HD Subjects Research Articles

BIOM-32. EVS CARRYING TENASCIN-C ENABLE TUMOR-SPECIFIC MUTATION ANALYSIS IN GLIOBLASTOMA PATIENTS

Abstract Extracellular vesicles (EVs) transport biological and specific information from tumors into the bloodstream, enabling non-invasive detection of tumor material and disease monitoring. Based on a proteomics screen, we performed immunophenotyping of eight glioma-related antigens (tenascin-C (TNC), integrin-beta 1 (ITGB1), profilin-1 (PFN1), CD44, CD133, GPNMB, HLA-II, SPARC) and tetraspanins (CD9, CD63 and CD81) in plasma EVs from GBM patients (before and after surgery (n = 38)), from matched GBM relapse patients (n = 11), and from healthy donors (HD, n = 12) using imaging flow cytometry. Double-positive TNC+/CD9+ EVs showed the strongest differences per mL of plasma in primary (FC = 7.6, p< .0001, ROC analysis AUC = 81%) and relapsed GBM (FC = 16.5, p< .0001; AUC = 90%) compared to HD subjects. High TNC signals were also observed in GBM-EVs by immunogold electron microscopy compared to HD-EVs. In paired analysis, TNC+/CD9+ EVs showed a 3.9-fold decrease after tumor removal (p< .001) and re-increased at GBM recurrence in these patients (FC = 8.4, p< .05; AUC = 84%). In tissue samples, TNC levels were 5.4-fold higher in GBM patients than in non-neoplastic cortex controls (p< .01) measured by immunohistochemistry and correlated positively with plasma TNC+/CD9+ EV levels in RTK-I/II GBM patients (r = 0.42, p< .05). Accordingly, spatial transcriptomics of GBM tissue sections revealed that TNC is specifically overexpressed in GBM cells. Furthermore, magnetic sorting of TNC in plasma EVs allowed detection of GBM-specific TERT*C228T mutations by digital droplet PCR. Mutated TERT DNA was enriched in TNC+ EVs (n = 13) compared to TNC- EVs (FC = 110, p< 0.0001), total EV DNA (FC = 36.7, p< 0.01), and cfDNA (FC = 7.2, p < 0.05). In conclusion, we identified TNC as a biomarker in circulating EVs from GBM patients that can be isolated and used for tumor-specific mutation analysis.

DNA methylation profiling across brain regions in Huntington’s disease.

AbstractBackgroundHuntington’s disease (HD) is an autosomal dominant condition that occurs due to the expansion of a CAG trinucleotide repeat in the Huntingtin (HTT) gene. The translated HTT protein has an expanded polyglutamine sequence thought to cause deleterious effects. These effects cause severe neurodegeneration in the striatum. In HD there is also clear atrophy in the cerebellum and a reduction in cortical thickness, including in the entorhinal cortex (EC). Epigenome wide association studies (EWAS) of DNA methylation differences in HD have thus far been limited to the cerebral cortex and use older technologies such as the Illumina 450K array. In this study, we performed an EWAS of HD in the striatum, EC and cerebellum, using the Illumina EPIC methylation array to profile 850, 000 sites across the genome.Method120 striatum, EC and cerebellum DNA samples from 22 control and 20 HD subjects were selected and matched for sex, age and post‐mortem interval. The samples were chosen to be as free from co‐existing pathologies as possible. The majority of subjects were represented in each brain region. The DNA was bisulfite converted, randomized and profiled using the EPIC array. The methylation intensities for each sample were subjected to quality control (QC). Following QC, the samples were analyzed in R for differences in methylation between HD and control samples within each brain region, before being subjected to cross‐regional analysis.ResultWe have used linear regression models to identify differentially methylated positions (DMPs) in specific brain regions in HD. We have used regional analyses to identify differentially methylated regions (DMRs) consisting of multiple adjacent DMPs. Finally, downstream analyses have highlighted epigenetically altered pathways in disease.ConclusionThis study builds a clearer picture of DNA methylation profiles in HD in disease relevant brain regions. Future studies should integrate this with other levels of genomic regulation.

Relative validity and reproducibility of food frequency questionnaire for individuals on hemodialysis (NUGE-HD study).

