Incomplete Distal Renal Tubular Acidosis from a Heterozygous Mutation of the V-ATPase B1 Subunit

Congenital distal renal tubular acidosis (dRTA) from mutations of the B1 subunit of the V-ATPase is considered an autosomal recessive disease. We analyzed a dRTA kindred with a truncation-mutation of B1 (p.Phe468fsX487) previously shown to have failure of assembly into the V1 domain of the V-ATPase. All heterozygous carriers in this kindred have normal plasma bicarbonate concentrations, thus evaded the diagnosis of RTA. However, inappropriately high urine pH, hypocitraturia, and hypercalciuria are present either individually or in combination in the heterozygotes at baseline. Two of the heterozygotes studied also have inappropriate urinary acidification with acute ammonium chloride loading and impaired urine-blood pCO2 gradient during bicarbonaturia indicating presence of H+ gradient and flux defects. In normal human renal papillae, wild type B1 is located primarily on the plasma membrane but papilla from one of the heterozygote who had kidney stones had renal tissue secured from surgery showed B1 in both plasma membrane as well as a diffuse intracellular staining. Titrating increasing amounts of the mutant B1 subunit did not exhibit negative dominance over the expression, cellular distribution, or H+-pump activity of the wild type B1 in mammalian HEK293 cells and in V-ATPase-deficient S. cerevisiae. This is the first demonstration of renal acidification defects and nephrolithiasis in heterozygous carriers of mutant B1 subunit; which cannot be attributable to negative dominance. We propose that heterozygosity may lead to mild real acidification defects due to haploinsufficiency. B1 heterozygosity should be considered in patients with calcium nephrolithiasis and urinary abnormalities such as alkalinuria or hypocitraturia.

Positive affect moderates the effect of negative affect on cardiovascular disease-related hospitalizations and all-cause mortality after cardiac rehabilitation

BACKGROUND Little is known as to whether negative emotions adversely impact the prognosis of patients who undergo cardiac rehabilitation. We prospectively investigated the predictive value of state negative affect (NA) assessed at discharge from cardiac rehabilitation for prognosis and the moderating role of positive affect (PA) on the effect of NA on outcomes. METHODS A total of 564 cardiac patients (62.49 ± 11.51) completed a comprehensive three-month outpatient cardiac rehabilitation program, filling in the Global Mood Scale (GMS) at discharge. The combined endpoint was cardiovascular disease (CVD)-related hospitalizations plus all-cause mortality at follow-up. Cox regression models estimated the predictive value of NA, as well as the moderating influence of PA on outcomes. Survival models were adjusted for sociodemographic factors, traditional cardiovascular risk factors, and severity of disease. RESULTS During a mean follow-up period of 3.4 years, 71 patients were hospitalized for a CVD-related event and 15 patients died. NA score (range 0-20) was a significant and independent predictor (hazard ratio (HR) 1.091, 95% confidence interval (CI) 1.012-1.175; p = 0.023) with a three-point higher level in NA increasing the relative risk by 9.1%. Furthermore, PA interacted significantly with NA (p < 0.001). The relative risk of poor prognosis with NA was increased in patients with low PA (p = 0.012) but remained unchanged in combination with high PA (p = 0.12). CONCLUSION The combination of NA with low PA was particularly predictive of poor prognosis. Whether reduction of NA and increase of PA, particularly in those with high NA, improves outcome needs to be tested.

Prevalence of paunch calf syndrome carriers in Italian Romagnola cattle.

The term 'paunch calf syndrome' encompasses the multi-organic lethal developmental dysplasia reported in the Romagnola breed of cattle and is characterised by facial deformities, an enlarged and floating abdomen containing considerable abdominal effusion, and hepatic fibrosis. Paunch calf syndrome is caused by a missense mutation in the KDM2B gene (c.2503G>A) that is thought to lead to an amino acid exchange (p.D835N). In this study, the prevalence of carriers of the mutant KDM2B allele (and thus the frequency of the allele) was assessed in selected subpopulations of Romagnola cattle. The prevalence of carriers within top-ranked Romagnola sires over the years 2007-2012 was 29.3% (allele frequency 14.6%). In young bull calves, 30.9% were carriers with an allele frequency of 15.4%.

Gender differences in paediatric patients of the swiss inflammatory bowel disease cohort study.

