AA-amyloidosis caused by visceral leishmaniasis in a human immunodeficiency virus-infected patient.

AA-amyloidosis in the setting of chronic visceral leishmaniasis (VL) has been reported in animal models but documentation in humans is unavailable. Here, we report on a Portuguese man who in 1996 was diagnosed with both human immunodeficiency virus (HIV)-infection and VL. Antiretroviral treatment led to sustained suppression of HIV viremia but CD4+ lymphocytes rose from 8 to only 160 cells/mL. Several courses of antimony treatment did not prevent VL relapses. Renal failure developed in 2006 and renal biopsy revealed AA-amyloidosis. The patient had cryoglobulinemia and serum immune complexes containing antibodies directed against seven leishmanial antigens. Antimony plus amphotericin B, followed by oral miltefosine resulted in a sustained VL treatment response with elimination of circulating Leishmania infantum DNA and CD4+ recovery. The concomitant reduction of serum AA levels and disappearance of circulating leishmanial immune complexes suggests that prolonged VL may lead to AA-amyloidosis in immunocompromised humans.

Site-specific conjugation of a radioiodinated phenethylamine derivative to a monoclonal antibody results in increased radioactivity localization in tumor.

The preparation of a novel radioiodination reagent, the (aminooxy)acetyl derivative of (p-[125]-iodophenyl)ethylamine, is described. Conventional radioiodination of proteins involves the formation of iodotyrosine residues, but for in vivo applications such as thyroid or stomach immunoscintigraphy, the susceptibility of these residues to tissue dehalogenases constitutes a serious disadvantage. Using our new compound, which has a particularly nonreactive aromatic ring, we confirm and extend studies published by other workers indicating the much greater in vivo stability of iodophenyl compounds compared to the more conventional iodophenolic ones. In addition, the aminooxy group of our reagent gives a stable and specific linkage to aldehyde groups formed by periodate oxidation on the sugar moiety of antibody molecules. In vitro, favorable binding activity and high stability was obtained with a (([125I]iodoaryl)amino)oxy labeled monoclonal antibody directed against carcinoembryonic antigen. In vivo, using paired labeling experiments in nude mice bearing colon carcinoma xenografts, the (([125I]iodoaryl)amino)oxy-MAb (MAb = monoclonal antibody) was compared with the same MAb 131I-labeled by conventional chloramine-T method. Tumor 125I concentration of (arylamino)oxy MAb (measured as percent injected dose per gram) was significantly higher as compared to values obtained with a conventionally labeled 131I antibody. Additionally, thyroid uptake, an indicator of iodine release from the antibody, was up to 25 times lower after injection of 125I-MAb obtained by the new method as compared to the conventionally iodinated 131I-MAb.

Initial clinical experience with the admiral oxygenator combined with separated suction.

The Admiral, a new microporous membrane oxygenator with a low surface area, decreased priming volume and two separate reservoirs, was tested in 30 adult patients. This study was undertaken to evaluate blood path resistance, gas exchange capabilities and blood trauma in clinical use, with and without shed blood separation. Patients were divided into 3 groups. Group 1 had valve surgery without separation of suction, Group 2 had coronary artery bypass grafting (CABG) with direct blood aspiration and Group 3 had coronary artery bypass grafting with shed blood separation. The suctioned, separated, cardiotomy blood in Group 3 was treated with an autotransfusion device at the end of bypass before being returned to the patient. Theoretical blood flow could be achieved in all cases without problem. The pressure drop through the oxygenator averaged 88 +/- 13 mmHg at 4 l/min and 109 +/- 12 mmHg at 5 l/min. O(2) transfer was 163 +/- 27 ml/min. Free plasma haemoglobin rose in all groups, but significantly less in group 3. Lactate dehydrogenase (LDH) rose significantly in Groups 1 and 2. Platelets decreased in all groups without significant differences. Clinical experience with this new oxygenator was safe, the reduced membrane surface did not impair gas exchange and blood trauma could be minimized easily by separating shed blood, using the second cardiotomy reservoir.