Adequate assessment of food intake is essential to establish the magnitude and direction of the relationship of food, nutrients, and bioactive compounds with clinical outcomes of individuals in hemodialysis. We evaluated the relative validity and reproducibility of a specific food frequency questionnaire for individuals on hemodialysis (FFQ-HD). Eighty-two participants (57.3% male, 57.5 ± 14.4 years) from the open cohort Nutrition and Genetics in Hemodialysis Outcomes participated in this study. The relative validity of the FFQ-HD was assessed using the mean of two 24-h food recall (24hR) adjusted for within-subject variability as a reference method. We also performed Pearson correlations, and agreement between tertile, kappa statistics, and Bland-Altman scatter plots were validated. Reproducibility was assessed after 1 year using intraclass correlation coefficient (ICC). Daily energy intake was not different between FFQ-HD and 24hR (mean difference of 50.1kcal). Intake of protein, linolenic acid, fiber, phosphorus, potassium, sodium, calcium, and sugar showed a moderate correlation (r between 0.4 and 0.5) among instruments, while mean correlation coefficient was r=0.38 to food group intake. Bland-Altman plots showed good agreement for micronutrients, phosphorus, sodium, and potassium and for the groups "flour, bread, and pasta" and "processed, canned meat, salts, and seasonings". The reproducibility of FFQ-HD for nutrients and food groups was satisfactory, reaching a maximum ICC of 0.72 and 0.59, respectively. The FFQ-HD showed moderate validity and reproducibility for calories, nutrients, and food groups of clinical and nutritional interest for HD subjects so that it can be a useful tool in epidemiological studies in this population.

Intradialytic periodized exercise improves cardiopulmonary fitness and respiratory function: A randomized controlled trial.

Chronic kidney disease (CKD) is a factor that predisposes to gradual physical deconditioning from its early stages leading to cardiorespiratory fitness and musculoskeletal system impairment. We evaluated the effects of combined and periodized intradialytic exercise training on cardiopulmonary fitness and respiratory function in HD subjects. A randomized controlled trial with HD subjects was allocated into two groups: exercise group (EXG) and usual care group (UCG). EXG performed a 12-week combined and periodized intradialytic training. UCG maintained the HD routine. Thirty-nine HD subjects were analyzed (EXG = 20; UCG = 19). The EXG in comparison with the UCG showed improvements in peak oxygen consumption (Δ3.1[0.4-5.5] vs. -0.2[-2.0-1.5]ml/kg/min; p = 0.003), forced expiratory volume in the first second (Δ0.1[-0.0-0.1] vs. -0.0[-0.1-0.0]L; p = 0.022), forced vital capacity (Δ0.1[0.0-0.2] vs. -0.1[-0.2-0.0]L; p = 0.005), peak expiratory flow (Δ0.4[-0.7-1.2] vs. -0.1[-0.5-0.2]L; p = 0.046), and maximal inspiratory pressure (Δ7.35[-8.5-17.5] vs. -4.0[-18.0-12.0]cmH2 O; p = 0.028). The EXG, different from the UCG, did not worsen the maximal expiratory pressure (Δ0.1[-8.8-7.5] vs. -2.5[-15.0-9.0]cmH2 O; p = 0.036). Besides, EXG showed a significant improvement in quadriceps strength (32.05 ± 10.61 vs. 33.35 ± 11.62 kg; p = 0.042). The combined and periodized intradialytic exercise training improved cardiopulmonary fitness, respiratory function, inspiratory muscle strength, and quadriceps strength, beyond maintaining the expiratory muscle strength in HD subjects.

Plasma neurofilament light in Huntington's disease: A marker for disease onset, but not symptom progression

ObjectiveTo investigate whether plasma NfL levels correlate with clinical symptom severity in premanifest (PM) and manifest HD (HD) individuals, and whether a NfL cut-point could distinguish PM from HD patients with reasonable accuracy. Method98 participants (33 control, 26 PM, 39 HD), underwent blood sample collection and clinical assessment, using both UHDRS and non-UHDRS measures, at one academic HD Center. Years to onset (YTO), probability of disease onset in 5 years, and predicted years until 60% onset probability were also calculated. NfL levels were measured using a Meso Scale Discovery assay. ResultsCohorts differed by age. NfL levels differed significantly across diagnostic groups and were significantly correlated with age. Age-adjusted NfL levels were not correlated with clinical measures in either HD or PM cohorts, but were correlated when cohorts were combined. In PM subjects, NfL levels correlated with YTO, probability of onset in 5 years, and years until 60% onset probability. Using ROC analysis, a NfL cut-point of <53.15 pg/ml distinguished HD from control; <74.84 pg/ml distinguished HD from PM. ConclusionsThese findings implicate plasma NfL as a peripheral prognostic marker for premanifest-HD. Notably, we show that significant correlations between NfL and clinical symptoms are detected only when PM + HD subjects are combined, but not within HD subjects alone. To date, prior studies have investigated the clinical usefulness of NfL exclusively in merged PM + HD cohorts. Our data suggests a biasing of these previous correlations, and hence potentially limited usefulness of plasma NfL in monitoring HD symptom progression, for example, in clinical trials.