PURPOSE Gender differences in paediatric patients with inflammatory bowel disease (IBD) are frequently reported as a secondary outcome and the results are divergent. To assess gender differences by analysing data collected within the Swiss IBD cohort study database since 2008, related to children with IBD, using the Montreal classification for a systematic approach. METHODS Data on gender, age, anthropometrics, disease location at diagnosis, disease behaviour, and therapy of 196 patients, 105 with Crohn's disease (CD) and 91 with ulcerative or indeterminate colitis (UC/IC) were retrieved and analysed. RESULTS THE CRUDE GENDER RATIO (MALE : female) of patients with CD diagnosed at <10 years of age was 2.57, the adjusted ratio was 2.42, and in patients with UC/IC it was 0.68 and 0.64 respectively. The non-adjusted gender ratio of patients diagnosed at ≥10 years was 1.58 for CD and 0.88 for UC/IC. Boys with UC/IC diagnosed <10 years of age had a longer diagnostic delay, and in girls diagnosed with UC/IC >10 years a more important use of azathioprine was observed. No other gender difference was found after analysis of age, disease location and behaviour at diagnosis, duration of disease, familial occurrence of IBD, prevalence of extra-intestinal manifestations, complications, and requirement for surgery. CONCLUSION CD in children <10 years affects predominantly boys with a sex ratio of 2.57; the impact of sex-hormones on the development of CD in pre-pubertal male patients should be investigated.

Ultrasound evaluation of synovitis in RA: correlation with clinical disease activity and sensitivity to change in an observational cohort study.

OBJECTIVE To evaluate the correlation between clinical measures of disease activity and a ultrasound (US) scoring system for synovitis applied by many different ultrasonographers in a daily routine care setting within the Swiss registry for RA (SCQM) and further to determine the sensitivity to change of this US Score. METHODS One hundred and eight Swiss rheumatologists were trained in performing the Swiss Sonography in Arthritis and Rheumatism (SONAR) score. US B-mode and Power Doppler (PwD) scores were correlated with DAS28 and compared between the clinical categories in a cross-sectional cohort of patients. In patients with a second US (longitudinal cohort), we investigated if change in US score correlated with change in DAS and evaluated the responsiveness of both methods. RESULTS In the cross-sectional cohort with 536 patients, correlation between the B-mode score and DAS28 was significant but modest (Pearson coefficient r = 0.41, P < 0.0001). The same was true for the PwD score (r = 0.41, P < 0.0001). In the longitudinal cohort with 183 patients we also found a significant correlation between change in B-mode and in PwD score with change in DAS28 (r = 0.54, P < 0.0001 and r = 0.46, P < 0.0001, respectively). Both methods of evaluation (DAS and US) showed similar responsiveness according to standardized response mean (SRM). CONCLUSIONS The SONAR Score is practicable and was applied by many rheumatologists in daily routine care after initial training. It demonstrates significant correlations with the degree of as well as change in disease activity as measured by DAS. On the level of the individual, the US score shows many discrepancies and overlapping results exist.

Intravitreal ranibizumab monotherapy to treat retinopathy of prematurity zone II, stage 3 with plus disease.

BACKGROUND Treatment of retinopathy of prematurity (ROP) stage 3 plus with bevacizumab is still very controversial. We report the outcome of 6 eyes of 4 premature infants with ROP stage 3 plus disease treated with ranibizumab monotherapy. METHODS Six eyes of 4 premature infants with threshold ROP 3 plus disease in zone II, were treated with one intravitreal injection of 0.03 ml ranibizumab. No prior laser or other intravitreal therapy was done. Fundus examination was performed prior to the intervention and at each follow-up visit. Changes in various mean vital parameters one week post intervention compared to one week pre-intervention were assessed. RESULTS The gestational age (GA) of patient 1, 2, 3, and 4 at birth was 24 5/7, 24 5/7, 24 4/7, and 26 1/7 weeks, respectively. The birth weight was 500 grams, 450 grams, 665 grams, and 745 grams, respectively. The GA at the date of treatment ranged from 34 3/7 to 38 6/7 weeks. In one infant, upper air way infection was observed 2 days post injection of the second eye. Three eyes required paracentesis to reduce the intraocular pressure after injection and to restore central artery perfusion. After six months, all eyes showed complete retinal vascularisation without any signs of disease recurrence. CONCLUSIONS Treatment of ROP 3 plus disease with intravitreal ranibizumab was effective in all cases and should be considered for treatment. One infant developed an upper air way infection suspicious for nasopharyngitis, which might be a possible side effect of ranibizumab. Another frequent complication was intraocular pressure rise after injection. More patients with longer follow-up duration are mandatory to confirm the safety and efficacy of this treatment. TRIAL REGISTRATION NUMBER NCT02164604 ; Date of registration: 13.06.2014.

High prevalence of hereditary thrombotic thrombocytopenic purpura in Central Norway: from clinical observation to evidence.

