Model Systems to Define Remyelination Therapies

Demyelinating diseases of the central nervous system (CNS), such as multiple sclerosis (MS), are characterized by multiple focal demyelinating lesions, resulting in various functional deficits. The pathology of MS is defined by local loss of myelin sheaths in the brain and spinal cord associated with infiltration of peripheral immune cells. Classically, MS starts with a series of relapses and remissions, followed several years later by a more progressive form of the disease and a steady functional decline. Although the mechanism of disease initiation is poorly understood, disease progression is associated with immune system activation toward CNS antigens including myelin proteins. Animal models of MS have been critical in the development of MS therapies, with experimental allergic encephalitis (EAE) being the most common. This model has been instrumental in defining the role of T cells in disease progression and in the development of targeted therapies. Understanding the biology of myelin repair has, however, largely come from other model systems including local targeted demyelination in vivo, slice preparations, and in vitro. This has led to the identification of a diverse array of potential new targets to modulate disease progression. Development of these new avenues is the target of intensive ongoing research

Karyotype analysis of Solanum torvum Sw. - an ethnobotanical Solanaceous species of Tripura, North East India

Solanum torvum Sw. is a wild Solanaceous plant species, commonly used by the indigenous people of Tripura. Cytological study of the species was carried out to determine the somatic chromosome number and to construct the karyotype formula. The detailed karyomorphological analysis revealed 2n=24 somatic chromosomes having haploid number n=12. The size of chromosomal complement was found to range from 2.14±0.21 to 4.02±0.26 µm with a pair of chromosomes bearing secondary constrictions. Strictly median primary constriction was recorded in two pairs of chromosomes. In general, karyotype formula was found to be A2B4C18. The detailed karyotype analysis revealed that chromosomes are generally small in size and fall under the Stebbins category of “2A” indicating symmetrical nature of the karyotype. The present study could be utilised in understanding the cytogenetic nature of the species and for future crop improvement programme

The role of adverse childhood experiences and mental health care use in psychological dysfunction of male multi-problem young adults

Adverse childhood experiences (ACEs) are associated with severe problems later in life. This study examines how eleven types of ACEs and mental health care use history are related to current psychological dysfunction among multi-problem young adults. A sample of 643 multi-problem young adult men (age 18-27) gave informed consent for us to collect retrospective regional psychiatric case register data and filled out questionnaires. ACEs were highly prevalent (mean 3.6, SD 2.0). Logistic regression analysis showed that compared with participants who experienced other ACEs, participants who experienced psychological problems in their family and grew up in a single-parent family were more likely to have used mental health care, and physically abused participants were less likely to have used mental health care. Linear regression analyses showed a dose-response relationship between ACEs and internalizing and externalizing problems. Linear regression analyses on the single ACE items showed that emotional abuse and emotional neglect were positively related to internalizing problems. Emotional and physical abuse and police contact of family members were positively related to externalizing problems. While multi-problem young adults experienced many ACEs, only a few ACEs were related to mental health care use in childhood and adolescence. Long-term negative effects of ACEs on psychological functioning were demonstrated; specifically, emotional abuse and emotional neglect showed detrimental consequences. Since emotional abuse and emotional neglect are not easily identified and often chronic, child health professionals should be sensitive to such problems

Criminal History and Adverse Childhood Experiences in Relation to Recidivism and Social Functioning in Multi-problem Young Adults

This study examines the relationship between criminal history and adverse childhood experiences (ACEs) and how they collectively predict (a) recidivism and (b) positive social functioning among multi-problem young adults. Criminal records and self-report data regarding ACEs and adult education/employment and quality of life (QoL) were collected for 692 multiproblem young adults (18–27 years). Results indicated that an extensive criminal history was related to non-violent and violent recidivism and lack of involvement in education/employment in young adulthood. On the contrary, a higher number of ACEs was related to lower QoL later in life, while this was not associated with recidivism or education/employment. These findings highlight again that past criminal behavior is a strong predictor of future criminality, particularly within this group of young adults with multiple problems. Furthermore, experiencing negative events in childhood shows to have long-term negative effects on QoL even for these individuals who already experience multiple life problems. Implications are discussed

