Association atypique d'une démence sémantique, d'un syndrome cortico-basal et d'une tauopathie 4R = [Atypical association of semantic dementia, corticobasal syndrome and 4R tauopathy]

Enjeu et contexte de la recherche La dégénérescence lobaire fronto-temporale (DLFT) est une pathologie neurodégénérative aussi fréquente que la maladie d'Alzheimer parmi les adultes de moins de 65 ans. Elle recouvre une constellation de syndromes neuropsychiatriques et moteurs dont les caractéristiques cliniques et anatomo-pathologiques se recoupent partiellement. La plupart des cas de démence sémantique ne présentent pas de troubles moteurs et révèlent à l'autopsie des lésions ubiquitine-positives. Son association à un syndrome cortico-basal et à une tauopathie 4R est donc très inhabituelle. Le cas que nous présentons est le premier à disposer d'une description clinique complète, tant sur le plan cognitif que moteur, et d'une analyse génétique et histopathologique. Résumé de l'article Il s'agit d'un homme de 57 ans, sans antécédents familiaux, présentant une démence sémantique accompagnée de symptômes inhabituels dans ce contexte, tels qu'une dysfonction exécutive et en mémoire épisodique, une désorientation spatiale et une dyscalculie. Le déclin physique et cognitif fut rapidement progressif. Une année et demie plus tard, il développait en effet des symptômes moteurs compatibles initialement avec un syndrome de Richardson, puis avec un syndrome cortico-basal. Son décès survint à l'âge de 60 ans des suites d'une pneumonie sur broncho-aspiration. L'autopsie cérébrale mit en évidence une perte neuronale et de nombreuses lésions tau-4R-positives dans les lobes frontaux, pariétaux et temporaux, les ganglions de la base et le tronc cérébral. Aucune mutation pathologique n'a été décelée dans le gène MAPT (microtubule-associated protein tau). L'ensemble de ces éléments sont discutés dans le cadre des connaissances actuelles sur la DLFT. Conclusions et perspectives Ce cas illustre le recoupement important des différents syndromes de la DLFT, parfois appelée le « complexe de Pick ». De plus, la démence sémantique pourrait s'avérer cliniquement moins homogène que prévu. Les définitions actuelles de la démence sémantique omettent la description des symptômes cognitifs extra-sémantiques malgré l'accumulation de preuves de leur existence. La faible prévalence de la démence sémantique, ainsi que des différences dans les examens neuropsychologiques, peuvent expliquer en partie la raison de cette omission. La variabilité histopathologique de chaque phénotype de DLFT peut également induire des différences dans leur expression clinique. Dans un domaine aussi mouvant que la DLFT, la co- occurrence ou la succession de plusieurs syndromes cliniques est en outre probablement la règle plutôt que l'exception.

International union of basic and clinical pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel.

The epithelial Na(+) channel (ENaC) and the acid-sensing ion channels (ASICs) form subfamilies within the ENaC/degenerin family of Na(+) channels. ENaC mediates transepithelial Na(+) transport, thereby contributing to Na(+) homeostasis and the maintenance of blood pressure and the airway surface liquid level. ASICs are H(+)-activated channels found in central and peripheral neurons, where their activation induces neuronal depolarization. ASICs are involved in pain sensation, the expression of fear, and neurodegeneration after ischemia, making them potentially interesting drug targets. This review summarizes the biophysical properties, cellular functions, and physiologic and pathologic roles of the ASIC and ENaC subfamilies. The analysis of the homologies between ENaC and ASICs and the relation between functional and structural information shows many parallels between these channels, suggesting that some mechanisms that control channel activity are shared between ASICs and ENaC. The available crystal structures and the discovery of animal toxins acting on ASICs provide a unique opportunity to address the molecular mechanisms of ENaC and ASIC function to identify novel strategies for the modulation of these channels by pharmacologic ligands.

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2) at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 4: seminal vesicles and lymph nodes.

