Serum uric acid and adiposity: deciphering causality using a bidirectional Mendelian randomization approach.

Although the relationship between serum uric acid (SUA) and adiposity is well established, the direction of the causality is still unclear in the presence of conflicting evidences. We used a bidirectional Mendelian randomization approach to explore the nature and direction of causality between SUA and adiposity in a population-based study of Caucasians aged 35 to 75 years. We used, as instrumental variables, rs6855911 within the SUA gene SLC2A9 in one direction, and combinations of SNPs within the adiposity genes FTO, MC4R and TMEM18 in the other direction. Adiposity markers included weight, body mass index, waist circumference and fat mass. We applied a two-stage least squares regression: a regression of SUA/adiposity markers on our instruments in the first stage and a regression of the response of interest on the fitted values from the first stage regression in the second stage. SUA explained by the SLC2A9 instrument was not associated to fat mass (regression coefficient [95% confidence interval]: 0.05 [-0.10, 0.19] for fat mass) contrasting with the ordinary least square estimate (0.37 [0.34, 0.40]). By contrast, fat mass explained by genetic variants of the FTO, MC4R and TMEM18 genes was positively and significantly associated to SUA (0.31 [0.01, 0.62]), similar to the ordinary least square estimate (0.27 [0.25, 0.29]). Results were similar for the other adiposity markers. Using a bidirectional Mendelian randomization approach in adult Caucasians, our findings suggest that elevated SUA is a consequence rather than a cause of adiposity.

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p < 5 × 10(-8)) for serum albumin (HPN-SCN1B, GCKR-FNDC4, SERPINF2-WDR81, TNFRSF11A-ZCCHC2, FRMD5-WDR76, and RPS11-FCGRT, in up to 53,190 European-ancestry and 9,380 Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease.

Variability of ascending aorta diameter measurements as assessed with electrocardiography-gated multidetector computerized tomography and computer assisted diagnosis software.

Recently, morphometric measurements of the ascending aorta have been done with ECG-gated multidector computerized tomography (MDCT) to help the development of future novel transcatheter therapies (TCT); nevertheless, the variability of such measurements remains unknown. Thirty patients referred for ECG-gated CT thoracic angiography were evaluated. Continuous reformations of the ascending aorta, perpendicular to the centerline, were obtained automatically with a commercially available computer aided diagnosis (CAD). Then measurements of the maximal diameter were done with the CAD and manually by two observers (separately). Measurements were repeated one month later. The Bland-Altman method, Spearman coefficients, and a Wilcoxon signed-rank test were used to evaluate the variability, the correlation, and the differences between observers. The interobserver variability for maximal diameter between the two observers was up to 1.2 mm with limits of agreement [-1.5, +0.9] mm; whereas the intraobserver limits were [-1.2, +1.0] mm for the first observer and [-0.8, +0.8] mm for the second observer. The intraobserver CAD variability was 0.8 mm. The correlation was good between observers and the CAD (0.980-0.986); however, significant differences do exist (P<0.001). The maximum variability observed was 1.2 mm and should be considered in reports of measurements of the ascending aorta. The CAD is as reproducible as an experienced reader.

Diagnosis and workup of 522 consecutive patients with neuroendocrine neoplasms in Switzerland.

BACKGROUND: Neuroendocrine neoplasms (NENs) are difficult to diagnose. We used SwissNET data to characterise NEN patients followed in the two academic centres of western Switzerland (WS), and to compare them with patients followed in eastern Switzerland (ES) as well as with international guidelines. METHOD: SwissNET is a prospective database covering data from 522 consecutive patients (285 men, 237 women) from WS (n = 99) and ES (n = 423). RESULTS: Mean ± SD age at diagnosis was 59.0 ± 15.7 years. Overall, 76/522 experienced a functional syndrome, with a median interval of 1.0 (IQR: 1.0-3.0) year between symptoms onset and diagnosis. A total of 51/522 of these tumours were incidental. The primary tumour site was the small intestine (29%), pancreas (21%), appendix (18%) and lung (11%) in both regions combined. In all, 513 functional imaging studies were obtained (139 in WS, 374 in ES). Of these, 381 were 111In-pentetreotide scintigraphies and 20 were 68Ga-DOTATOC PET. First line therapy was surgery in 87% of patients, medical therapy (biotherapy or chemotherapy) in 9% and irradiation in 3% for both regions together. CONCLUSION: Swiss NEN patients appear similar to what has been described in the literature. Imaging by somatostatin receptor scintigraphy (SRS) is widely used in both regions of Switzerland. In good accordance with published guidelines, data on first line therapy demonstrate the crucial role of surgery. The low incidence of biotherapy suggests that long-acting somatostatin analogues are not yet widely used for their anti-proliferative effects. The SwissNET initiative should help improve compliance with ENETS guidelines in the workup and care of NEN patients.