A genome-wide association study of early menopause and the combined impact of identified variants.

Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.

Effets hémodynamiques d'un inhibiteur de l'effet vasculaire de la vasopressine chez des patients avec insuffisance cardiaque congestive [Hemodynamic effects of an inhibitor of the vascular effects of vasopressin in patients with congestive heart failure]

To assess the role of vasopressin (AVP) in congestive heart failure (CHF), we investigated 10 patients with CHF refractory to conventional treatment, 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 there was no significant hemodynamic and cutaneous blood flow response to the AVP antagonist. Plasma AVP was 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 was 55 pg/ml and plasma osmolality 290 mosm/kg. He responded to the AVP antagonist with a marked 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 2.21 X min-1 X m-2 and cutaneous blood flow rose 5-fold. Thus, most patients with CHF have only moderately elevated plasma AVP and its role in determining peripheral vascular resistance appears to be limited. AVP may become important in rare patients presenting with marked hemodynamic instability and very high plasma AVP.

Effects of a dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240, on endocrine and renal functions in healthy volunteers.

OBJECTIVE: To investigate the endocrine and renal effects of the dual inhibitor of angiotensin converting enzyme and neutral endopeptidase, MDL 100,240. DESIGN: A randomized, placebo-controlled, crossover study was performed in 12 healthy volunteers. METHODS: MDL 100,240 was administered intravenously over 20 min at single doses of 6.25 and 25 mg in subjects with a sodium intake of 280 (n = 6) or 80 (n = 6) mmol/day. Measurements were taken of supine and standing blood pressure, plasma angiotensin converting enzyme activity, angiotensin II, atrial natriuretic peptide, urinary atrial natriuretic peptide and cyclic GMP excretion, effective renal plasma flow and the glomerular filtration rate as p-aminohippurate and inulin clearances, electrolytes and segmental tubular function by endogenous lithium clearance. RESULTS: Supine systolic blood pressure was consistently decreased by MDL 100,240, particularly after the high dose and during the low-salt intake. Diastolic blood pressure and heart rate did not change. Plasma angiotensin converting enzyme activity decreased rapidly and dose-dependently. In both the high- and the low-salt treatment groups, plasma angiotensin II levels fell and renin activity rose accordingly, while plasma atrial natriuretic peptide levels remained unchanged. In contrast, urinary atrial natriuretic peptide excretion increased dose-dependently under both diets, as did urinary cyclic GMP excretion. Effective renal plasma flow and the glomerular filtration rate did not change. The urinary flow rate increased markedly during the first 2 h following administration of either dose of MDL 100,240 (P < 0.001) and, similarly, sodium excretion tended to increase from 0 to 4 h after the dose (P = 0.07). Potassium excretion remained stable. Proximal and distal fractional sodium reabsorption were not significantly altered by the treatment. Uric acid excretion was increased. The safety and clinical tolerance of MDL 100,240 were good. CONCLUSIONS: The increased fall in blood pressure in normal volunteers together with the preservation of renal hemodynamics and the increased urinary volume, atrial natriuretic peptide and cyclic GMP excretion distinguish MDL 100,240 as a double-enzyme inhibitor from inhibitors of the angiotensin converting enzyme alone. The differences appear to be due, at least in part, to increased renal exposure to atrial natriuretic peptide following neutral endopeptidase blockade.

A novel derivative of the chelon desferrioxamine for site-specific conjugation to antibodies.