BACKGROUND Hereditary thrombotic thrombocytopenic purpura (TTP) caused by ADAMTS13 mutations is a rare, but serious condition. The prevalence is unknown, but seems to be high in Norway. OBJECTIVES To identify all patients with hereditary TTP in Central Norway and to investigate the prevalence of hereditary TTP and the population frequencies of two common ADAMTS13 mutations. Patients/Methods Patients were identified in a cross-sectional study within Central Norway Health Region by means of three different search strategies. Frequencies of ADAMTS13 mutations, c.4143_4144dupA and c.3178 C>T (p.R1060W) were investigated in a population-based cohort (500 alleles) and in healthy blood donors (2104 alleles) by taking advantage of the close neighbourhood of the ADAMTS13 and ABO blood group gene loci. The observed prevalence of hereditary TTP was compared to the rates of ADAMTS13 mutation carriers in different geographical regions. RESULTS We identified 11 families with hereditary TTP in Central Norway during the 10-year study period. The prevalence of hereditary TTP in Central Norway was 16.7 x 10(-6) . The most prevalent mutation was c.4143_4144dupA, accounting for two thirds of disease causing alleles among patients and having an allelic frequency of 0.33% in the Central, 0.10% in the Western, and 0.04% in the Southeastern Norwegian population. The allelic frequency of c.3178 C>T (p.R1060W) in the population was even higher (0.3-1%), but this mutation was infrequent among patients, with no homozygous cases. CONCLUSIONS We found a high prevalence of hereditary TTP in Central Norway and an apparently different penetrance of ADAMTS13 mutations. This article is protected by copyright. All rights reserved.

Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease.

BACKGROUND The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. AIM To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. METHODS Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. RESULTS The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). CONCLUSIONS Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication.

Endothelial progenitor cells as a biological marker of peripheral artery disease.

The role of endothelial progenitor cells (EPCs) in peripheral artery disease (PAD) remains unclear. We hypothesized that EPC mobilization and function play a central role in the development of endothelial dysfunction and directly influence the degree of atherosclerotic burden in peripheral artery vessels. The number of circulating EPCs, defined as CD34(+)/KDR(+) cells, were assessed by flow cytometry in 91 subjects classified according to a predefined sample size of 31 non-diabetic PAD patients, 30 diabetic PAD patients, and 30 healthy volunteers. Both PAD groups had undergone endovascular treatment in the past. As a functional parameter, EPC colony-forming units were determined ex vivo. Apart from a broad laboratory analysis, a series of clinical measures using the ankle-brachial index (ABI), flow-mediated dilatation (FMD) and carotid intima-media thickness (cIMT) were investigated. A significant reduction of EPC counts and proliferation indices in both PAD groups compared to healthy subjects were observed. Low EPC number and pathological findings in the clinical assessment were strongly correlated to the group allocation. Multivariate statistical analysis revealed these findings to be independent predictors of disease appearance. Linear regression analysis showed the ABI to be a predictor of circulating EPC number (p=0.02). Moreover, the functionality of EPCs was correlated by linear regression (p=0.017) to cIMT. The influence of diabetes mellitus on EPCs in our study has to be considered marginal in already disease-affected patients. This study demonstrated that EPCs could predict the prevalence and severity of symptomatic PAD, with ABI as the determinant of the state of EPC populations in disease-affected groups.

Impact of Diabetic Status on Outcomes After Revascularization With Drug-Eluting Stents in Relation to Coronary Artery Disease Complexity: Patient-Level Pooled Analysis of 6081 Patients.