Cholesteryl ester levels are elevated in the caudate and putamen of Huntington\u2019s disease patients

Huntington’s disease (HD) is an autosomal dominant neurodegenerative illness caused by a mutation in the huntingtin gene (HTT) and subsequent protein (mhtt), to which the brain shows a region-specific vulnerability. Disturbances in neural cholesterol metabolism are established in HD human, murine and cell studies; however, cholesteryl esters (CE), which store and transport cholesterol in the brain, have not been investigated in human studies. This study aimed to identify region-specific alterations in the concentrations of CE in HD. The Victorian Brain Bank provided post-mortem tissue from 13 HD subjects and 13 age and sex-matched controls. Lipids were extracted from the caudate, putamen and cerebellum, and CE were quantified using targeted mass spectrometry. ACAT 1 protein expression was measured by western blot. CE concentrations were elevated in HD caudate and putamen compared to controls, with the elevation more pronounced in the caudate. No differences in the expression of ACAT1 were identified in the striatum. No remarkable differences in CE were detected in HD cerebellum. The striatal region-specific differences in CE profiles indicate functional subareas of lipid disturbance in HD. The increased CE concentration may have been induced as a compensatory mechanism to reduce cholesterol accumulation.

Abstract A12: Combining the immunophenotyping of MDSCs and lymphocytes with artificial intelligence (AI) to predict early-stage breast cancer

Abstract The purpose of this study was to analyze immunophenotyping flow cytometry data using artificial intelligence (AI) to identify individuals presenting with early-stage breast cancer (stage I/II). Peripheral blood was collected from 64 subjects diagnosed with a biopsy-confirmed breast cancer (BC; Stage I n = 42 and Stage II n = 22) along with 80 tumor-free control female donors (HD). Subjects were excluded if they had a previous history of cancer and/or a medical intervention for a breast pathology. For each subject, we profiled various myeloid and lymphoid cell populations using standard multiparametric flow cytometry. Importantly, the cell surface markers included would identify myeloid-derived suppressor cell (MDSC) subsets—known key contributors in supporting tumor progression and tumor escape. Previous studies have investigated whether measuring MDSCs can act as a liquid biopsy to detect tumor development, monitor progression, and/or predict therapeutic responses. Next, a series of feedforward artificial neural networks, or multilayer perceptrons (MLPs), were created in silico to classify samples as either BC or HD. The network inputs consisted of the channel values for each cell event from each fluorescent and scatter parameter and were used to construct three datasets: the training dataset—to “teach” two output categories (BC or HD) through backpropagation and parameter fitting; the validation dataset—to evaluate the fit to minimize overfitting; and the test dataset—to rank the trained networks against each other and estimate the classification performance. Finally, a naive testing set (i.e., never seen by the network) was used to determine the overall performance of the top-ranking networks after voting. With this approach, we were able to distinguish BC subjects from HD subjects with 92.3% sensitivity and 86.7% specificity (AUROC = 0.8987; CI95% 0.8047 to 0.9927). Additionally, we tested 14 samples collected from subjects with biopsy-confirmed ductal carcinoma in situ (DCIS). Even though they are clinically deemed as precancerous (stage 0), 11 out of 14 of these subjects were classified as BC, indicating its possible utility for detecting the existence of even a noninvasive cancerous lesion. By pairing supervised machine learning with the immunophenotyping of MDSCs and other leukocytes using flow cytometry, we have developed a novel method for possibly distinguishing breast cancer subjects from those who are tumor free with high levels of accuracy using a simple blood draw. Although further study is needed, we believe this could potentially prove clinically useful in combination with current screening methods, such as mammography, to reduce the number of unnecessary biopsies performed each year. Citation Format: George A. Dominguez, John Roop, Alexander Polo, Anthony Campisi, Dmitry I. Gabrilovich, Amit Kumar. Combining the immunophenotyping of MDSCs and lymphocytes with artificial intelligence (AI) to predict early-stage breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A12.

Social reinforcement learning as a predictor of real-life experiences in individuals with high and low depressive symptomatology.

