Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease)

OBJECTIVE: To critically re-evaluate cases diagnosed as adult neuronal ceroid lipofuscinosis (ANCL) in order to aid clinicopathologic diagnosis as a route to further gene discovery. METHODS: Through establishment of an international consortium we pooled 47 unsolved cases regarded by referring centers as ANCL. Clinical and neuropathologic experts within the Consortium established diagnostic criteria for ANCL based on the literature to assess each case. A panel of 3 neuropathologists independently reviewed source pathologic data. Cases were given a final clinicopathologic classification of definite ANCL, probable ANCL, possible ANCL, or not ANCL. RESULTS: Of the 47 cases, only 16 fulfilled the Consortium's criteria of ANCL (5 definite, 2 probable, 9 possible). Definitive alternate diagnoses were made in 10, including Huntington disease, early-onset Alzheimer disease, Niemann-Pick disease, neuroserpinopathy, prion disease, and neurodegeneration with brain iron accumulation. Six cases had features suggesting an alternate diagnosis, but no specific condition was identified; in 15, the data were inadequate for classification. Misinterpretation of normal lipofuscin as abnormal storage material was the commonest cause of misdiagnosis. CONCLUSIONS: Diagnosis of ANCL remains challenging; expert pathologic analysis and recent molecular genetic advances revealed misdiagnoses in >1/3 of cases. We now have a refined group of cases that will facilitate identification of new causative genes

Assessing the role of rare genetic variants in drug-resistant, non-lesional focal epilepsy.

OBJECTIVE: Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug-resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. METHODS: We performed exome sequencing of 1,128 individuals with non-familial non-acquired focal epilepsy (NAFE) (762 non-responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non-responders, 185 responders). We performed gene-based and gene-set-based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. RESULTS: We found no gene or gene set that reached genome-wide significance. Yet, we identified several prospective candidate genes - among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non-familial NAFE and in association with drug-resistant NAFE. INTERPRETATION: Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non-familial NAFE and imply their involvement in drug-resistant epilepsy. Future large-scale genetic research studies are needed to substantiate these findings

Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases

Researching Complex Interventions in Health: The State of the Art : Exeter, UK. 14-15 October 2015.

Erratum to this paper available at http://hdl.handle.net/10871/23087

Modelling overdispersion with integer-valued moving average processes

A new first-order integer-valued moving average, INMA(1), model based on the negative binomial thinning operation defined by Risti´c et al. [21] is proposed and characterized. It is shown that this model has negative binomial (NB) marginal distribution when the innovations follow a NB distribution and therefore it can be used in situations where the data present overdispersion. Additionally, this model is extended to the bivariate context. The Generalized Method of Moments (GMM) is used to estimate the unknown parameters of the proposed models and the results of a simulation study that intends to investigate the performance of the method show that, in general, the estimates are consistent and symmetric. Finally, the proposed model is fitted to a real dataset and the quality of the adjustment is evaluated.publishe

Metabolism and pharmacokinetics of a potent N -acylindole antagonist of the OXE receptor for the eosinophil chemoattractant 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE) in rats and monkeys

We previously identified the indole 264 as a potent in vitro antagonist of the human OXE receptor that mediates the actions of the powerful eosinophil chemoattractant 5-oxo-ETE. No antagonists of this receptor are currently commercially available or are being tested in clinical studies. The lack of a rodent ortholog of the OXE receptor has hampered progress in this area because of the unavailability of commonly used mouse or rat animal models. In the present study, we examined the feasibility of using the cynomolgus monkey as an animal model to investigate the efficacy of orally administered 264 in future in vivo studies. We first confirmed that 264 is active in monkeys by showing that it is a potent inhibitor of 5-oxo-ETE-induced actin polymerization and chemotaxis in granulocytes. The major microsomal metabolites of 264 were identified by cochromatography with authentic chemically synthesized standards and LC-MS/MS as its ω2-hydroxy and ω2-oxo derivatives, formed by ω2-oxidation of its hexyl side chain. Small amounts of ω1-oxidation products were also identified. None of these metabolites have substantial antagonist potency. High levels of 264 appeared rapidly in the blood following oral administration to both rats and monkeys, and declined to low levels by 24 h. As with microsomes, its major plasma metabolites in monkeys were ω2-oxidation products. We conclude that the monkey is a suitable animal model to investigate potential therapeutic effects of 264. This, or a related compound with diminished susceptibility to ω2-oxidation, could be a useful therapeutic agent in eosinophilic disorders such as asthma

Testing association of rare genetic variants with resistance to three common antiseizure medications

