Cognitive deficits after recovery from thrombotic thrombocytopenic purpura

BACKGROUND: Patients with apparent complete recovery from thrombotic thrombocytopenic purpura (TTP) often complain of problems with memory, concentration, and fatigue. STUDY DESIGN AND METHODS: Twenty-four patients who were enrolled in the Oklahoma TTP-HUS Registry for their initial episode of TTP, 1995-2006, and who had ADAMTS13 activity of less than 10 percent were evaluated for a broad range of cognitive functions 0.1 to 10.6 years (median, 4.0 years) after their most recent episode. At the time of their evaluation, they had normal physical and Mini-Mental State Examinations and no evidence of TTP. RESULTS: The patients, as a group, performed significantly worse on 4 of the 11 cognitive domains tested than standardized US data from neurologically normal individuals adjusted for age, sex, and education (p < 0.05). These four domains measured complex attention and concentration skills, information processing speed, rapid language generation, and rote memorization. Twenty-one (88%) patients performed below expectations on at least 1 of the 11 domains. No clear patterns were observed between cognitive test results and patients' characteristics or features of the preceding TTP, including age, occurrence of severe neurologic abnormalities, multiple episodes, and interval from an acute episode. CONCLUSION: Patients who have recovered from TTP may have persistent cognitive abnormalities. The abnormalities observed in these patients are characteristic of disorders associated with diffuse subcortical microvascular disease. Studies of larger patient groups will be required to confirm these preliminary observations and to determine patient characteristics that may contribute to persistent cognitive abnormalities.

Specific attentional impairments and complex visual hallucinations in eye disease

OBJECTIVE: To test the prediction by the Perception and Attention Deficit (PAD) model of complex visual hallucinations that cognitive impairment, specifically in visual attention, is a key risk factor for complex hallucinations in eye disease. METHODS: Two studies of elderly patients with acquired eye disease investigated the relationship between complex visual hallucinations (CVH) and impairments in general cognition and verbal attention (Study 1) and between CVH, selective visual attention and visual object perception (Study 2). The North East Visual Hallucinations Inventory was used to classify CVH. RESULTS: In Study 1, there was no relationship between CVH (n=10/39) and performance on cognitive screening or verbal attention tasks. In Study 2, participants with CVH (n=11/31) showed poorer performance on a modified Stroop task (p<0.05), a novel imagery-based attentional task (p<0.05) and picture (p<0.05) but not silhouette naming (p=0.13) tasks. Performance on these tasks correctly classified 83% of the participants as hallucinators or non-hallucinators. CONCLUSIONS: The results suggest that, consistent with the PAD model, complex visual hallucinations in people with acquired eye disease are associated with visual attention impairment.

Stereoselective synthesis and structure determination of a bicyclo[3.3.2]decapeptide

By analogy to the structural diversity of covalent bond networks between atoms within organic molecules, one can design topologically diverse peptides from mathematical graphs by assigning amino acids to graph nodes and peptide bonds to graph edges. The key is to use diamino acids or amino diacids as equivalents of trivalent graph nodes, which enables a variety of graph topologies beyond the standard linear and monocyclic graphs in natural peptides. Here the bicyclic decapeptide A1FGk2VFPE1AG2 (1b) was prepared and crystallized to assign its bridge stereochemistry. The bridge configuration appears as planned by the chirality of the branching amino acids. Bicyclization furthermore depends on the presence of matched chiralities in the branching amino acids. The stereoselective formation of the second bridge opens the way for the synthesis of a large family of bicyclic peptides as promising new scaffolds for drug design.

Natural course of pontocerebellar hypoplasia type 2A

INTRODUCTION Pontocerebellar hypoplasia Type 2 (PCH2) is a rare autosomal recessive condition, defined on MRI by a small cerebellum and ventral pons. Clinical features are severe developmental delay, microcephaly and dyskinesia.Ninety percent carry a p.A307S mutation in the TSEN54-gene. Our aim was to describe the natural course including neurological and developmental features and other aspects of care in a homogeneous group of PCH2 patients all carrying the p.A307S mutation. PATIENTS AND METHODS Patients were recruited via the German patients' organizations. Inclusion criteria were imaging findings of PCH2 and a p.A307S mutation. Data were collected using medical reports and patient questionnaires discussed in a standardized telephone interview. RESULTS Thirty-three patients were included. When considering survival until age 11 years, 53% of children had died Weight, length and head circumference, mostly in the normal range at birth, became abnormal, especially head circumference (-5.58 SD at age 5 yrs). Neurologic symptoms: Choreathetosis was present in 88% (62% with pyramidal signs), 12% had pure spasticity. Epileptic seizures were manifest in 82%, status epilepticus in 39%. Non-epileptic dystonic attacks occurred in 33%. General symptoms: feeding difficulties were recorded in 100%, sleep disorder in 96%, apneas in 67% and recurrent infections in 52%; gastroesophageal reflux disease was diagnosed in 73%, 67% got percutaneous endoscopic gastrostomy and 36% a Nissen-fundoplication. Neurodevelopmental data: All children made progress, but on a low level: such as fixing and following with the eyes was seen in 76%, attempting to grasp objects (76%), moderate head control (73%), social smile (70%), rolling from prone to supine (58%), and sitting without support (9%). Ten percent lost achieved abilities on follow-up. The presence of prenatal symptoms did not correlate with outcome. CONCLUSION Phenotype of this genetically homogeneous group of PCH2 children was severe with reduced survival, but compatible with some developmental progress. Our data support the hypothesis of an early onset degeneration which thereafter stabilizes.

