PTH and 1.25 vitamin D response to a low-calcium diet is associated with bone mineral density in renal stone formers.

BACKGROUND: Renal calcium stones and hypercalciuria are associated with a reduced bone mineral density (BMD). Therefore, the effect of changes in calcium homeostasis is of interest for both stones and bones. We hypothesized that the response of calciuria, parathyroid hormone (PTH) and 1.25 vitamin D to changes in dietary calcium might be related to BMD. METHODS: A single-centre prospective interventional study of 94 hyper- and non-hypercalciuric calcium stone formers consecutively retrieved from our stone clinic. The patients were investigated on a free-choice diet, a low-calcium diet, while fasting and after an oral calcium load. Patient groups were defined according to lumbar BMD (z-score) obtained by dual X-ray absorptiometry (group 1: z-score <-0.5, n = 30; group 2: z-score -0.5-0.5, n = 36; group 3: z-score >0.5, n = 28). The effect of the dietary interventions on calciuria, 1.25 vitamin D and PTH in relation to BMD was measured. RESULTS: An inverse relationship between BMD and calciuria was observed on all four calcium intakes (P = 0.009). On a free-choice diet, 1.25 vitamin D and PTH levels were identical in the three patient groups. However, the relative responses of 1.25 vitamin D and PTH to the low-calcium diet were opposite in the three groups with the highest increase of 1.25 vitamin D in group 1 and the lowest in group 3, whereas PTH increase was most pronounced in group 3 and least in group 1. CONCLUSION: Calcium stone formers with a low lumbar BMD exhibit a blunted response of PTH release and an apparently overshooting production of 1.25 vitamin D following a low-calcium diet.

Automated analysis of background EEG and reactivity during therapeutic hypothermia in comatose patients after cardiac arrest.

Visual analysis of electroencephalography (EEG) background and reactivity during therapeutic hypothermia provides important outcome information, but is time-consuming and not always consistent between reviewers. Automated EEG analysis may help quantify the brain damage. Forty-six comatose patients in therapeutic hypothermia, after cardiac arrest, were included in the study. EEG background was quantified with burst-suppression ratio (BSR) and approximate entropy, both used to monitor anesthesia. Reactivity was detected through change in the power spectrum of signal before and after stimulation. Automatic results obtained almost perfect agreement (discontinuity) to substantial agreement (background reactivity) with a visual score from EEG-certified neurologists. Burst-suppression ratio was more suited to distinguish continuous EEG background from burst-suppression than approximate entropy in this specific population. Automatic EEG background and reactivity measures were significantly related to good and poor outcome. We conclude that quantitative EEG measurements can provide promising information regarding current state of the patient and clinical outcome, but further work is needed before routine application in a clinical setting.

The Visual Dysphagia Questionnaire: Evaluating the first Tool for Assessing Food Consistency-Dependent Dysphagia in Eosinophilic Esophagitis

Background and Aims: The international EEsAI study group iscurrently developing the first a ctivity index specific forEosinophilic Esophagitis (EoE). None of the existing dysphagiaquestionnaires take into account the consistency of theingested food t hat considerably impacts the symptompresentation. Goal: To d evelop and evaluate an E oE-specificquestionnaire assessing dysphagia caused by foods of differentconsistencies.Methods: B ased on patient interviews and chart reviews, a nexpert panel ( EEsAI study g roup) identified internationallystandardizedfood prototypes t ypically a ssociated with EoErelateddysphagia. Food consistencies were c orrelated withEoE-related d ysphagia, t aking into account p otential f oodavoidance and f ood processing. This V isual D ysphagiaQuestionnaire (VDQ) was piloted in 20 patients and is currentlyevaluated in a cohort of 150 adult EoE patients.Results: T he following 8 food c onsistency prototypes w ereidentified: soft foods (pudding, jelly), grits, toast bread, Frenchfries, dry rice, ground meat, raw fibrous f oods (eg. apple,carrot), s olid m eat. Dysphagia was r anked o n a 4-point Likertscale (0=no difficulties; 3= severe difficulties, food will not pass).First analysis demonstrated that severity of dysphagia is relatedto the eosinophil load and presence of esophageal strictures.Conclusions: T he VDQ i s the first EoE-specific tool f orassessing dysphagia caused by i nternationally-standardizedfoods of different consistencies. This instrument also addressesfood avoidance behaviour and food processing habits. This toolperformed well in a p ilot study a nd is currently evaluated in acohort of 150 adult EoE patients.

