate, 77 +/- 14 beats/min; systemic arterial pressure, 120/79 +/- 18/8 mm Hg; pulmonary arterial pressure, 42/21 +/- 12/8 mm Hg; pulmonary capillary wedge pressure, 19 +/- 7 mm Hg; cardiac index, 2.2 +/- 0.6 liters/min/m2; plasma AVP, 2.3 +/- 0.8 pg/ml; and plasma osmolality, 284 +/- 14 mosm/kg H2O. The tenth patient had the most severe CHF. His plasma AVP level was 55 pg/ml and plasma osmolality was 290 mosm/kg. He responded to the AVP antagonist with a decrease in systemic arterial pressure from 115/61 to 79/41 mm Hg, in pulmonary arterial pressure from 58/31 to 33/13 mm Hg and in pulmonary capillary wedge pressure from 28 to 15 mm Hg. Simultaneously, cardiac index increased from 1.1 to 2.2 liters/min/m2 and heart rate from 113 to 120 beats/min; cutaneous blood flow increased 5-fold.(ABSTRACT TRUNCATED AT 250 WORDS)