BACKGROUND Diabetes mellitus and angiographic coronary artery disease complexity are intertwined and unfavorably affect prognosis after percutaneous coronary interventions, but their relative impact on long-term outcomes after percutaneous coronary intervention with drug-eluting stents remains controversial. This study determined drug-eluting stents outcomes in relation to diabetic status and coronary artery disease complexity as assessed by the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score. METHODS AND RESULTS In a patient-level pooled analysis from 4 all-comers trials, 6081 patients were stratified according to diabetic status and according to the median SYNTAX score ≤11 or >11. The primary end point was major adverse cardiac events, a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization within 2 years. Diabetes mellitus was present in 1310 patients (22%), and new-generation drug-eluting stents were used in 4554 patients (75%). Major adverse cardiac events occurred in 173 diabetics (14.5%) and 436 nondiabetic patients (9.9%; P<0.001). In adjusted Cox regression analyses, SYNTAX score and diabetes mellitus were both associated with the primary end point (P<0.001 and P=0.028, respectively; P for interaction, 0.07). In multivariable analyses, diabetic versus nondiabetic patients had higher risks of major adverse cardiac events (hazard ratio, 1.25; 95% confidence interval, 1.03-1.53; P=0.026) and target lesion revascularization (hazard ratio, 1.54; 95% confidence interval, 1.18-2.01; P=0.002) but similar risks of cardiac death (hazard ratio, 1.41; 95% confidence interval, 0.96-2.07; P=0.08) and myocardial infarction (hazard ratio, 0.89; 95% confidence interval, 0.64-1.22; P=0.45), without significant interaction with SYNTAX score ≤11 or >11 for any of the end points. CONCLUSIONS In this population treated with predominantly new-generation drug-eluting stents, diabetic patients were at increased risk for repeat target-lesion revascularization consistently across the spectrum of disease complexity. The SYNTAX score was an independent predictor of 2-year outcomes but did not modify the respective effect of diabetes mellitus. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00297661, NCT00389220, NCT00617084, and NCT01443104.

Use of Calcium Channel Blockers is Associated with Mortality in Patients with Chronic Kidney Disease.

BACKGROUND/AIMS The use of antihypertensive medicines has been shown to reduce proteinuria, morbidity, and mortality in patients with chronic kidney disease (CKD). A specific recommendation for a class of antihypertensive drugs is not available in this population, despite the pharmacodynamic differences. We have therefore analysed the association between antihypertensive medicines and survival of patients with chronic kidney disease. METHODS Out of 2687 consecutive patients undergoing kidney biopsy a cohort of 606 subjects with retrievable medical therapy was included into the analysis. Kidney function was assessed by glomerular filtration rate (GFR) estimation at the time point of kidney biopsy. Main outcome variable was death. RESULTS Overall 114 (18.7%) patients died. In univariate regression analysis the use of alpha-blockers and calcium channel antagonists, progression of disease, diabetes mellitus (DM) type 1 and 2, arterial hypertension, coronary heart disease, peripheral vascular disease, male sex and age were associated with mortality (all p<0.05). In a multivariate Cox regression model the use of calcium channel blockers (HR 1.89), age (HR 1.04), DM type 1 (HR 8.43) and DM type 2 (HR 2.17) and chronic obstructive pulmonary disease (HR 1.66) were associated with mortality (all p < 0.05). CONCLUSION The use of calcium channel blockers but not of other antihypertensive medicines is associated with mortality in primarily GN patients with CKD.

Quality of Life in Swiss Paediatric Inflammatory Bowel Disease Patients: Do Patients and Their Parents Experience Disease in the Same Way?

BACKGROUND AND AIMS Inflammatory bowel diseases (IBDs) may impair quality of life (QoL) in paediatric patients. We aimed to evaluate in a nationwide cohort whether patients experience QoL in a different way when compared with their parents. METHODS Sociodemographic and psychosocial characteristics were prospectively acquired from paediatric patients and their parents included in the Swiss IBD Cohort Study. Disease activity was evaluated by the Paediatric Crohn's Disease Activity Index (PCDAI) and the Paediatric Ulcerative Colitis Activity Index (PUCAI). We assessed QoL using the KIDSCREEN questionnaire. The QoL domains were analysed and compared between children and parents according to type of disease, parents' age, origin, education and marital status. RESULTS We included 110 children and parents (59 Crohn's disease [CD], 45 ulcerative colitis [UC], 6 IBD unclassified [IBDU]). There was no significant difference in QoL between CD and UC/IBDU, whether the disease was active or in remission. Parents perceived overall QoL, as well as 'mood', 'family' and 'friends' domains, lower than the children themselves, independently of their place of birth and education. However, better concordance was found on 'school performance' and 'physical activity' domains. Marital status and age of parents significantly influenced the evaluation of QoL. Mothers and fathers being married or cohabiting perceived significantly lower mood, family and friends domains than their children, whereas mothers living alone had a lower perception of the friends domain; fathers living alone had a lower perception of family and mood subscores. CONCLUSION Parents of Swiss paediatric IBD patients significantly underestimate overall QoL and domains of QoL of their children independently of origin and education.