The 2009 International Society of Urological Pathology Consensus Conference in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to the infiltration of tumor into the seminal vesicles and regional lymph nodes were coordinated by working group 4. There was a consensus that complete blocking of the seminal vesicles was not necessary, although sampling of the junction of the seminal vesicles and prostate was mandatory. There was consensus that sampling of the vas deferens margins was not obligatory. There was also consensus that muscular wall invasion of the extraprostatic seminal vesicle only should be regarded as seminal vesicle invasion. Categorization into types of seminal vesicle spread was agreed by consensus to be not necessary. For examination of lymph nodes, there was consensus that special techniques such as frozen sectioning were of use only in high-risk cases. There was no consensus on the optimal sampling method for pelvic lymph node dissection specimens, although there was consensus that all lymph nodes should be completely blocked as a minimum. There was also a consensus that a count of the number of lymph nodes harvested should be attempted. In view of recent evidence, there was consensus that the diameter of the largest lymph node metastasis should be measured. These consensus decisions will hopefully clarify the difficult areas of pathological assessment in radical prostatectomy evaluation and improve the concordance of research series to allow more accurate assessment of patient prognosis.

Lack of association between beta-herpesvirus infection and bronchiolitis obliterans syndrome in lung transplant recipients in the era of antiviral prophylaxis.

BACKGROUND: Cytomegalovirus (CMV), human herpesvirus-6 and -7 (HHV-6 and -7) are beta-herpesviruses that commonly reactivate and have been proposed to trigger acute rejection and chronic allograft injury. We assessed the contribution of these viruses in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Quantitative real-time polymerase chain reaction of bronchoalveolar lavage samples were performed for CMV, HHV-6 and -7 in a prospective cohort of lung transplant recipients. A time-dependent Cox regression analysis was used to correlate the risk of BOS and acute rejection in patients with and without beta-herpesviruses infection. RESULTS: Ninety-three patients were included in the study over a period of 3 years. A total of 581 samples from bronchoalveolar lavage were obtained. Sixty-one patients (65.6%) had at least one positive result for one of the beta-herpesviruses: 48 patients (51.6%) for CMV and 19 patients (20.4%) for both HHV-6 and -7. Median peak viral load was 3419 copies/mL for CMV, 258 copies/mL for HHV-6, and 665 copies/mL for HHV-7. Acute rejection (>or=grade 2) occurred in 46.2% and BOS (>or=stage 1) in 19.4% of the patients. In the Cox regression model the relative risk of acute rejection or BOS was not increased in patients with any beta-herpesviruses reactivation. Acute rejection was the only independently associated risk factor for BOS. CONCLUSIONS: In lung transplant recipients receiving prolonged antiviral prophylaxis, reactivation of beta-herpesviruses within the allograft was common. However, despite high viral loads in many patients, virus replication was not associated with the development of rejection or BOS.

A Swiss neighbourhood index of socioeconomic position: Development and Association with Mortality

Background Area-based measures of socioeconomic position (SEP) suitable for epidemiological research are lacking in Switzerland. The authors developed the Swiss neighbourhood index of SEP (Swiss-SEP). Methods Neighbourhoods of 50 households with overlapping boundaries were defined using Census 2000 and road network data. Median rent per square metre, proportion households headed by a person with primary education or less, proportion headed by a person in manual or unskilled occupation and the mean number of persons per room were analysed in principle component analysis. The authors compared the index with independent income data and examined associations with mortality from 2001 to 2008. Results 1.27 million overlapping neighbourhoods were defined. Education, occupation and housing variables had loadings of 0.578, 0.570 and 0.362, respectively, and median rent had a loading of −0.459. Mean yearly equivalised income of households increased from SFr42 000 to SFr72 000 between deciles of neighbourhoods with lowest and highest SEP. Comparing deciles of neighbourhoods with lowest to highest SEP, the age- and sex-adjusted HR was 1.38 (95% CI 1.36 to 1.41) for all-cause mortality, 1.83 (95% CI 1.71 to 1.95) for lung cancer, 1.48 (95% CI 1.44 to 1.51) for cardiovascular diseases, 2.42 (95% CI 1.94 to 3.01) for traffic accidents, 0.93 (95% CI 0.85 to 1.02) for breast cancer and 0.86 (95% CI 0.78 to 0.95) for suicide. Conclusions Developed using a novel approach to define neighbourhoods, the Swiss-SEP index was strongly associated with household income and some causes of death. It will be useful for clinical- and population-based studies, where individual-level socioeconomic data are often missing, and to investigate the effects on health of the socioeconomic characteristics of a place.