Adiponectin isoform distribution in serum and in follicular fluid of women undergoing treatment by ICSI.

Adiponectin is an adipokine, present in the circulation in comparatively high concentrations and different molecular weight isoforms. For the first time, the distribution of these isoforms in serum and follicular fluid (FF) and their usefulness as biological markers for infertility investigations was studied. In vitro study. University based hospital. Fifty-four women undergoing intracytoplasmic sperm injection (ICSI). Oocytes were retrieved, fertilized in vitro using ICSI, and the resulting embryos transferred. Serum was collected immediately prior to oocyte retrieval. Adiponectin isoforms (high molecular weight (HMW), medium and low molecular weight) were determined in serum and FF. Total adiponectin and the different isoform levels were compared with leptin and ovarian steroid concentrations. Adiponectin isoforms in serum and FF. Adiponectin isoform distribution differed between serum and FF; the HMW fraction made up half of all adiponectin in the serum but only 23.3% in the FF. Total and HMW adiponectin in both serum and FF correlated negatively with the body mass index and the concentration of leptin. No correlations were observed for total adiponectin or its isoforms with estradiol, progesterone, anti-Mullerian hormone, inhibin B, or the total follicle stimulating hormone (FSH) dose administered during the ovarian stimulation phase. This study shows for the first time that adiponectin isoform distribution varies between the serum and FF compartments in gonadotropin stimulated patients. A trend towards higher HMW adiponectin serum levels in successful ICSI cycles compared to implantation failures was observed; studies with larger patient groups are required to confirm this observation.

Interstitial pregnancies' diagnosis and management: an eleven cases series.

PRINCIPLES: Interstitial pregnancy represents 2% of ectopic pregnancies, but it is a highly morbid condition with a 2.5% of maternal mortality. Its diagnostic and therapeutic management remains controversial. The aim of this review is to describe the management of interstitial pregnancy in our institution between 2001 and 2011 and to define some general rules for the clinical practice. METHODS: Single institution retrospective study. RESULTS: Eleven women were treated for interstitial pregnancy. The median age was 33 years and the median gestity was 4. Seven patients had a history of gynaecological surgery and four interstitial pregnancies followed in vitro fertilisation. The diagnosis was made at a median gestational age of seven weeks with a median beta-HCG level of 5,838 U/l. Six of the eleven patients received an initial treatment with intracornual methotrexate, three with intramuscular methotrexate and two with surgery. The median time to beta-HCG resolution was 58 days. Three of the eleven patients needed a second line treatment: two after intramuscular methotrexate and one after intracornual methotrexate. Six patients had further pregnancies and delivered by caesarean section. CONCLUSIONS: A high prevalence of previous ectopic pregnancies, gynaecological surgery and of pregnancies resulting from in vitro fertilisation was observed. The earliness of the diagnosis was the factor that allowed a conservative treatment in most cases. Beta-HCG level follow up was fundamental in allowing a second line therapy but beta-HCG can persist over a long period of time and this must be taken into account due to its possible psychological impact. Intracornual methotrexate seems to be more efficacious than intramuscular methotrexate in our series.