Self-Expanding Versus Balloon-Expandable Stents in Acute Myocardial Infarction: Results From the APPOSITION II Study: Self-Expanding Stents in ST-Segment Elevation Myocardial Infarction.

OBJECTIVES: This study sought to investigate whether self-expanding stents are more effective than balloon-expandable stents for reducing stent malapposition at 3 days after implantation in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. BACKGROUND: Acute myocardial infarction is associated with vasoconstriction and large thrombus burden. Resolution of vasoconstriction and thrombus load during the first hours to days after primary percutaneous coronary intervention may lead to stent undersizing and malapposition, which may subsequently lead to stent thrombosis or restenosis. In addition, aggressive stent deployment may cause distal embolization. METHODS: Eighty patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were randomized to receive a self-expanding stent (STENTYS, STENTYS SA, Paris, France) (n = 43) or a balloon-expandable stent (VISION, Abbott Vascular, Santa Clara, California; or Driver, Medtronic, Minneapolis, Minnesota) (n = 37) at 9 European centers. The primary endpoint was the proportion of stent strut malapposition at 3 days after implantation measured by optical coherence tomography. Secondary endpoints included major adverse cardiac events (cardiac death, recurrent myocardial infarction, emergent bypass surgery, or clinically driven target lesion revascularization). RESULTS: At 3 days after implantation, on a per-strut basis, a lower rate of malapposed stent struts was observed by optical coherence tomography in the self-expanding stent group than in the balloon-expandable group (0.58% vs. 5.46%, p < 0.001). On a per-patient basis, none of the patients in the self-expanding stent group versus 28% in the balloon-expandable group presented ≥5% malapposed struts (p < 0.001). At 6 months, major adverse cardiac events were 2.3% versus 0% in the self-expanding and balloon-expandable groups, respectively (p = NS). CONCLUSIONS: Strut malapposition at 3 days is significantly lower in ST-segment elevation myocardial infarction patients allocated to self-expanding stents when than in those allocated to balloon-expandable stents. The impact of this difference on clinical outcome and the risk of late stent thrombosis need to be evaluated further. (Randomized Comparison Between the STENTYS Self-expanding Coronary Stent and a Balloon-expandable Stent in Acute Myocardial Infarction [APPOSITION II]; NCT01008085).

BK DNA viral load in plasma: evidence for an association with hemorrhagic cystitis in allogeneic hematopoietic cell transplant recipients.

We performed a case-control study to determine the association of BK plasma viremia with hemorrhagic cystitis (HC) in hematopoietic cell transplant (HCT) recipients. Thirty cases of HC (14 of which occurred after platelet engraftment with documented BK viruria [BK-HC]) were compared with matched controls. Weekly plasma samples were tested for BK virus DNA by polymerase chain reaction (PCR). BK viremia detected before or during the disease was independently associated with HC (adjusted odds ratio = 30, P < .001); BK viremia was even important before clinical symptoms of HC occurred (odds ratio = 11, P < .001). Cases of HC and BK-HC had a significantly higher peak of BK plasma viral load than controls. BK virus was detected by in situ hybridization in bladder biopsies of 2 cases with severe HC and long-lasting BK viremia. BK virus seems to play a role in the development of HC and quantitative detection of BK DNA in plasma appears to be a marker of BK virus disease in HCT recipients.

Early stage disc degeneration does not have an appreciable affect on stiffness and load transfer following vertebroplasty and kyphoplasty.