We describe the preparation of the modified chelator aminooxyacetyl-ferrioxamine, and the replacement of its iron atom by 67Ga at high specific activity. The aminooxy function of this compound was allowed to react with the aldehyde groups generated by the periodate oxidation of the oligosaccharide of a mouse IgG1 monoclonal antibody (MAb) directed against carcino-embryonic antigen (CEA). The use of the aminooxy group allowed a stable bond to be formed between the chelon and the antibody with no need for reduction. Iron was removed from the ferrioxamine moiety and replaced by 67Ga either before or after conjugation of the chelon to the antibody. In either case the labelled antibody was injected into nude mice bearing a human colon carcinoma having the appropriate antigenicity. Unoxidized antibody, labelled with 125I by conventional methods, was co-injected as an internal control. Additional control experiments were carried out with a non-immune IgG using the same 67Ga-labelled modified chelon as above. The in vivo distribution of the modified antibodies was evaluated at various times between 24 and 96 hr after injection. The methods used were gamma-camera imaging and, more quantitatively, gamma-counting of the various organs after dissection. Interestingly, with the metal-chelon-labelled antibody, the intensity and specificity of tumor labelling was comparable and in some cases superior to the results obtained with radio-iodinated antibody. In particular, there was almost no increase in liver and spleen uptake of radioactive metal relative to radio-iodine, contrary to what has been observed with most antibodies labelled with 111In after conjugation with DTPA.

Oxidative and nonoxidative glucose metabolism following graded doses of oral glucose in man.

The oxidative and nonoxidative glucose metabolism represent the two major mechanisms of the utilization of a glucose load. Eight normal subjects were administered oral loads of 50, 100 and 150 g glucose and gas exchange measurements were performed for eight hours by means of computerized continuous indirect calorimetry. The glycemic peaks were almost identical with all three doses with a rise to between 141 and 147 mg/dl at 60 min. The fall back to basal level was reached later with the high than with the low glucose doses. The glucose oxidation rate rose to values between 223 and 253 mg/min after the three glucose doses, but while falling immediately after the peak at 120 min following the 50 g load, the glucose oxidation rate remained at its maximum rate until 210 min for the 100 g glucose load and plateaued up to 270 min for the 150 g glucose dose. The oxidation rates then fell gradually to reach basal levels at 270, 330 and 420 min according to the increasing size of the load. Altogether 55 +/- 3 g glucose were oxidized during the 8 hours following the 50 g glucose load, 75 +/- 3 g after the 100 g load and 80 +/- 5 g after the 150 g load. The nonoxidative glucose disposal, which corresponds essentially to glucose storage, varied according to the size of the glucose load, with uptakes of 20 +/- 1, 60 +/- 1 and 110 +/- 1 g glucose 180 min after the 50, 100 and 150 g glucose loads respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Age-specific incidence of all neoplasms after colorectal cancer.

PURPOSE: Patients diagnosed with a specific neoplasm tend to have a subsequent excess risk of the same neoplasm. The age incidence of a second neoplasm at the same site is approximately constant with age, and consequently the relative risk is greater at younger age. It is unclear whether such a line of reasoning can be extended from a specific neoplasm to the incidence of all neoplasms in subjects diagnosed with a defined neoplasm. METHODS: We considered the age-specific incidence of all non-hormone-related epithelial neoplasms after a first primary colorectal cancer (n = 9542) in the Vaud Cancer Registry data set. RESULTS: In subjects with a previous colorectal cancer, the incidence rate of all other epithelial non-hormone-related cancers was stable around 800 per 100,000 between age 30 and 60 years, and rose only about twofold to reach 1685 at age 70 to 79 years and 1826 per 100,000 at age 80 years or older. After excluding synchronous cancers, the rise was only about 1.5-fold, that is, from about 700 to 1000. In the general population, the incidence rate of all epithelial non-hormone-related cancers was 29 per 100,000 at age 30 to 39 years, and rose 30-fold to 883 per 100,000 at age 70 to 79 years. Excluding colorectal cancers, the rise of all non-hormone-related cancers was from 360 per 100,000 at age 40 to 49 years to 940 at age 70 to 79 years after colorectal cancer, and from 90 to 636 per 100,000 in the general population (i.e., 2.6- vs. 7.1-fold). CONCLUSIONS: The rise of incidence with age of all epithelial non-hormone-related second cancers after colorectal cancer is much smaller than in the general population. This can possibly be related to the occurrence of a single mutational event in a population of susceptible individuals, although alternative models are plausible within the complexity of the process of carcinogenesis.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Le conflit des interprétations en histoire. Lectures juives et chrétiennes de la chute de Jérusalem