Genetic analysis of variation in human meiotic recombination

The number of recombination events per meiosis varies extensively among individuals. This recombination phenotype differs between female and male, and also among individuals of each gender. In this study, we used high-density SNP genotypes of over 2,300 individuals and their offspring in two datasets to characterize recombination landscape and to map the genetic variants that contribute to variation in recombination phenotypes. We found six genetic loci that are associated with recombination phenotypes. Two of these (RNF212 and an inversion on chromosome 17q21.31) were previously reported in the Icelandic population, and this is the first replication in any other population. Of the four newly identified loci (KIAA1462, PDZK1, UGCG, NUB1), results from expression studies provide support for their roles in meiosis. Each of the variants that we identified explains only a small fraction of the individual variation in recombination. Notably, we found different sequence variants associated with female and male recombination phenotypes, suggesting that they are regulated by different genes. Characterization of genetic variants that influence natural variation in meiotic recombination will lead to a better understanding of normal meiotic events as well as of non-disjunction, the primary cause of pregnancy loss. © 2009 Chowdhury et al

Detection of autoantibodies against reactive oxygen species modified glutamic acid decarboxylase-65 in type 1 diabetes associated complications

<p>Abstract</p> <p>Background</p> <p>Autoantibodies against glutamate decarboxylase-65 (GAD₆₅Abs) are thought to be a major immunological tool involved in pathogenic autoimmunity development in various diseases. GAD₆₅Abs are a sensitive and specific marker for type 1 diabetes (T1D). These autoantibodies can also be found in 6-10% of patients classified with type 2 diabetes (T2D), as well as in 1-2% of the healthy population. The latter individuals are at low risk of developing T1D because the prevalence rate of GAD₆₅Abs is only about 0.3%. It has, therefore, been suggested that the antibody binding to GAD₆₅in these three different GAD₆₅Ab-positive phenotypes differ with respect to epitope specificity. The specificity of reactive oxygen species modified GAD₆₅(ROS-GAD₆₅) is already well established in the T1D. However, its association in secondary complications of T1D has not yet been ascertained. Hence this study focuses on identification of autoantibodies against ROS-GAD₆₅(ROS-GAD₆₅Abs) and quantitative assays in T1D associated complications.</p> <p>Results</p> <p>From the cohort of samples, serum autoantibodies from T1D retinopathic and nephropathic patients showed high recognition of ROS-GAD₆₅as compared to native GAD₆₅(N-GAD₆₅). Uncomplicated T1D subjects also exhibited reactivity towards ROS-GAD₆₅. However, this was found to be less as compared to the binding recorded from complicated subjects. These results were further proven by competitive ELISA estimations. The apparent association constants (AAC) indicate greater affinity of IgG from retinopathic T1D patients (1.90 × 10^-6M) followed by nephropathic (1.81 × 10^-6M) and uncomplicated (3.11 × 10^-7M) T1D patients for ROS-GAD₆₅compared to N-GAD₆₅.</p> <p>Conclusion</p> <p>Increased oxidative stress and blood glucose levels with extended duration of disease in complicated T1D could be responsible for the gradual formation and/or exposing cryptic epitopes on GAD₆₅that induce increased production of ROS-GAD₆₅Abs. Hence regulation of ROS-GAD₆₅Abs could offer novel tools for analysing and possibly treating T1D complications.</p

Association of Impulsivity and Polymorphic MicroRNA-641 Target Sites in the SNAP-25 Gene.