Several studies have reported diminished learning from non-social outcomes in depressed individuals. However, it is not clear how depression impacts learning from social feedback. Notably, mood disorders are commonly associated with deficits in social functioning, which raises the possibility that potential impairments in social learning may negatively affect real-life social experiences in depressed subjects. Ninety-two participants with high (HD; N = 40) and low (LD; N = 52) depression scores were recruited. Subjects performed a learning task, during which they received monetary outcomes or social feedback which they were told came from other people. Additionally, participants answered questions about their everyday social experiences. Computational models were fit to the data and model parameters were related to social experience measures. HD subjects reported a reduced quality and quantity of social experiences compared to LD controls, including an increase in the amount of time spent in negative social situations. Moreover, HD participants showed lower learning rates than LD subjects in the social condition of the task. Interestingly, across all participants, reduced social learning rates predicted higher amounts of time spent in negative social situations, even when depression scores were controlled for. These findings indicate that deficits in social learning may affect the quality of everyday social experiences. Specifically, the impaired ability to use social feedback to appropriately update future actions, which was observed in HD subjects, may lead to suboptimal interpersonal behavior in real life. This, in turn, may evoke negative feedback from others, thus bringing about more unpleasant social encounters.

Impaired social learning predicts reduced real-life motivation in individuals with depression: A computational fMRI study

BackgroundMajor depressive disorder is associated with altered social functioning and impaired learning, on both the behavioural and the neural level. These deficits are likely related, considering that successful social interactions require learning to predict other people's emotional responses. Yet, there is little research examining this relation. MethodsForty-three individuals with high (HD; N = 21) and low (LD; N = 22) depression scores answered questions regarding their real-life social experiences and performed a social learning task during fMRI scanning. As part of the task, subjects learned associations between name cues and rewarding (happy faces) or aversive (fearful faces) social outcomes. Using computational modelling, behavioural and neural correlates of social learning were examined and related to real-life social experiences. ResultsHD participants reported reduced motivation to engage in real-life social activities and demonstrated elevated uncertainty about social outcomes in the task. Moreover, HD subjects displayed altered encoding of social reward predictions in the insula, temporal lobe and parietal lobe. Interestingly, across all subjects, higher task uncertainty and reduced parietal prediction encoding were associated with decreased motivation to engage in real-life social activities. LimitationsThe size of the included sample was relatively small. The results should thus be regarded as preliminary and replications in larger samples are called for. ConclusionTaken together, our findings suggest that reduced learning from social outcomes may impair depressed individuals’ ability to predict other people's responses in real life, which renders social situations uncertain. This uncertainty, in turn, may contribute to reduced social engagement (motivation) in depression.

MON-111 Effect of the dialysate calcium concentration and of the mineral bone disease therapies on mortality in the REIN registry

The different chemical elements of the dialysate could influence survival and calcium especially modifies the mineral and bone metabolism and the vascular calcification rate. Having garnered both the dialysate calcium concentration and the mineral bone disease (MBD) therapies, we studied the influence of these prescriptions on survival. Data from the national Renal Epidemiology Information Network registry were extracted for all the subjects having started hemodialysis from 2010 to 2013. Their exposure to the different dialysate calcium concentrations was established by center and classified by tertiles of the percentage of use of calcium <1.5mmol/l and >1.5mmol/L., updated yearly. Drug therapies involved in the MBD metabolism were extracted at the patient level from the SNIIRAM (Service National d'Information Inter régime de l'Assurance Maladie) and converted in a daily dose updated monthly. Cox survival analysis was performed on 25,629 incident patients being alive after 3 months of dialysis, adjusted for 14 baseline co-morbidities, biological data, 4 technical data and the acid of the dialysate and accounting for patient clustering within facilities. Dialysate exposure and MBD therapies were analyzed as time-dependent variables. Analysis was censored at Dec 31, 2014, or at kidney transplantation, loss to follow-up, dialysis weaning and transfer to peritoneal dialysis or home hemodialysis. The 1.5 mmol/L dialysate calcium concentration was the main dialysate in 81% of the dialysis centers in 2010 to 83% in 2014 followed by the >1.5mmol/L used as the main dialysate in 19% of the centers in 2010 to 14% in 2014. Most centers were using several formulas in up to 78% for 3 formulas in 2010 to 86% in 2014. The dialysate calcium <1.5mmol/L was scarcely used at a median level of 2.5% by center in 2010 to 4.4% in 2014. In full adjusted Cox survival analyses, all-cause mortality HRs of dialysate calcium >1.5 mmol/L and <1.5mmol/l by tertile of use by center were not associated with survival. The number of formula used by center was also not significantly associated with survival. Sole the cardiovascular mortality HR of the use of dialysate calcium >1.5mmol/L in all tertiles was significantly lowered to about 0.75 [0.57;0.91] compared to no use. The MBD therapies were broadly associated with survival improvement for calcium, native vitamine D, active vitamine D, sevelamer, lanthanum and cinacalcet and depending of the daily dose used. No influence of the dialysate calcium concentration was evidenced on survival whereas all MBD therapies were associated with a survival improvement depending on the daily dose used. More information towards HD subjects is needed.