Vertebroplasty and kyphoplasty have been reported to alter the mechanical behavior of the treated and adjacent-level segments, and have been suggested to increase the risk for adjacent-level fractures. The intervertebral disc (IVD) plays an important role in the mechanical behavior of vertebral motion segments. Comparisons between normal and degenerative IVD motion segments following cement augmentation have yet to be reported. A microstructural finite element model of a degenerative IVD motion segment was constructed from micro-CT images. Microdamage within the vertebral body trabecular structure was used to simulate a slightly (I = 83.5% of intact stiffness), moderately (II = 57.8% of intact stiffness), and severely (III = 16.0% of intact stiffness) damaged motion segment. Six variable geometry single-segment cement repair strategies (models A-F) were studied at each damage level (I-III). IVD and bone stresses, and motion segment stiffness, were compared with the intact and baseline damage models (untreated), as well as, previous findings using normal IVD models with the same repair strategies. Overall, small differences were observed in motion segment stiffness and average stresses between the degenerative and normal disc repair models. We did however observe a reduction in endplate bulge and a redistribution in the microstructural tissue level stresses across both endplates and in the treated segment following early stage IVD degeneration. The cement augmentation strategy placing bone cement along the periphery of the vertebra (model E) proved to be the most advantageous in treating the degenerative IVD models by showing larger reductions in the average bone stresses (vertebral and endplate) as compared to the normal IVD models. Furthermore, only this repair strategy, and the complete cement fill strategy (model F), were able to restore the slightly damaged (I) motion segment stiffness above pre-damaged (intact) levels. Early stage IVD degeneration does not have an appreciable effect in motion segment stiffness and average stresses in the treated and adjacent-level segments following vertebroplasty and kyphoplasty. Placing bone cement in the periphery of the damaged vertebra in a degenerative IVD motion segment, minimizes load transfer, and may reduce the likelihood of adjacent-level fractures.

The future of longevity: background and perspectives

In many developed countries, including Switzerland, the ongoing increase in life expectancy is driven by the mortality decline among older persons. This has important consequences for both the provision of health care and the management of pension funds. In this context, the Swiss Federal Office of Statistics mandated a small group of experts to provide a critical review on the future evolution of mortality in developed countries. The report starts with an analysis of the past trends in life expectancy. Longevity is defined here as the duration (or the length) of life as observed in population or in individuals. The oldest and still most used indicators of longevity are life expectancy at birth (LE0) at a population level, and maximum life span (MLS) at the individual level (page 9) and in healthy life expectancy (page 19). A discussion on the future evolution of mortality and health is then presented (page 27). A set of recommendations is finally proposed (page 39).

When genetic load does not correlate with phenotypic spectrum: lessons from the GnRH receptor (GNRHR).

CONTEXT: A broad spectrum of GnRH-deficient phenotypes has been identified in individuals with both mono- and biallelic GNRHR mutations. OBJECTIVE: The objective of the study was to determine the correlation between the severity of the reproductive phenotype(s) and the number and functional severity of rare sequence variants in GNRHR. SUBJECTS: Eight hundred sixty-three probands with different forms of GnRH deficiency, 46 family members and 422 controls were screened for GNRHR mutations. The 70 subjects (32 patients and 38 family members) harboring mutations were divided into four groups (G1-G4) based on the functional severity of the mutations (complete or partial loss of function) and the number of affected alleles (monoallelic or biallelic) with mutations, and these classes were mapped on their clinical phenotypes. RESULTS: The prevalence of heterozygous rare sequence variants in GNRHR was significantly higher in probands vs. controls (P < 0.01). Among the G1-G3 groups (homozygous subjects with successively decreasing severity and number of mutations), the hypogonadotropic phenotype related to their genetic load. In contrast, subjects in G4, with only monoallelic mutations, demonstrated a greater diversity of clinical phenotypes. CONCLUSIONS: In patients with GnRH deficiency and biallelic mutations in GNRHR, genetic burden defined by severity and dose is associated with clinical phenotype. In contrast, for patients with monoallelic GNRHR mutations this correlation does not hold. Taken together, these data indicate that as-yet-unidentified genetic and/or environmental factors may combine with singly mutated GNRHR alleles to produce reproductive phenotypes.