Association of biomarkers of lipid modification with functional and morphological indices of coronary stenosis severity in stable coronary artery disease.

Biomarkers of blood lipid modification and oxidative stress have been associated with increased cardiovascular morbidity. We sought to determine whether these biomarkers were related to functional indices of stenosis severity among patients with stable coronary artery disease. We studied 197 consecutive patients with stable coronary artery disease due to single vessel disease. Fractional flow reserve (FFR) ≤ 0.80 was assessed as index of a functionally significant lesion. Serum levels of secretory phospholipase A2 (sPLA2) activity, secretory phospholipase A2 type IIA (sPLA2-IIA), myeloperoxydase (MPO), lipoprotein-associated phospholipase A2 (Lp-PLA2), and oxidized low-density lipoprotein (OxLDL) were assessed using commercially available assays. Patients with FFR > 0.8 had higher sPLA2 activity, sPLA2 IIA, and OxLDL levels than patients with FFR ≤ 0.8 (21.25 [16.03-27.28] vs 25.85 [20.58-34.63] U/mL, p < 0.001, 2.0 [1.5-3.4] vs 2.6 [2.0-3.4] ng/mL, p < 0.01; and 53.0 [36.0-71.0] vs 64.5 [50-89.25], p < 0.001 respectively). Patients with FFR > 0.80 had similar Lp-PLA2 and MPO levels versus those with FFR ≤ 0.8. sPLA2 activity, sPLA2 IIA significantly increased area under the curve over baseline characteristics to predict FFR ≤ 0.8 (0.67 to 0.77 (95 % confidence interval [CI]: 0.69-0.85) p < 0.01 and 0.67 to 0.77 (95 % CI: 0.69-0.84) p < 0.01, respectively). Serum sPLA2 activity as well as sPLA2-IIA level is related to functional characteristics of coronary stenoses in patients with stable coronary artery disease.

Association of poorly controlled diabetes with low serum leptin in morbid obesity.

OBJECTIVES: Leptin may be involved in the regulation of body weight, food intake, and energy expenditure. In view of a possible link between leptin concentrations and diabetes that has been suggested in obese rodents, we investigated the potential relationship between serum leptin concentrations and hyperglycaemia in French patients with morbid obesity. SUBJECTS: Fasting leptin concentrations were measured in 241 morbidly obese patients with various degrees of glucose tolerance in a cross-sectional study. RESULTS: Fasting serum leptin concentrations did not differ between normoglycaemia (NG, 61.5 +/- 24.0 ng/ml) and glucose intolerant morbidly obese subjects (IGT, 56.5 +/- 18.5 ng/ml) and were slightly lower in those with controlled diabetes (55.1 +/- 30.3 ng/ml, P = 0.06 when compared to NG subjects). In contrast, leptin concentrations were 30% lower in patients with poorly controlled diabetes (43.0 +/- 22.2 ng/ml, P = 0.001 vs NG subjects). Leptin concentrations were negatively correlated with fasting glucose in all groups combined (p = -0.24, P = 0.0001) and particularly in NIDDM subjects (p = 0.31, P = 0.0054). Although leptin concentrations were higher in women than in men, similar significant correlation with fasting glucose was found when females were analyzed separately. A positive correlation was found with BMI (p = 0.25, P = 0.0001) in all groups. Multivariate analysis revealed that fasting glucose was independently associated with serum leptin concentrations (F = 12.5, P = 0.0005). Sex, age, BMI, waist/hip ratio, fasting glucose and insulin, total cholesterol and triglycerides, tested in the model, explained 42% of the leptin variability in this population. CONCLUSIONS: Poorly controlled diabetes was accompanied by a significant reduction of serum leptin concentrations in morbidly obese subjects. We suggest that a relative leptin deficiency (lower than expected for the BMI) associated with insulin deficiency in this population might contribute to a vicious cycle maintaining (or even worsening) obesity itself and/or its metabolic complications.