Task-switching abilities in pre-manifest Huntington's disease subjects

IntroductionHuntington's Disease (HD) cognitive dysfunction occurs before unequivocal motor signs become apparent. The predominant early cognitive abnormal domains may include deficits in psychomotor speed, negative emotion recognition and executive functioning. Our study is aimed to investigate the executive control of cognition in pre-manifest (pre) HD subjects, by means of a task-switching protocol. MethodsWe recruited 30 pre-HD subjects and 18 age-, sex- and education-matched Healthy Controls (HC). Subjects were assigned to two experimental groups: 15 pre-HD1 with a Total Motor Score (TMS) ≤4 (far from onset) and 15 pre-HD2 with a 5 ≤ TMS≤9 (near to onset and Diagnostic Confidence Level (DCL) still<4). Two different tasks were performed in rapid and random succession, so that the task was either changed from one trial to the next one (switch trials) or repeated (repetition trials). Switch trials are usually slower than repetitions, causing a so-called Switch Cost (SC). ResultsPre-HD subjects had worse performance than HC in the switch and repetition trials, as indicated by increased SC and reaction times. In particular, pre-HD2 showed impaired switching abilities with reaction times slower than pre-HD1 and HC. ConclusionsOur study highlighted a task-switching impairment since HD was still at a pre-manifest stage. Such abnormalities worsen when pre-HD subjects start to show subtle motor manifestations, still nonspecific and insufficient to define the clinical diagnosis of HD (DCL<4). Considering that such abilities have obvious implications for activities of daily living, early cognitive rehabilitation programs addressing such deficits might be useful in the premanifest stage of the disease.

Genetic Modification of Huntington Disease Acts Early in the Prediagnosis Phase

Age at onset of Huntington disease, an inherited neurodegenerative disorder, is influenced by the size of the disease-causing CAG trinucleotide repeat expansion in HTT and by genetic modifier loci on chromosomes 8 and 15. Stratifying by modifier genotype, we have examined putamen volume, total motor score (TMS), and symbol digit modalities test (SDMT) scores, both at study entry and longitudinally, in normal controls and CAG-expansion carriers who were enrolled prior to the emergence of manifest HD in the PREDICT-HD study. The modifiers, which included onset-hastening and onset-delaying alleles on chromosome 15 and an onset-hastening allele on chromosome 8, revealed no major effect in controls but distinct patterns of modification in prediagnosis HD subjects. Putamen volume at study entry showed evidence of reciprocal modification by the chromosome 15 alleles, but the rate of loss of putamen volume was modified only by the deleterious chromosome 15 allele. By contrast, both alleles modified the rate of change of the SDMT score, but neither had an effect on the TMS. The influence of the chromosome 8 modifier was evident only in the rate of TMS increase. The data indicate that (1) modification of pathogenesis can occur early in the prediagnosis phase, (2) the modifier loci act in genetic interaction with the HD mutation rather than through independent additive effects, and (3) HD subclinical phenotypes are differentially influenced by each modifier, implying distinct effects in different cells or tissues. Together, these findings indicate the potential benefit of using genetic modifier strategies for dissecting the prediagnosis pathogenic process in HD.

DNA Damage Signatures in Peripheral Blood Cells as Biomarkers in Prodromal Huntington's Disease