Pratiques comptables des hôpitaux et faisabilité d'un calcul de coûts basés sur les Diagnosis Related Groups

Travaux effectués dans le cadre de l'étude "Case Mix" menée par l'Institut universitaire de médecine sociale et préventive de Lausanne et le Service de la santé publique et de la planification sanitaire du canton de Vaud, en collaboration avec les cantons de Berne, Fribourg, Genève, Jura, Neuchâtel, Soleure, Tessin et Valais

Genome-wide meta-analysis for serum calcium identifies significantly associated SNPs near the calcium-sensing receptor (CASR) gene.

Calcium has a pivotal role in biological functions, and serum calcium levels have been associated with numerous disorders of bone and mineral metabolism, as well as with cardiovascular mortality. Here we report results from a genome-wide association study of serum calcium, integrating data from four independent cohorts including a total of 12,865 individuals of European and Indian Asian descent. Our meta-analysis shows that serum calcium is associated with SNPs in or near the calcium-sensing receptor (CASR) gene on 3q13. The top hit with a p-value of 6.3 x 10(-37) is rs1801725, a missense variant, explaining 1.26% of the variance in serum calcium. This SNP had the strongest association in individuals of European descent, while for individuals of Indian Asian descent the top hit was rs17251221 (p = 1.1 x 10(-21)), a SNP in strong linkage disequilibrium with rs1801725. The strongest locus in CASR was shown to replicate in an independent Icelandic cohort of 4,126 individuals (p = 1.02 x 10(-4)). This genome-wide meta-analysis shows that common CASR variants modulate serum calcium levels in the adult general population, which confirms previous results in some candidate gene studies of the CASR locus. This study highlights the key role of CASR in calcium regulation.

How critical is timing for the diagnosis of influenza in general practice?

QUESTIONS UNDER STUDY: The diagnostic significance of clinical symptoms/signs of influenza has mainly been assessed in the context of controlled studies with stringent inclusion criteria. There was a need to extend the evaluation of these predictors not only in the context of general practice but also according to the duration of symptoms and to the dynamics of the epidemic. PRINCIPLES: A prospective study conducted in the Medical Outpatient Clinic in the winter season 1999-2000. Patients with influenza-like syndrome were included, as long as the primary care physician envisaged the diagnosis of influenza. The physician administered a questionnaire, a throat swab was performed and a culture acquired to document the diagnosis of influenza. RESULTS: 201 patients were included in the study. 52% were culture positive for influenza. By univariate analysis, temperature >37.8 degrees C (OR 4.2; 95% CI 2.3-7.7), duration of symptoms <48 hours (OR 3.2; 1.8-5.7), cough (OR 3.2; 1-10.4) and myalgia (OR 2.8; 1.0-7.5) were associated with a diagnosis of influenza. In a multivariable logistic analysis, the best model predicting influenza was the association of a duration of symptom <48 hours, medical attendance at the beginning of the epidemic (weeks 49-50), fever >37.8 and cough, with a sensitivity of 79%, specificity of 69%, positive predictive value of 67%, negative predictive value of 73% and an area under the ROC curve of 0.74. CONCLUSIONS: Besides relevant symptoms and signs, the physician should also consider the duration of symptoms and the epidemiological context (start, peak or end of the epidemic) in his appraisal, since both parameters considerably modify the value of the clinical predictors when assessing the probability of a patient having influenza.

Prenatal diagnosis of urinary malformations: results in a series of 93 consecutive cases.

OBJECTIVE: To evaluate the pertinence of prenatal diagnosis in cases of congenital uropathy. STUDY DESIGN: Retrospective evaluation over a period of 6.5 years. METHOD: 93 cases were involved in the comparison of prenatal ultrasonographic diagnosis with neonatal findings, autopsy results, and follow-up data. RESULTS: 33 fetuses had renal parenchymal lesions, 44 had excretory system lesions, and 6 had bladder and/or urethral lesions. Seventy-three pregnancies lead to live births. Eighteen terminations of pregnancy were performed on the parents' request for extremely severe malformations. Two intrauterine deaths were observed, and two infants died in the postnatal period. Prenatal diagnosis was obtained at an average of 27 weeks gestation. Diagnostic concordance was excellent in 82% and partial in 12% of cases with renal parenchymal lesions; the false-positive rate was 6%. For excretory system lesions, concordance was excellent in 87% and partial in 7.4% of cases, with a false-positive rate of 5.6%. Finally, concordance was excellent in 100% of cases of bladder and/or urethral lesions. The overall rate of total concordance was 86%. Partial concordance cases consisted of malformations different from those previously diagnosed, but prenatal diagnosis nevertheless lead to further investigations in the neonatal period and to proper management. The false-positive diagnoses (5.4%) never lead to termination of pregnancy. CONCLUSION: Prenatal diagnosis of congenital uropathy is effective. A third-trimester ultrasonographic examination is necessary to ensure proper neonatal management, considering that the majority of cases are diagnosed at this gestational age.