(Résumé de l'ouvrage) Ce recueil regroupe les contributions de 35 spécialistes qui reprennent l'orientation principale ayant déterminé la recherche de Gottfried Hammann, professeur d'histoire du christianisme et de l'Eglise à la Faculté de théologie de l'Université de Neuchâtel. Les deux notions d'histoire et d'herméneutique indiquent les piliers sur lesquels repose l'arc historiographique contemporain, cette ligne courbe qui se dessine entre le passé et sa reconstitution. L'historien est appelé à réfléchir soigneusement à sa double tâche de documentaliste et d'interprète.

Les diacres d'Ignace

(Résumé de l'ouvrage) Ce recueil regroupe les contributions de 35 spécialistes qui reprennent l'orientation principale ayant déterminé la recherche de Gottfried Hammann, professeur d'histoire du christianisme et de l'Eglise à la Faculté de théologie de l'Université de Neuchâtel. Les deux notions d'histoire et d'herméneutique indiquent les piliers sur lesquels repose l'arc historiographique contemporain, cette ligne courbe qui se dessine entre le passé et sa reconstitution. L'historien est appelé à réfléchir soigneusement à sa double tâche de documentaliste et d'interprète.

Improvement of chronic congestive heart-failure by oral captopril

Catopril, an inhibitor of angiotensin converting enzyme, was given orally during cardiac catheterisation to 6 normotensive patients with refractory congestive heart-failure. 60--180 minutes after administration of 25 mg captopril, arterial pressure fell by 25%, cardiac index rose by 38%, and left-ventricular pressure and right-atrial pressure fell by 25% and 40% respectively. Plasma-renin activity rose while plasma noradrenaline and aldosterone fell. These data suggest that, in the short term, captopril can reduce both preload and afterload, and improve cardiac function, in refractory congestive heart-failure.

Association of adiposity genetic variants with menarche timing in 92,105 women of European descent.

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

Trends in drug consumption and risk of transmission of HIV and hepatitis C virus among injecting drug users in Switzerland, 1993-2006

As a part of the HIV behavioural surveillance system in Switzerland, repeated cross-sectional surveys were conducted in 1993, 1994, 1996, 2000 and 2006 among attenders of all low threshold facilities (LTFs) with needle exchange programmes and/or supervised drug consumption rooms for injection or inhalation in Switzerland. Data were collected in each LTF over five consecutive days, using a questionnaire that was partly completed by an interviewer and partly self administered. The questionnaire was structured around three topics: socio-demographic characteristics, drug consumption, health and risk/preventive behaviour. Analysis was restricted to attenders who had injected drugs during their lifetime (IDUs). Between 1993 and 2006, the median age of IDUs rose by 10 years. IDUs are severely marginalised and their social situation has improved little. The borrowing of used injection equipment (syringe or needle already used by other person) in the last six months decreased (16.5% in 1993, 8.9% in 2006) but stayed stable at around 10% over the past three surveys. Other risk behaviour, such as sharing spoons, cotton or water, was reported more frequently, although also showed a decreasing trend. The reported prevalence of HIV remained fairly stable at around 10% between 1993 and 2006; reported levels of hepatitis C virus (HCV) prevalence were high (56.4% in 2006). In conclusion, the overall decrease in the practice of injection has reduced the potential for transmission of infections. However as HCV prevalence is high this is of particular concern, as the current behaviour of IDUs indicates a potential for further spreading of the infection. Another noteworthy trend is the significant decrease in condom use in the case of paid sex.