Association of calcemia and serum vitamin D with 24H-urinary calcium excretion in a swiss population-based study

Background: Elevated urinary calcium excretion is associated with reduced bone mineral density. Population-based data on urinary calcium excretion are scarce. We explored the association of serum calcium and circulating levels of vitamin D (including 25(OH)D2 and 25(OH)D3) with urinary calcium excretion in men and women in a population-based study. Methods: We used data from the "Swiss Survey on Salt" conducted between 2010 and 2012 and including people aged 15 years and over. Twenty-four hour urine collection, blood analysis, clinical examination and anthropometric measures were collected in 11 centres from the 3 linguistic regions of Switzerland. Vitamin D was measured centrally using liquid chromatography - tandem mass spectrometry. Hypercalciuria was defined as urinary calcium excretion >0.1 mmol/kg/24h. Multivariable linear regression was used to explore factors associated with 24-hour urinary calcium excretion (mmol/24h) squared root transformed, taken as the dependant variable. Vitamin D was divided into monthspecific tertiles with the first tertile having the lowest value and the third tertile having the highest value. Results: The 669 men and 624 women had mean (SD) age of 49.2 (18.1) and 47 (17.9) years and a prevalence of hypercalciuria of 8.9% and 8.0%, respectively. In adjusted models, the association of urinary calcium excretion with protein-corrected serum calcium was (β coefficient } standard error, according to urinary calcium squared root transformed) 1.125 } 0.184 mmol/L per square-root (mmol/24h) (P<0.001) in women and 0.374 } 0.224 (P=0.096) in men. Men in the third month-specific vitamin D tertile had higher urinary calcium excretion than men in the first tertile (0.170 } 0.05 nmol/L per mmol/24h, P=0.001) and the corresponding association was 0.048 } 0.043, P= 0.272 in women. Conclusion: About one in eleven person has hypercalciuria in the Swiss population. The positive association of serum calcium with urinary calcium excretion was steeper in women than in men, independently of menopausal status. Circulating vitamin D was associated positively with urinary calcium excretion only in men. The reasons underlying the observed sex differences in the hormonal control of urinary calcium excretion need to be explored in further studies.

Association of urethral toxicity with dose exposure in combined high-dose-rate brachytherapy and intensity-modulated radiation therapy in intermediate- and high-risk prostate cancer.

INTRODUCTION: To report acute and late toxicities in patients with intermediate- and high-risk prostate cancer treated with combined high-dose-rate brachytherapy (HDR-B) and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: From March 2003 to September 2005, 64 men were treated with a single implant HDR-B with 21 Gy given in three fractions, followed by 50 Gy IMRT along with organ tracking. Median age was 66.1 years, and risk of recurrence was intermediate in 47% of the patients or high in 53% of the patients. Androgen deprivation therapy was received by 69% of the patients. Toxicity was scored according to the CTCAE version 3.0. Median follow-up was 3.1 years. RESULTS: Acute grade 3 genitourinary (GU) toxicity was observed in 7.8% of the patients, and late grades 3 and 4 GU toxicity was observed in 10.9% and 1.6% of the patients. Acute grade 3 gastrointestinal (GI) toxicity was experienced by 1.6% of the patients, and late grade 3 GI toxicity was absent. The urethral V(120) (urethral volume receiving &gt; or =120% of the prescribed HDR-B dose) was associated with acute (P=.047) and late &gt; or = grade 2 GU toxicities (P=.049). CONCLUSIONS: Late grades 3 and 4GU toxicity occurred in 10.9% and 1.6% of the patients after HDR-B followed by IMRT in association with the irradiated urethral volume. The impact of V(120) on GU toxicity should be validated in further studies.