Microbial diagnosis of bloodstream infection: towards molecular diagnosis directly from blood.

When a bloodstream infection (BSI) is suspected, most of the laboratory results-biochemical and haematologic-are available within the first hours after hospital admission of the patient. This is not the case for diagnostic microbiology, which generally takes a longer time because blood culture, which is to date the reference standard for the documentation of the BSI microbial agents, relies on bacterial or fungal growth. The microbial diagnosis of BSI directly from blood has been proposed to speed the determination of the etiological agent but was limited by the very low number of circulating microbes during these paucibacterial infections. Thanks to recent advances in molecular biology, including the improvement of nucleic acid extraction and amplification, several PCR-based methods for the diagnosis of BSI directly from whole blood have emerged. In the present review, we discuss the advantages and limitations of these new molecular approaches, which at best complement the culture-based diagnosis of BSI.

Cytological diagnosis of pancreatic neuroendocrine neoplasms

The main cytological features of neuroendocrine pancreatic neoplasm are described along with a discussion about the difficulties in classification/grading and the new reporting system for reporting pancreatic cytopathology. An overview about the ancillary techniques and the differential diagnosis is also given.

Spectrum of digoxin-induced ocular toxicity: a case report and literature review.

BACKGROUND: Digoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient. CASE PRESENTATION: Digoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay. CONCLUSION: This case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.

Diagnostic microbiologique de la pneumonie [Microbiological diagnosis of pneumonia].

Les pneumonies causent une mortalité et une morbidité significatives. De manière simplifiée, deux types de pneumonie sont décrits : la pneumonie communautaire et la pneumonie nosocomiale avec le pneumocoque et l'Haemophilus influenzae comme causes principales pour la première, le Pseudomonas et diverses entérobactéries pour la deuxième. La réalité est cependant plus complexe puisque l'on distingue aussi la pneumonie d'aspiration par exemple. La culture est très importante dans le cas des pneumonies nosocomiales car elle permet de déterminer la sensibilité aux antibiotiques de l'agent infectieux et d'adapter le traitement. Pour les patients immunosupprimés, le diagnostic différentiel est plus large et la recherche par tests moléculaires de certains virus, de champignons filamenteux et du Pneumocystis peut se révéler informative. Pneumonia is an importance cause of mortality and morbidity in adults. Two types of pneumonia are defined: community-acquired and nosocomial pneumonia with their corresponding etiology such as pneumococci or Haemophilus influenzae and Pseudomonas or enterobacteriaceae, respectively. However, the reality is more complex with aspiration pneumonia, pneumonia in immunocompromised patient, and pneumonia in ventilated patients. Culture in the case of nosocomial pneumonia is especially important to obtain the antibiotic susceptibility of the infectious agent and to adjust therapy. Moreover for immunocompromised patients, the differential diagnosis is much wider looking for viruses, filamentous fungi and Pneumocystis can be very informative, using new molecular assays.

Cryptococcus neoformans meningitis with negative cryptococcal antigen: Evaluation of a new immunochromatographic detection assay.

Detection of cryptococcal antigen in serum or cerebrospinal fluid allows cryptococcal meningitis diagnosis within few hours with >90% sensitivity. In an HIV-positive patient with Cryptococcus neoformans meningitis, initial antigen detection by immunoagglutination was negative. We thus evaluated a new immunochromatographic detection assay that exhibited a higher sensitivity.