Background: Blood biomarkers, that may improve the management of the pre−manifest phase of Huntington's disease (PRE−HD), are actively searched. We investigated telomere length (TL) and DNA damage signatures (DDS) as potential predictive biomarkers in peripheral blood mononuclear cells (PBMC) of PRE−HD and HD patients. Methods: We analysed the DNA isolated from fresh PBMC of 58 HD and 23 PRE−HD subjects with similar CAG expansion in the huntingtin (HTT) gene (44·20±2·85, 43·55±2·70; mean±SD) and 44 healthy controls (HC). We measured the TL by qPCR and double−strand DNA breaks by flow cytometric analysis of phosphorylated γ−H2AX (pγ−H2AX). Findings: PBMC from PRE−HD and HD groups showed shorter telomeres (p<0·0001) and significant increase of DDS compared to the controls (p<0·0001). Four individuals with pre−HD were monitored at several time points: the pγ−H2AX signal increased overtime; in three of them pγ−H2AX levels decreased with the appearance of clinical signs, although remained higher compared to HC. In PRE−HD subjects, the baseline levels of pγ−H2AX correlated robustly with the progression of the HD phenotype measured after three years. Interpretation: PBMC from PRE−HD subjects show progressive DDS in the absence of clinical signs. The basal levels of DNA damage are predictive factors of disease progression over time. The availability of an easily accessible and detectable biomarker in PRE−HD, negligible in HC, and potentially reversible, provides a novel tool to identify patient−specific drugs that prevent or slow down the appearance of HD phenotype in carriers. Funding Statement: LIRH Foundation received funding from the Cure Huntington’s Disease Initiative Foundation for collecting patient data and samples in the REGISTRY and ENROLL-HD platforms and from the Italian Government (funds from “5x1000” of taxes). The Italian Ministry of Health supports the research on Huntington’s disease to IRCCS Casa Sollievo della Sofferenza (CSS, funds from Ricerca Corrente [RC1601MD13] and from Ricerca Finalizzata [RF2016-02364123] to FS and SM). GR received funding from the University of Rome La Sapienza (Ricerca di Ateneo RM116154EC242C10). GR and SR received funding from the Cure Huntington’s Disease Initiative Foundation for collecting patient data and samples in the REGISTRY and ENROLLHD platforms. Declaration of Interests: All the authors declare no competing interests. Ethics Approval Statement: All human studies were carried in compliance with the Declaration of Helsinki, approved by local ethics committees and all participants have given written informed consent.

Evaluation of nutritional status in chronic kidney disease patients undergoing hemodialysis

Background: Kidneys perform the important function of excreting nitrogenous waste products and regulating the volume and composition of body fluids. Malnutrition is common phenomenon in maintenance dialysis patients and risk factor for poor quality of life and increased morbidity and mortality. An association of low albumin levels with increased mortality and morbidity in hemodialysis patients has been hypothesized. Present study aims to go through nutritional status of CKD patients in our institute and their relation to disease or dialysis outcome.Methods: Study is conducted on 100 CKD patients on haemodialysis admitted in various medical wards of the Mc Gann hospital attached to Shimoga institute of medical sciences, Shimoga, Karnataka, India. From August 1st, 2016 to April 30th, 2017 detailed history was taken in all the patients and a thorough physical examination was done. Dietary history was taken and blood is collected for analysis of Hb, blood urea, SR electrolyte, serum calcium, phosphorus, serum albumin, cholesterol, creatinine and CRP. BMI is calculated in all patients.Results: There were 60 males and 40 females. Average age is 46±3.6 years. Most of these patients belong to the age group of 41-50 years (37%). According to WHO BMI classification 55% had BMI between 18.5 to 24.9. 17% less than 18.5. 13% more than 30BMI. Blood urea, serum creatinine was elevated as expected. Mean Hb is 8.21±2.57 gm/dl. Serum albumin is lower mean being 2.66±1.86 gm/dl. CRP elevated 16.5±2.36. low calcium is also seen.Conclusions: The malnutrition in CKD is associated with increased morbidity and mortality rates. Despite the better understanding of the pathophysiologic mechanisms of uremic malnutrition and the improvements made in nutritional support, the nutritional condition of CKD and ESRD patients remains a significant cause for concern. Multimodal therapeutic strategies should be considered. Present study showed elevated prevalence of malnutrition in HD subjects. The nutritional status in patients on HD needs more attention. The role of nutrition in the management of CKD is important and needs to be further researched and newer guidelines are need of the hour.

Advanced glycation end-products (AGEs) accumulation in skin: relations with chronic kidney disease-mineral and bone disorder.