Effect of mutation and genetic background on drug resistance in Mycobacterium tuberculosis.

Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter -15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter -15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.

Sensitive and rapid detection of ganciclovir resistance by PCR based MALDI-TOF analysis.

BACKGROUND: Cytomegalovirus (CMV) infection is associated with significant morbidity and mortality in transplant recipients. Resistance against ganciclovir is increasingly observed. According to current guidelines, direct drug resistance testing is not always performed due to high costs and work effort, even when resistance is suspected. OBJECTIVES: To develop a more sensitive, easy applicable and cost-effective assay as proof of concept for direct drug resistance testing in CMV surveillance of post-transplant patients. STUDY DESIGN: Five consecutive plasma samples from a heart transplant patient with a primary CMV infection were analyzed by quantitative real-time polymerase chain reaction (rtPCR) as a surrogate marker for therapy failure, and by direct drug resistance detection assays such as Sanger sequencing and the novel primer extension (PEX) reaction matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) based method. RESULTS: This report demonstrates that PEX reaction followed by MALDI-TOF analysis detects the A594V mutation, encoding ganciclovir resistance, ten days earlier compared to Sanger sequencing and more than 30 days prior to an increase in viral load. CONCLUSION: The greatly increased sensitivity and rapid turnaround-time combined with easy handling and moderate costs indicate that this procedure could make a major contribution to improve transplantation outcomes.

Ethnic differences in proximal and distal tubular sodium reabsorption are heritable in black and white populations.

BACKGROUND: Segmental handling of sodium along the proximal and distal nephron might be heritable and different between black and white participants. METHODS: We randomly recruited 95 nuclear families of black South African ancestry and 103 nuclear families of white Belgian ancestry. We measured the (FENa) and estimated the fractional renal sodium reabsorption in the proximal (RNaprox) and distal (RNadist) tubules from the clearances of endogenous lithium and creatinine. In multivariable analyses, we studied the relation of RNaprox and RNadist with FENa and estimated the heritability (h) of RNaprox and RNadist. RESULTS: Independent of urinary sodium excretion, South Africans (n = 240) had higher RNaprox (unadjusted median, 93.9% vs. 81.0%; P < 0.001) than Belgians (n = 737), but lower RNadist (91.2% vs. 95.1%; P < 0.001). The slope of RNaprox on FENa was steeper in Belgians than in South Africans (-5.40 +/- 0.58 vs. -0.78 +/- 0.58 units; P < 0.001), whereas the opposite was true for the slope of RNadist on FENa (-3.84 +/- 0.19 vs. -13.71 +/- 1.30 units; P < 0.001). h of RNaprox and RNadist was high and significant (P < 0.001) in both countries. h was higher in South Africans than in Belgians for RNaprox (0.82 vs. 0.56; P < 0.001), but was similar for RNadist (0.68 vs. 0.50; P = 0.17). Of the filtered sodium load, black participants reabsorb more than white participants in the proximal nephron and less postproximally. CONCLUSION: Segmental sodium reabsorption along the nephron is highly heritable, but the capacity for regulation in the proximal and postproximal tubules differs between whites and blacks.

Mammographic screening for breast cancer: background of a pilot program in the Canton of Vaud.

For several years now, substantial efforts have been devoted to the development and the implementation of a screening program for breast cancer in the Canton of Vaud. A four-year pilot phase is now starting, involving two regional hospitals with their catchment areas; women over 50 and under 70 years old will be invited to participate in the program. A double view mammography will be made, with a double reading made by the hospital radiologists; a third reading will be made in case of discrepancy between the two first radiologists. Patients classified as positive for screening (e.g., with a suspect radiological image) will be referred to their practitioner for further diagnosis and treatment. The medical and public health background of this program is discussed, more specifically the reasons for developing a screening program, the choice of mammography rather than other tools, and the need to implement screening as an organized program.

Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA.