Toward Cove-Edged Low Band Gap Graphene Nanoribbons

Graphene nanoribbons (GNRs), defined as nanometer-wide strips of graphene, have attracted increasing attention as promising candidates for next-generation semiconductors. Here, we demonstrate a bottom-up strategy toward novel low band gap GNRs (E-g = 1.70 eV) with a well-defined cove-type periphery both in solution and on a solid substrate surface with chrysene as the key monomer. Corresponding cyclized chrysene-based oligornerS consisting of the dimer and tetramer are obtained via an Ullmann Coupling followed by oxidative intramolecular cyclodehydrogenation in solution, and much higher GNR homologues via on-surface synthesis. These oligomers adopt nonplanar structures due to the isteric repulsion between the two C-H bonds at the inner cove position. Characterizations by single crystal X-ray analysis, UV-vis absorption spectroscopy, NMR spectroscopy, and scanning tunneling microscopy (STM) are described. The interpretation is assisted by density functional theory (DFT) calculations.

A Logarithmic Image Prior for Blind Deconvolution

Blind Deconvolution consists in the estimation of a sharp image and a blur kernel from an observed blurry image. Because the blur model admits several solutions it is necessary to devise an image prior that favors the true blur kernel and sharp image. Many successful image priors enforce the sparsity of the sharp image gradients. Ideally the L0 “norm” is the best choice for promoting sparsity, but because it is computationally intractable, some methods have used a logarithmic approximation. In this work we also study a logarithmic image prior. We show empirically how well the prior suits the blind deconvolution problem. Our analysis confirms experimentally the hypothesis that a prior should not necessarily model natural image statistics to correctly estimate the blur kernel. Furthermore, we show that a simple Maximum a Posteriori formulation is enough to achieve state of the art results. To minimize such formulation we devise two iterative minimization algorithms that cope with the non-convexity of the logarithmic prior: one obtained via the primal-dual approach and one via majorization-minimization.

Comparison of porcine and human coagulation by thrombelastometry

Although the pig is a standard model for the evaluation of various diseases in humans, including coagulopathy, it is not clear whether results in animals can be extrapolated to man.

Postmortem Imaging of sudden cardiac death

Postmortem imaging is increasingly used in forensic practice in cases of natural deaths related to cardiovascular diseases, which represent the most common causes of death in developed countries. While radiological examination is generally considered to be a good complement for conventional autopsy, it was thought to have limited application in cardiovascular pathology. At present, multidetector computed tomography (MDCT), CT angiography, and cardiac magnetic resonance imaging (MRI) are used in postmortem radiological investigation of cardiovascular pathologies. This review presents the actual state of postmortem imaging for cardiovascular pathologies in cases of sudden cardiac death (SCD), taking into consideration both the advantages and limitations. The radiological evaluation of ischemic heart disease (IHD), the most frequent cause of SCD in the General population of industrialized countries, includes the examination of the coronary arteries and myocardium. Postmortem CT angiography (PMCTA) is very useful for the detection of stenoses and occlusions of coronary arteries but less so for the identification of ischemic myocardium. MRI is the method of choice for the radiological investigation of the myocardium in clinical practice, but ist accessibility and application are still limited in postmortem practice. There are very few reports implicating postmortem radiology in the investigation of other causes of SCD, such as cardiomyopathies, coronary artery abnormalities, and valvular pathologies. Cardiomyopathies representing the most frequent cause of SCD in young athletes cannot be diagnosed by echocardiography, the most widely available technique in clinical practice for the functional evaluation of the heart and the detection of cardiomyopathies. PMCTA and MRI have the potential to detect advanced stages of diseases when morphological substrate is present, but these methods have yet to be sufficiently validated for postmortem cases. Genetically determined channelopathies cannot be detected radiologically. This review underlines the need to establish the role of postmortem radiology in the diagnosis of SCD.