Chronic kidney disease (CKD) is associated with high morbidity and mortality rates, main causes related with cardiovascular disease (CVD) and bone mineral disorder (CKD-BMD). Uremic toxins, as advanced glycation end products (AGEs), are non-traditional cardiovascular risk factor and play a role on development of CKD-BMD in CKD. The measurement of skin autofluorescence (sAF) is a noninvasive method to assess the level of AGEs in tissue, validated in CKD patients. The aim of this study is analyze AGEs measured by sAF levels (AGEs-sAF) and its relations with CVD and BMD parameters in HD patients. Twenty prevalent HD patients (HD group) and healthy subjects (Control group, n = 24), performed biochemical tests and measurements of anthropometric parameters and AGEs-sAF. In addition, HD group performed measurement of intact parathormone (iPTH), transthoracic echocardiogram and radiographies of pelvis and hands for vascular calcification score. AGEs-sAF levels are elevated both in HD and control subjects ranged according to the age, although higher at HD than control group. Single high-flux HD session does not affect AGEs-sAF levels. AGEs-sAF levels were not related to ventricular mass, interventricular septum or vascular calcification in HD group. AGEs-sAF levels were negatively associated with serum iPTH levels. Our study detected a negative correlation of AGEs-sAF with serum iPTH, suggesting a role of AGEs on the pathophysiology of bone disease in HD prevalent patients. The nature of this relation and the clinical application of this non-invasive methodology for evaluation AGEs deposition must be confirmed and clarified in future studies.

Increased social anhedonia and reduced helping behaviour in young people with high depressive symptomatology

BackgroundSocial anhedonia, the decreased enjoyment of pleasant social experiences, is associated with depression. However, whether social anhedonia in depression affects prosocial behaviours is unclear. The current study aimed to examine how high levels of depressive symptomatology in young people affect responses to usually rewarding social situations, including helping behaviour. MethodsWe recruited 46 females, 16 scoring high on the Beck Depression Inventory (BDI scores>20, Mage=19; HD) and 30 scoring low (BDI<10, Mage=20; LD). In a social emotion task (SET), participants were presented with social scenarios and asked to rate their expected emotional responses. Subsequently, participants’ helping behaviour was measured by dropping a pile of papers near them and recording their responses. Lastly, participants completed the SET again. ResultsThe SET at time 1 revealed that HD individuals reported significantly stronger negative (p<.001) and weaker positive (p<.05) emotional responses to social situations than LD subjects. Additionally, all participants showed a significant increase in positive responses (p<.05) on the SET between time 1 and time 2. Moreover, HD subjects were less likely to engage in actual helping behaviour than LD participants. LimitationsLimitations of the study are that only females were tested and that no psychiatric screening interview was conducted. ConclusionsOur results indicate that young females with high levels of depression symptoms expect to respond less positively to social situations and engage less in helping behaviour compared to those with low depressive symptomatology. Social anhedonia in depression may thus contribute to decreased engagement in rewarding social situations. This, in turn, may lead to social withdrawal and might maintain depression symptoms though a lack of exposure to positive social feedback.

248. Results of a Phase 1 and 2a Trial on rAAV. sFlt-1 in Treatment of Wet Age-Related Macular Degeneration

Purpose: To assess safety following subretinal rAAV.sFlt-1 injection at one year. Secondary endpoints were assessed for evidence of biologic activity. Methods: Under the protocol, Phase 1 followed a dose escalation design where eligible subjects received subretinal injection of low dose (LD, N=3, 10E10 vg) and high dose (HD, N=3, 10E11 vg) rAAV.sFlt-1, or control regimen (N=2). In Phase 2a eligible subjects were randomized to receive HD (N=21) rAAV. sFlt-1 or control regimen (N=11). All 40 subjects were assessed using ophthalmic exam and laboratory testing, and received intravitreal ranibizumab retreatment according to protocol-driven criteria for worsening wet Age-related Macular Degeneration (AMD). Results: During the 1-year follow-up to the primary endpoint, no serious adverse events related to rAAV. sFlt-1 were observed. However, transient adverse events such as subretinal hemorrhage, inflammation, and increased intraocular pressure were reported. One LD subject and 11 HD subjects were phakic at baseline; following subretinal injection with vitrectomy all of these subjects experienced cataract progression which was operated by month 10. In the control group, 13 subjects received a mean 3.5 (median 4, range 0-5) ranibizumab retreatments, and had a change in mean Best Corrected Visual Acuity (BCVA) of -8.4 Early Treatment Diabetic Retinopathy Study (ETDRS) letters and a decrease in mean retinal Center Point Thickness (CPT) from 450 µm at baseline (BL) to 355 µm. Subjects in the LD group received a mean 0.33 (median 0, range 0-1) ranibizumab retreatments, and had a mean vision gain of 8.7 ETDRS letters and decreased mean CPT from 449 µm to 315 µm. Retreatment outcomes in the HD group suggested a bimodal distribution: 14 subjects received ≤ 2 ranibizumab retreatments (HD. 1 subgroup) with a mean vision gain of 6.6 ETDRS letters and a mean CPT decrease from 406 µm to 360 µm, and 10 HD subjects received ≥ 3 ranibizumab retreatments (HD. 2 subgroup) with a mean vision change of -2.7 ETDRS letters and increase mean CPT from 407 µm to 456 µm. At BL, serum neutralizing antibodies to AAV were detected in 5/13 (38%) controls, 1/3 LD group (33%), 11/14 HD. 1 subgroup (77%) and 2/10 (20%) HD. 2 subgroup. Five HD group subjects who were seronegative at BL seroconverted after rAAV.sFlt-1 therapy. Conclusions: Subretinal rAAVsFlt-1 was well-tolerated with a favorable safety profile in subjects with wet AMD. Encouraging signs of a response with vision gain and fewer ranibizumab retreatment were observed in the majority of the subjects. Serum neutralizing antibodies to AAV prior to treatment did not adversely affect clinical outcomes.