Measuring health state preferences for hemophilia: Development of a disease-specific utility instrument

Research has shown that disease-specific health related quality of life (HRQoL) instruments are more responsive than generic instruments to particular disease conditions. However, only a few studies have used disease-specific instruments to measure HRQoL in hemophilia. The goal of this project was to develop a disease-specific utility instrument that measures patient preferences for various hemophilia health states. The visual analog scale (VAS), a ranking method, and the standard gamble (SG), a choice-based method incorporating risk, were used to measure patient preferences. Study participants (n = 128) were recruited from the UT/Gulf States Hemophilia and Thrombophilia Center and stratified by age: 0–18 years and 19+. ^ Test retest reliability was demonstrated for both VAS and SG instruments: overall within-subject correlation coefficients were 0.91 and 0.79, respectively. Results showed statistically significant differences in responses between pediatric and adult participants when using the SG (p = .045). However, no significant differences were shown between these groups when using the VAS (p = .636). When responses to VAS and SG instruments were compared, statistically significant differences in both pediatric (p < .0001) and adult (p < .0001) groups were observed. Data from this study also demonstrated that persons with hemophilia with varying severity of disease, as well as those who were HIV infected, were able to evaluate a range of health states for hemophilia. This has important implications for the study of quality of life in hemophilia and the development of disease-specific HRQoL instruments. ^ The utility measures obtained from this study can be applied in economic evaluations that analyze the cost/utility of alternative hemophilia treatments. Results derived from the SG indicate that age can influence patients' preferences regarding their state of health. This may have implications for considering treatment options based on the mean age of the population under consideration. Although both instruments independently demonstrated reliability and validity, results indicate that the two measures may not be interchangeable. ^

Predictors of survival in Alzheimer's disease

Alzheimer's disease (AD) is associated with greater mortality and reduced survival among individuals with Alzheimer's disease as compared to those without dementia. It is uncertain how these survival estimates change when the clinical signs and/or symptoms of comorbid conditions are present in individuals' with Alzheimer's disease. Cardiovascular risk factors such as hypertension, hyperlipidemia, congestive heart failure, coronary artery disease, and diabetes mellitus are common conditions in the aged population. Independently, these factors influence mortality and may have an additive effect on reduced survival in an individual with concomitant Alzheimer's disease. The bulk of the evidence from previous research efforts suggests an association between vascular co-morbidities and Alzheimer's disease incidence, but their role in survival remains to be elucidated. The objective of this proposed study was to examine the effects of cardiovascular comorbidities on the survival experience of individuals with probable Alzheimer's disease in order to identify prognostic factors for life expectancy following onset of disease. This study utilized data from the Baylor College of Medicine Alzheimer's Disease Center (ADC) longitudinal study of Alzheimer's disease and other memory disorders. Individuals between the ages of 55-69, 70-79, and ≥80 had a median survival from date of onset of 9.2 years, 8.0 years, and 7.2 years, respectively (p<0.001) and 5.5 years, 4.3 years, and 3.4 years from diagnosis. Sex was the strongest predictor of death from onset of AD, with females having a 30 percent lower risk compared to males. These findings further support the notion that age (both from onset and from diagnosis) and sex are the strongest predictors of survival among those with AD. ^

A systematic review and meta-analysis of diabetes disease management programs

Context. Despite the rapid growth of disease management programs, there are still questions about their efficacy and effectiveness for improving patient outcomes and their ability to reduce costs associated with chronic disease. ^ Objective. To determine the effectiveness of disease management programs on improving the results of HbA1c tests, lipid profiles and systolic blood pressure (SBP) readings among diabetics. These three quantitative measures are widely accepted methods of determining the quality of a patient's diabetes management and the potential for future complications. ^ Data Sources. MEDLINE and CINAHL were searched from 1950 to June 2008 using MeSH terms designed to capture all relevant studies. Scopus pearling and hand searching were also done. Only English language articles were selected. ^ Study Selection. Titles and abstracts for the 2347 articles were screened against predetermined inclusion and exclusion criteria, yielding 217 articles for full screening. After full article screening, 29 studies were selected for inclusion in the review. ^ Data Extraction. From the selected studies, data extraction included sample size, mean change over baseline, and standard deviation for each control and experimental arm. ^ Results. The pooled results show a mean HbA1c reduction of 0.64%, 95% CI (-0.83 to -0.44), mean SBP reduction of 7.39 mmHg (95% CI to -11.58 to -3.2), mean total cholesterol reduction of 5.74 mg/dL (95% CI, -10.01 to -1.43), and mean LDL cholesterol reduction of 3.74 mg/dL (95% CI, -8.34 to 0.87). Results for HbA1c, SBP and total cholesterol were statistically significant, while the results for LDL cholesterol were not. ^ Conclusions. The findings suggest that disease management programs utilizing five hallmarks of care can be effective at improving intermediate outcomes among diabetics. However, given the significant heterogeneity present, there may be fundamental differences with respect to study-specific interventions and populations that render them inappropriate for meta-analysis. ^