Background In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20(+) large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. DESIGN AND METHODS: Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. RESULTS: A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06). Conclusions We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20(+) B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted.

Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection: Determinants and Outcomes.

BACKGROUND Current guidelines give recommendations for preferred combination antiretroviral therapy (cART). We investigated factors influencing the choice of initial cART in clinical practice and its outcome. METHODS We analyzed treatment-naive adults with human immunodeficiency virus (HIV) infection participating in the Swiss HIV Cohort Study and starting cART from January 1, 2005, through December 31, 2009. The primary end point was the choice of the initial antiretroviral regimen. Secondary end points were virologic suppression, the increase in CD4 cell counts from baseline, and treatment modification within 12 months after starting treatment. RESULTS A total of 1957 patients were analyzed. Tenofovir-emtricitabine (TDF-FTC)-efavirenz was the most frequently prescribed cART (29.9%), followed by TDF-FTC-lopinavir/r (16.9%), TDF-FTC-atazanavir/r (12.9%), zidovudine-lamivudine (ZDV-3TC)-lopinavir/r (12.8%), and abacavir/lamivudine (ABC-3TC)-efavirenz (5.7%). Differences in prescription were noted among different Swiss HIV Cohort Study sites (P < .001). In multivariate analysis, compared with TDF-FTC-efavirenz, starting TDF-FTC-lopinavir/r was associated with prior AIDS (relative risk ratio, 2.78; 95% CI, 1.78-4.35), HIV-RNA greater than 100 000 copies/mL (1.53; 1.07-2.18), and CD4 greater than 350 cells/μL (1.67; 1.04-2.70); TDF-FTC-atazanavir/r with a depressive disorder (1.77; 1.04-3.01), HIV-RNA greater than 100 000 copies/mL (1.54; 1.05-2.25), and an opiate substitution program (2.76; 1.09-7.00); and ZDV-3TC-lopinavir/r with female sex (3.89; 2.39-6.31) and CD4 cell counts greater than 350 cells/μL (4.50; 2.58-7.86). At 12 months, 1715 patients (87.6%) achieved viral load less than 50 copies/mL and CD4 cell counts increased by a median (interquartile range) of 173 (89-269) cells/μL. Virologic suppression was more likely with TDF-FTC-efavirenz, and CD4 increase was higher with ZDV-3TC-lopinavir/r. No differences in outcome were observed among Swiss HIV Cohort Study sites. CONCLUSIONS Large differences in prescription but not in outcome were observed among study sites. A trend toward individualized cART was noted suggesting that initial cART is significantly influenced by physician's preference and patient characteristics. Our study highlights the need for evidence-based data for determining the best initial regimen for different HIV-infected persons.

Low-dose cidofovir for the treatment of polyomavirus-associated nephropathy: two case reports and review of the literature.

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) is a serious complication and cause of graft loss in kidney transplant recipients. In the absence of specific antiviral drugs, early detection of the disease and reduction of immunosuppressive regimen is the cornerstone of therapy. Cidofovir, a nucleoside analogue, has been found to inhibit BK virus (BKV) replication in vitro and has been proposed as treatment of refractory PVAN at low doses; however, its efficacy has never been demonstrated in randomized controlled trials. METHODS: Cidofovir therapy (0.5 mg/kg at a 2-week interval for eight consecutive doses) was initiated in two patients with biopsy-proven PVAN and persistent BKV DNA viraemia (> or = 10,000 copies/ml despite sustained reduction of the immunosuppressive regimen). In addition to these two case reports, we performed a critical review of the literature on the use of cidofovir in PVAN. RESULTS: No significant decrease of BKV viral load in blood was observed during cidofovir therapy and in follow-up of the two patients treated with cidofovir. Our literature review identified 21 publications reporting the use of cidofovir for the treatment of PVAN. All were case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of data or concomitant reduction of immunosuppressive regimen. The four remaining publications were case reports. CONCLUSIONS: In vitro and clinical data to support the efficacy of cidofovir in the treatment of PVAN are currently lacking. More promising compounds should be identified for further clinical studies.