Impulsivity is a personality trait of high impact and is connected with several types of maladaptive behavior and psychiatric diseases, such as attention deficit hyperactivity disorder, alcohol and drug abuse, as well as pathological gambling and mood disorders. Polymorphic variants of the SNAP-25 gene emerged as putative genetic components of impulsivity, as SNAP-25 protein plays an important role in the central nervous system, and its SNPs are associated with several psychiatric disorders. In this study we aimed to investigate if polymorphisms in the regulatory regions of the SNAP-25 gene are in association with normal variability of impulsivity. Genotypes and haplotypes of two polymorphisms in the promoter (rs6077690 and rs6039769) and two SNPs in the 3' UTR (rs3746544 and rs1051312) of the SNAP-25 gene were determined in a healthy Hungarian population (N = 901) using PCR-RFLP or real-time PCR in combination with sequence specific probes. Significant association was found between the T-T 3' UTR haplotype and impulsivity, whereas no association could be detected with genotypes or haplotypes of the promoter loci. According to sequence alignment, the polymorphisms in the 3' UTR of the gene alter the binding site of microRNA-641, which was analyzed by luciferase reporter system. It was observed that haplotypes altering one or two nucleotides in the binding site of the seed region of microRNA-641 significantly increased the amount of generated protein in vitro. These findings support the role of polymorphic SNAP-25 variants both at psychogenetic and molecular biological levels

Upregulation of CENP-H in tongue cancer correlates with poor prognosis and progression

<p>Abstract</p> <p>Background</p> <p>Centromere protein H (CENP-H) is one of the fundamental components of the human active kinetochore. Recently, CENP-H was identified to be associated with tumorigenesis. This study was aimed to investigate the clinicopathologic significance of CENP-H in tongue cancer.</p> <p>Methods</p> <p>RT-PCR, real time RT-PCR and Western blot were used to examine the expression of CENP-H in tongue cancer cell lines and biopsies. CENP-H protein level in paraffin-embedded tongue cancer tissues were tested by immunohistochemical staining and undergone statistical analysis. CENP-H-knockdown stable cell line was established by infecting cells with a retroviral vector pSuper-retro-CENP-H-siRNA. The biological function of CENP-H was tested by MTT assay, colony formation assay, and Bromodeoxyuridine (BrdU) incorporation assay.</p> <p>Results</p> <p>CENP-H expression was higher in tongue cancer cell lines and cancer tissues (T) than that in normal cell and adjacent noncancerous tongue tissues (N), respectively. It was overexpressed in 55.95% (94/168) of the paraffin-embedded tongue cancer tissues, and there was a strong correlation between CENP-H expression and clinical stage, as well as T classification. CENP-H can predict the prognosis of tongue cancer patients especially those in early stage. Depletion of CENP-H can inhibit the proliferation of tongue cancer cells (Tca8113) and downregulate the expression of Survivin.</p> <p>Conclusion</p> <p>These findings suggested that CENP-H involves in the development and progression of tongue cancer. CENP-H might be a valuable prognostic indicator for tongue cancer patients within early stage.</p

Genomic Profiling of Advanced-Stage Oral Cancers Reveals Chromosome 11q Alterations as Markers of Poor Clinical Outcome

Identifying oral cancer lesions associated with high risk of relapse and predicting clinical outcome remain challenging questions in clinical practice. Genomic alterations may add prognostic information and indicate biological aggressiveness thereby emphasizing the need for genome-wide profiling of oral cancers. High-resolution array comparative genomic hybridization was performed to delineate the genomic alterations in clinically annotated primary gingivo-buccal complex and tongue cancers (n = 60). The specific genomic alterations so identified were evaluated for their potential clinical relevance. Copy-number changes were observed on chromosomal arms with most frequent gains on 3q (60%), 5p (50%), 7p (50%), 8q (73%), 11q13 (47%), 14q11.2 (47%), and 19p13.3 (58%) and losses on 3p14.2 (55%) and 8p (83%). Univariate statistical analysis with correction for multiple testing revealed chromosomal gain of region 11q22.1–q22.2 and losses of 17p13.3 and 11q23–q25 to be associated with loco-regional recurrence (P = 0.004, P = 0.003, and P = 0.0003) and shorter survival (P = 0.009, P = 0.003, and P 0.0001) respectively. The gain of 11q22 and loss of 11q23-q25 were validated by interphase fluorescent in situ hybridization (I-FISH). This study identifies a tractable number of genomic alterations with few underlying genes that may potentially be utilized as biological markers for prognosis and treatment decisions in oral cancers

Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome

Purpose Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. Methods We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Results Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Conclusion Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome