Phosphodiesterase 4D Gene and Risk of Noncardiogenic Ischemic Stroke in a Korean Population

Recently published studies from different populations provide apparently conflicting evidence on the association between the phosphodiesterase 4D (PDE4D) gene and ischemic stroke. The relationship between a representative PDE4D genotype and ischemic stroke was explored in a case-control study of 205 consecutive Korean patients with noncardiogenic ischemic stroke and 103 healthy controls who were neurologically and radiologically proven to be stroke-free. We selected and genotyped a PDE4D single nucleotide polymorphism (SNP 41, rs152312) as a candidate marker for susceptibility to ischemic stroke because SNP 41 has shown the most significant association with stroke in both a meta-analysis and the original Icelandic study of the PDE4D gene. No significant difference was observed between the cases and controls in the distribution of the PDE4D SNP 41 genotypes. The results from the adjusted conditional logistic regression analysis (adjusted for age, hypertension, diabetes and smoking status) showed no significant association between PDE4D SNP 41 genotypes and an increased risk of noncardiogenic ischemic stroke. The PDE4D gene is not a major risk factor for noncardiogenic ischemic stroke in a Korean population, which supports the recent evidence suggesting that the causative genetic variants of ischemic stroke may differ across populations

Spectrum of Perforin Gene Mutations in Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disease of early childhood characterized by nonmalignant accumulation and multivisceral infiltration of activated T lymphocytes and histiocytes (macrophages). Cytotoxic T and natural killer (NK) cell activity is markedly reduced or absent in these patients, and mutations in a lytic granule constituent, perforin, were recently identified in a number of FHL individuals. Here, we report a comprehensive survey of 34 additional patients with FHL for mutations in the coding region of the perforin gene and the relative frequency of perforin mutations in FHL. Perforin mutations were identified in 7 of the 34 families investigated. Six children were homozygous for the mutations, and one patient was a compound heterozygote. Four novel mutations were detected: one nonsense, two missense, and one deletion of one amino acid. In four families, a previously reported mutation at codon 374, causing a premature stop codon, was identified, and, therefore, this is the most common perforin mutation identified so far in FHL patients. We found perforin mutations in 20% of all FHL patients investigated (7/34), with a somewhat higher prevalence, ∼30% (6/20), in children whose parents originated from Turkey. No other correlation between the type of mutation and the phenotype of the patients was evident from the present study. Our combined results from mutational analysis of 34 families and linkage analysis of a subset of consanguineous families indicate that perforin mutations account for 20%–40% of the FHL cases and the FHL 1 locus on chromosome 9 for ∼10%, whereas the major part of the FHL cases are caused by mutations in not-yet-identified genes

MEK Inhibitors Reverse cAMP-Mediated Anxiety in Zebrafish

SummaryAltered phosphodiesterase (PDE)-cyclic AMP (cAMP) activity is frequently associated with anxiety disorders, but current therapies act by reducing neuronal excitability rather than targeting PDE-cAMP-mediated signaling pathways. Here, we report the novel repositioning of anti-cancer MEK inhibitors as anxiolytics in a zebrafish model of anxiety-like behaviors. PDE inhibitors or activators of adenylate cyclase cause behaviors consistent with anxiety in larvae and adult zebrafish. Small-molecule screening identifies MEK inhibitors as potent suppressors of cAMP anxiety behaviors in both larvae and adult zebrafish, while causing no anxiolytic behavioral effects on their own. The mechanism underlying cAMP-induced anxiety is via crosstalk to activation of the RAS-MAPK signaling pathway. We propose that targeting crosstalk signaling pathways can be an effective strategy for mental health disorders, and advance the repositioning of MEK inhibitors as behavior stabilizers in the context of increased cAMP

Genetic studies of stroke in Northern Sweden

Stroke is a common disorder of later life with a complex etiology, including both environmental and genetic risk factors. The inherited predisposition is challenging to study due to the complexity of the stroke phenotype. Genetic studies in an isolated population have successfully identified a positional candidate gene for stroke, phosphodiesterase 4D (PDE4D). The aim of this thesis was to identify stroke susceptibility loci and positional candidate genes, taking advantage of low genetic variation in the northern Sweden population. All stroke cases were identified in a population-based stroke registry at the northern Sweden MONICA Centre. 56 families containing multiple cases of stroke and a follow up set of an additional 53 families were used for linkage studies. For association studies, 275 cases of first ever stroke together with 550 matched community controls were included. In paper I, we used a candidate region approach to investigate the PDE4D region on chromosome 5q. Linkage was obtained with a maximum allele-sharing LOD score of 2.06; P = 0.001. However, no significant association of ischemic stroke to the previously defined at-risk allele in PDE4D was observed. We next performed a genome wide linkage scan to explore new susceptibility loci for common forms of stroke (paper II). Non-parametric multipoint linkage analysis yielded allele-sharing LOD scores > 1.2 at nine locations; 1p34, 5q13, 7q35, 9q22, 9q34, 13q32, 14q32, 18p11, 20q13. The highest allele-sharing LOD score was obtained on chromosome 18p (LOD = 2.14). Fine mapping resulted in increased allele-sharing LOD scores for chromosome 5q13 and 9q22. In the follow up analysis of the nine regions, including all 109 families, the highest allele-sharing LOD scores were obtained on chromosomes 5q, 13q and 18p although none reached the initial genome wide values. In paper III, we focused on the chromosome 5q region, and further mapping and haplotype analysis in the families was performed. A common 1 cM haplotype was found to be shared among affected members of five families. In this region only the regulatory subunit 1 of phosphatidylinositol 3-kinase (PIK3R1) gene was located. Association of three single nucleotide polymorphisms in the PIK3R1 gene to common stroke was obtained in the case-control material. Finally, in paper IV, an extended pedigree containing seven families connected to common founders eight generations back was identified by genealogical analysis, and submitted to a separate genome wide scan analysis. A significant allele-sharing LOD score of 4.66 (genome wide P < 0.001) at chromosome 9q31-33 was obtained. Haplotype analysis identified a minimal common region of 3.2 cM, which was shared by four of the seven families. These four families contained all of the primary intracerebral hemorrhagic cases present in the extended pedigree. In conclusion we have replicated linkage of stroke susceptibility to the PDE4D region on chromosome 5q, but no significant association of ischemic stroke to PDE4D was observed. Linkage analysis of stroke did not identify any new major stroke loci, indicating that multiple minor susceptibility loci in addition to the previously known locus on chromosome 5q could contribute to the disease. In the chromosome 5q region a novel positional candidate gene for stroke was identified, the PIK3R1 gene. The PIK3R1 protein has several biological actions with potential roles in stroke susceptibility. Also a novel susceptibility locus for common forms of stroke at chromosome 9q was identified in a large pedigree, which may be of special importance for susceptibility to hemorrhagic stroke

Lack of aggregation of ischemic stroke subtypes within affected sibling pairs

ABSTRAK Rahmat,  Angga  Nur.  2014.  Pengembangan  Trainer  Sistem  Recloser  Berbasis Smart  Relay  Untuk  Menunjang  Matakuliah  Sistem  Distribusi  Dan Transmisi Di Jurusan Teknik Elektro Universitas Negeri Malang. Skripsi, Jurusan  Teknik  Elektro,  Fakultas  Teknik,  Universitas  Negeri  Malang. Pembimbing: (1) Yuni Rahmawati, S.T., M.T., (2) Sujito, S.T., M.T. Kata Kunci: Sistem Recloser, trainer, smart relay   Recloser  atau  Penutup  Balik  Otomatis  merupakan  salah  satu  peralatan proteksi pada jaringan distribusi tenaga listrik. Recloser peralatan yang berfungsi membuka  jaringan  ketika  terjadi  hubung  singkat  atau  arus  lebih  kemudian menutup balik secara otomatis ketika gangguan tersebut hilang dengan sendirinya. selain  itu  sebagai  pengaman  seksi  sehingga  dapat melokalisir/membatasi  daerah yang terganggu. Mata kuliah Sistem Distribusi dan Transmisi  Jurusan Teknik Universitas Negeri Malang merupakan mata  kuliah  yang  disajikan  untuk  program  keahlian Elektro  (Arus  Kuat). Media  pembelajaran  yang membantu  proses  pembelajaran mata kuliah  ini  sangat  terbatas. Keterbatasan  ini dikarenakan peralatan distribusi tidak mungkin  dihadirkan  secara  nyata  ketika  proses  pembelajaran.  berdasarkan observasi  dan  wawancara  kepada  dosen  pengampu  yang  telah  dilakukan  maka diperlukan  media  pembelajaran  yang  hampir  menyerupai  peralatan  distribusi tenaga listrik tersebut. Di Jurusan Teknik Elektro terdapat Trainer sistem recloser berbasis PLC, namun kondisi trainer tersebut sedang rusak, selain itu pengawatan trainer masih rumit dan pengontrolannya  terbatas, sehingga mahasiswa kesulitan dalam memahami  prinsip  kerja  recloser. Trainer  sistem  recloser  berbasis  smart relay  digunakan  sebagai  alternatif media  pembelajaran  yang mampu mengatasi kekurangan  media  pembelajaran  sebelumnya.  Smart  relay  merupakan  sebuah peralatan  elektronik  yang mampu menggantikan  fungsi  relay  konvensional  dan bisa  diberikan  instruksi  atau  program.  Trainer  sistem  recloser  berbasis  smart relay  ini, memiliki  kelebihan,  antara  lain:  pengawatan mudah  dan  pengontrolan lebih banyak.   Model  pengembangan  yang  digunakan  adalah  model  pengembangan Sugiyono  yang  dikombinasikan  dengan metode  Borg  dan  Gall.  Pemilihan  pada model pengembangan tersebut dikarenakan keruntutan dalam setiap tahapnya dan terdapat  beberapa  revisi  yang  justru  berguna  untuk membuat  produk  yang  lebih baik daripada sebelumnya. Tahap model pengembangan yang dilaksanakan, yaitu: (1) Potensi dan Masalah; (2) Pengumpulan Data; (3) Desain Produk; (4) Validasi Desain; (5) Revisi Desain; (6) Produksi; (7) Ujicoba Perseorangan; (8) Revisi; (9) Ujicoba Kelompok Kecil;  (10) Revisi;  (11) Ujicoba Lapangan;  (12) Revisi;  (13) Laporan; dan (14) Produksi Masal.    Berdasarkan  pelaksanaan  metode  penelitian  dan  pengembangan  maka diperoleh  data  hasil    dari  ahli  media  sebesar  95%,  ahli  materi  sebesar  91%, ujicoba kelompok kecil  sebesar 92%, dan ujicoba kelompok besar  sebesar 88%. Dapat  disimpulkan  bahwa  trainer  sistem  recloser  berbasis  smart  relay  telah memenuhi kriteria valid dan layak digunakan sebagai media pembelajaran

Bayesian semiparametric meta-analysis for genetic association studies.

We present a Bayesian semiparametric model for the meta-analysis of candidate gene studies with a binary outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping genetic markers in the same genetic region. Meta-analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequilibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta-analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian semiparametric model which models the observed genotype group frequencies conditional to the case/control status and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach allows borrowing of strength across studies and across markers. The analysis is based on a mixture of Dirichlet processes model as the underlying semiparametric model. Full posterior inference is performed through Markov chain Monte Carlo algorithms. The approach is demonstrated on simulated and real data