Survival of zirconia- and metal-supported fixed dental prostheses: a systematic review

Purpose: The aim of this review was to systematically evaluate and compare the frequency of veneer chipping and core fracture of zirconia fixed dental prostheses (FOPS) and porcelain-fused-to-metal (PFM) FDPs and determine possible influencing factors. Materials and Methods: The SCOPUS database and International Association of Dental Research abstracts were searched for clinical studies involving zirconia and PFM FDPs. Furthermore, studies that were integrated into systematic reviews on PFM FDPs were also evaluated. The principle investigators of any clinical studies on zirconia FDPs were contacted to provide additional information. Based on the available information for each FOP, a data file was constructed. Veneer chipping was divided into three grades (grade 1 = polishing, grade 2 = repair, grade 3 = replacement). To assess the frequency of veneer chipping and possible influencing factors, a piecewise exponential model was used to adjust for a study effect. Results: None of the studies on PFM FDPs (reviews and additional searching) sufficiently satisfied the criteria of this review to be included. Thirteen clinical studies on zirconia FDPs and two studies that investigated both zirconia and PFM FDPs were identified. These studies involved 664 zirconia and 134 PFM FDPs at baseline. Follow-up data were available for 595 zirconia and 127 PFM FDPs. The mean observation period was approximately 3 years for both groups. The frequency of core fracture was less than 1% in the zirconia group and 0% in the PFM group. When all studies were included, 142 veneer chippings were recorded for zirconia FDPs (24%) and 43 for PFM FDPs (34%). However, the studies differed extensively with regard to veneer chipping of zirconia: 85% of all chippings occurred in 4 studies, and 43% of all chippings included zirconia FDPs. If only studies that evaluated both types of core materials were included, the frequency of chipping was 54% for the zirconia-supported FDPs and 34% for PFM FDPs. When adjusting the survival rate for the study effect, the difference between zirconia and PFM FDPs was statistically significant for all grades of chippings (P = .001), as well as for chipping grade 3 (P = .02). If all grades of veneer chippings were taken into account, the survival of PFM FDPs was 97%, while the survival rate of the zirconia FDPs was 90% after 3 years for a typical study. For both PFM and zirconia FDPs, the frequency of grades 1 and 2 veneer chippings was considerably higher than grade 3. Veneer chipping was significantly less frequent in pressed materials than in hand-layered materials, both for zirconia and PFM FDPs (P = .04). Conclusions: Since the frequency of veneer chipping was significantly higher in the zirconia FDPs than PFM FDPs, and as refined processing procedures have started to yield better results in the laboratory, new clinical studies with these new procedures must confirm whether the frequency of veneer chipping can be reduced to the level of PFM. Int J Prosthodont 2010;23:493-502

Association of electrocardiogram abnormalities and incident heart failure events.

Unless effective preventive strategies are implemented, aging of the population will result in a significant worsening of the heart failure (HF) epidemic. Few data exist on whether baseline electrocardiographic (ECG) abnormalities can refine risk prediction for HF. METHODS: We examined a prospective cohort of 2,915 participants aged 70 to 79 years without preexisting HF, enrolled between April 1997 and June 1998 in the Health, Aging, and Body Composition (Health ABC) study. Minnesota Code was used to define major and minor ECG abnormalities at baseline and at year 4 follow-up. Using Cox models, we assessed (1) the association between ECG abnormalities and incident HF and (2) the incremental value of adding ECG to the Health ABC HF Risk Score using the net reclassification index. RESULTS: At baseline, 380 participants (13.0%) had minor, and 620 (21.3%) had major ECG abnormalities. During a median follow-up of 11.4 years, 485 participants (16.6%) developed incident HF. After adjusting for the Health ABC HF Risk Score variables, the hazard ratio (HR) was 1.27 (95% CI 0.96-1.68) for minor and 1.99 (95% CI 1.61-2.44) for major ECG abnormalities. At year 4, 263 participants developed new and 549 had persistent abnormalities; both were associated with increased subsequent HF risk (HR 1.94, 95% CI 1.38-2.72 for new and HR 2.35, 95% CI 1.82-3.02 for persistent ECG abnormalities). Baseline ECG correctly reclassified 10.5% of patients with HF events, 0.8% of those without HF events, and 1.4% of the overall population. The net reclassification index across the Health ABC HF risk categories was 0.11 (95% CI 0.03-0.19). CONCLUSIONS: Among older adults, baseline and new ECG abnormalities are independently associated with increased risk of HF. The contribution of ECG screening for targeted prevention of HF should be evaluated in clinical trials.