Role of Age and Uric Acid Levels on Dialysis Efficacy among End Stage Renal Disease Patients in Saudi Arabia

Background: Patients with end stage kidney dysfunction is increasing dramatically in Saudi Arabia; especially in the age group of more than 65 years, which constitutes 21% of all chronic kidney disease (CKD) patients. In recent years, more attention is paid to uric acid (UA) as a risk factor in kidney impairment patients. Objectives: To assess the relationship between serum uric acid levels and hemodialysis efficiency among end stage renal disease patients in Hail, Saudi Arabia. Methods: A total of 255 hemodialysis patients (102 males and 153 females) were enrolled in this retrospective study. The range was 25 to 83 years with median age of 51 years. Blood samples drawn from patients before and after the hemodialysis session were analyzed for urea, creatinine, and uric acid. Results: The proportion of female patinets with CKD was significantly higher (60%,(p<0.05), than the males in the patient group examined. Among hemodialysis patients, the incidence of hypertension was 86 % (p<0.05). There was a negative association between UA and hemodialysis efficiency in patients aged less than 50 years. In addition, a significant correlation was observed between levels of UA and urea (r=0.579 p <0.001) and creatinine (r=0.736 p <0.001). Conclusion: Taken together, the results of this study indicate that the hemodialysis efficiency in HD subjects, particularly in the < 50 years of age may be improved by decreasing the serum uric levels.

Clinical and Biological Determinants of Sclerostin Plasma Concentration in Hemodialysis Patients

Background: Sclerostin is a potent inhibitor of bone formation, but the meaning of its serum levels remains undetermined. We evaluated the association between sclerostin levels and clinical or biological data in hemodialyzed patients (HD), notably parathormone (PTH), biomarkers of bone turnover, vascular calcifications and mortality after 2 years. Methods: 164 HD patients were included in this observational study. The calcification score was assessed with the Kauppila method. Patients were followed for 2 years. Results: Median sclerostin levels were significantly (p < 0.0001) higher in HD versus healthy subjects (n = 94) (1,375 vs. 565 pg/ml, respectively). In univariate analysis a significant association (p < 0.05) was found between sclerostin and age, height, dialysis vintage, albumin, troponin, homocysteine, PTH, C-terminal telopeptide of collagen type I, bone-specific alkaline phosphatase and osteoprotegerin, but not with the calcification score. In a multivariate model, the association remained with age, height, dialysis vintage, troponin, homocysteine, phosphate, PTH, but also with vascular calcifications. Association was positive for all variables, except PTH and vascular calcifications. The baseline sclerostin concentration was not different in survivors and non-survivors. Conclusions: We confirm a higher concentration of sclerostin in HD patients, a positive association with age and a negative association with PTH. A positive association with phosphate, homocysteine and troponin calls for additional research. The clinical interest of sclerostin to assess vascular calcifications in HD is limited and no association was found between sclerostin and mortality.

Deep white matter in Huntington's disease.

White matter (WM) abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using Magnetic Resonance Imaging (MRI). In the present study, we examined the microstructure of the long-range large deep WM tracts by applying two different MRI approaches: Diffusion Tensor Imaging (DTI) -based tractography, and T2*weighted (iron sensitive) imaging. We collected Pre-HD subjects (n = 25), HD patients (n = 25) and healthy control subjects (n = 50). Results revealed increased axial (AD) and radial diffusivity (RD) and iron levels in Pre-HD subjects compared to controls. Fractional anisotropy decreased between the Pre-HD and HD phase and AD/RD increased and although impairment was pervasive in HD, degeneration occurred in a pattern in Pre-HD. Furthermore, iron levels dropped for HD patients. As increased iron levels are associated with remyelination, the data suggests that Pre-HD subjects attempt to repair damaged deep WM years before symptoms occur but this process fails with disease progression.