OBJECTIVE: Drug resistance is a major concern in the treatment of individuals with epilepsy. No genetic markers for resistance to individual antiseizure medication (ASM) have yet been identified. We aimed to identify the role of rare genetic variants in drug resistance for three common ASMs: levetiracetam (LEV), lamotrigine (LTG), and valproic acid (VPA). METHODS: A cohort of 1622 individuals of European descent with epilepsy was deeply phenotyped and underwent whole exome sequencing (WES), comprising 575 taking LEV, 826 LTG, and 782 VPA. We performed gene- and gene set-based collapsing analyses comparing responders and nonresponders to the three drugs to determine the burden of different categories of rare genetic variants. RESULTS: We observed a marginally significant enrichment of rare missense, truncating, and splice region variants in individuals who were resistant to VPA compared to VPA responders for genes involved in VPA pharmacokinetics. We also found a borderline significant enrichment of truncating and splice region variants in the synaptic vesicle glycoprotein (SV2) gene family in nonresponders compared to responders to LEV. We did not see any significant enrichment using a gene-based approach. SIGNIFICANCE: In our pharmacogenetic study, we identified a slightly increased burden of damaging variants in gene groups related to drug kinetics or targeting in individuals presenting with drug resistance to VPA or LEV. Such variants could thus determine a genetic contribution to drug resistance

Presence of depression and anxiety before and after coronary artery bypass graft surgery and their relationship to age

<p>Abstract</p> <p>Background</p> <p>Scientific literature on depression and anxiety in patients with coronary heart disease (CHD) consistently reports data of elevated anxiety and depression scores indicating clinically relevant quantities of these psychopathological conditions. Depression is considered to be a risk factor for the development of CHD and deteriorates the outcome after cardiac rehabilitation efforts. The aim of our study was to evaluate the presence of clinically relevant anxiety and depression in patients before and after coronary artery bypass grafting (CABG). Additionally we evaluated their relationship to age because of the increasing number of elderly patients undergoing CABG surgery.</p> <p>Methods</p> <p>One hundred and forty-two consecutive patients who underwent CABG in our hospital were asked to fill in the "Hospital Anxiety and Depression Scale – German Version (HADS)" to measure depression and anxiety scores two days before and ten days after CABG surgery. Differences between these pre- and post-surgical scores were then calculated as means for changes, and the amount of elevated scores were appraised. In order to investigate the relationship between age and anxiety and depression, respectively, Spearman correlations between age and the difference scores were calculated. In addition, ANOVA procedures with the factor "age group" and McNemar tests were calculated. Therefore the sample was divided into four equally sized age groups.</p> <p>Results</p> <p>25.8% of the patients were clinically depressed before and 17.5% after surgery; 34.0% of the patients were clinically anxious before and 24.7% after surgery. This overall change is not significant. We found a significant negative correlation between age and the difference between the two time points for anxiety (Spearman rho = -.218; p = 0.03), but not for depression (Spearman rho = -.128; p = 0.21). ANOVA and McNemar-Tests revealed that anxiety scores and the number of patients high in anxiety declined statistically meaningful only in the youngest patient group. Such a relationship could not be found for depression.</p> <p>Conclusion</p> <p>Our data show a relationship between age and anxiety. Younger patients are more anxious before CABG surgery than older ones and show a decline in symptoms while elderly patients show hardly any change.</p

A Biopersistence Study following Exposure to Chrysotile Asbestos Alone or in Combination with Fine Particles

In designing a study to evaluate the inhalation biopersistence of a chrysotile asbestos that was used as a component of a joint-compound, a feasibility study was initiated to evaluate the short-term biopersistence of the chrysotile alone and of the chrysotile in combination witht the sanded reformulated joint-compound. Two groups of Wistar rats were exposed to either 7RF3 chrysotile (Group 2) or to 7RF3 chrysotile combined with aerosolized sanded joint-compound (Group 3). In addition, a control group was exposed to flltered-air. The chrysotile used in the Ready Mix joint compound is rapidly removed from the lung. The chrysotile alone exposure group had a clearance half-time of fibers L > 20 μm of 2.2 days; in the chrysotile plus sanded exposure group the clearance half-time of fibers L > 20 μm was 2.8 days. However, across all size ranges there was approximately an order of magnitude decrease in the mean number of fibers remaining in the lungs of Group 3 as compared to Group 2 despite similiar aerosol exposures. Histopathological examination showed that the chrysotile exposed lungs had the same appearance as the flltered-air controls. This study uniquely illustrates that additional concurrent exposure to an aerosol of the sanded joint-compound, with large numbers of fine-particles depositing in the lungs, accelerates the recruitment of macrophages, resulting in a tenfold decrease in the number of fibers remaining in the lung. The increased number of macrophages in the chrysotile/sanded joint exposure group was confirmed histologically, with this being the only exposure-related histological finding reported