Oxidative Damage on RNA Nucleobases

Oxidatively damaged RNA has recently gathered more attention and has been closely related to different neurodegenerative diseases. The principles of oxidative stress and its influence on nucleic acids are reported. In contrast to DNA oxidative lesions of RNA have been scarcely described in the literature so far. These known stable RNA base modifications which arise under oxidative stress are reviewed here with regard to their biophysical properties and their potential mutagenicity. Furthermore the possible mechanisms of how cells deal with oxidized RNA are discussed. Posttranscriptional RNA modifications and the oxidation of RNA as an early event in several neurodegenerative diseases are not in the scope of this review.

Orphan drugs and paediatric medicinal products

While the safety and availability of medicinal products for the majority of adult patients has steadily improved in recent decades, for children and people suffering from rare diseases (orphan diseases) there is a lack of approved medicinal products for these patient populations. Since the research and development of medicinal products is associated with high costs, the costs for paediatric medicinal products and medicines for rare diseases (orphan drugs) may barely be covered under normal market conditions due to the small patient populations. In order to prevent the continued exclusion of children and persons suffering from rare diseases from medical progress and to eliminate the deficits in the research and development of medicinal products for these patient groups, the European Union created, along the lines of the U.S. model, a system of incentives and constraints. Since 2000, under Regulation (EC) No. 141/2000 (Orphan Drug Regulation) there has been an incentive system to encourage the research and development of orphan drugs. With the goal of improving the health of children in Europe, Regulation (EC) No. 1901/2006 (Paediatric Regulation) combines economic incentives with the requirement to conduct paediatric studies. This article explains and comments on the specific regulatory framework for orphan drugs and paediatric medicinal products in the European Union.

Lack of cathelicidin processing in Papillon-Lefèvre syndrome patients reveals essential role of LL-37 in periodontal homeostasis.

BACKGROUND Loss-of-function point mutations in the cathepsin C gene are the underlying genetic event in patients with Papillon-Lefèvre syndrome (PLS). PLS neutrophils lack serine protease activity essential for cathelicidin LL-37 generation from hCAP18 precursor. AIM We hypothesized that a local deficiency of LL-37 in the infected periodontium is mainly responsible for one of the clinical hallmark of PLS: severe periodontitis already in early childhood. METHODS To confirm this effect, we compared the level of neutrophil-derived enzymes and antimicrobial peptides in gingival crevicular fluid (GCF) and saliva from PLS, aggressive and chronic periodontitis patients. RESULTS Although neutrophil numbers in GCF were present at the same level in all periodontitis groups, LL-37 was totally absent in GCF from PLS patients despite the large amounts of its precursor, hCAP18. The absence of LL-37 in PLS patients coincided with the deficiency of both cathepsin C and protease 3 activities. The presence of other neutrophilic anti-microbial peptides in GCF from PLS patients, such as alpha-defensins, were comparable to that found in chronic periodontitis. In PLS microbial analysis revealed a high prevalence of Aggregatibacter actinomycetemcomitans infection. Most strains were susceptible to killing by LL-37. CONCLUSIONS Collectively, these findings imply that the lack of protease 3 activation by dysfunctional cathepsin C in PLS patients leads to the deficit of antimicrobial and immunomodulatory functions of LL-37 in the gingiva, allowing for infection with A. actinomycetemcomitans and the development of severe periodontal disease.

Cross-sectional study of 168 patients with hepatorenal tyrosinaemia and implications for clinical practice

BackgroundHepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data.MethodsVia questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications.ResultsEarly treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 ¿M) and NTBC-levels in the therapeutic range (20¿40 ¿M). Side effects of NTBC are mild and often transient.Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood).ConclusionBased on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.

Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes.

One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. We performed various experiments, e.g. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions.

The European Narcolepsy Network (EU-NN) database.

Narcolepsy with cataplexy is a rare disease with an estimated prevalence of 0.02% in European populations. Narcolepsy shares many features of rare disorders, in particular the lack of awareness of the disease with serious consequences for healthcare supply. Similar to other rare diseases, only a few European countries have registered narcolepsy cases in databases of the International Classification of Diseases or in registries of the European health authorities. A promising approach to identify disease-specific adverse health effects and needs in healthcare delivery in the field of rare diseases is to establish a distributed expert network. A first and important step is to create a database that allows collection, storage and dissemination of data on narcolepsy in a comprehensive and systematic way. Here, the first prospective web-based European narcolepsy database hosted by the European Narcolepsy Network is introduced. The database structure, standardization of data acquisition and quality control procedures are described, and an overview provided of the first 1079 patients from 18 European specialized centres. Due to its standardization this continuously increasing data pool is most promising to provide a better insight into many unsolved aspects of narcolepsy and related disorders, including clear phenotype characterization of subtypes of narcolepsy, more precise epidemiological data and knowledge on the natural history of narcolepsy, expectations about treatment effects, identification of post-marketing medication side-effects, and will contribute to improve clinical trial designs and provide facilities to further develop phase III trials.