NR1 Receptor Gene Variation is a Modifier of Age at Onset in Turkish Huntington’s Disease Patients

The length of the CAG repeat tract is the major determinant of age of onset (AO) of Huntington’s Disease (HD) However, there remains a significant variance in AO when the expanded repeat size is ruled out. The search for genetic modifiers has revealed various candidate loci; however, many reports have been contradictory. The N-methyl-d-aspartate receptors (NMDAR) have been proposed as an important putative modifier. We aimed to determine whether polymorphisms in NMDAR-coding genes have an effect on the AO. We analyzed the association between GRIN1 (rs6293), GRIN2A (rs1969060), and GRIN2B (rs1806201, rs890) polymorphisms and AO of Turkish HD patients. According to our findings, expanded CAG repeat size explains 41.8% of the variance in AO. Upon classification of genotypes into CAG repeat length intervals, rs6293 can be considered as an AO modifier for Turkish HD patients with 50 or higher CAG repeats. In addition to that, we found a significant association of this polymorphism to HD, with the GG genotype constituting a risk factor. Candidate genetic modifiers should be tested in different populations since their effects may exist only in groups of specific ethnic origins. Defining such modifiers will help in complete understanding of HD pathogenesis and in designing therapeutic targets

Molecular Mechanisms of Polyglutamine Pathology and Lessons Learned from Huntington’s Disease

Identification of polymorphic repeating units on DNA as a cause of many neurological disorders has introduced a new concept in molecular biology: Dynamic mutations. Many of the identified dynamic mutations involve expansion of trinucleotide repeats within disease genes. Nine neurodegenerative disorders are currently known to be caused by expanding CAG trinucleotide repeats. These are Huntington’s Disease (HD), Dentato-Rubral Pallidoluysian Atrophy (DRPLA), Spinal and Bulbar Muscular Atrophy (SBMA), and Spinocerebellar Ataxia (SCA) Type 1, 2, 3, 6, 7 and 17. All are inherited in an autosomal dominant fashion except for SBMA, which is X-linked recessive. In all polyQ diseases, the disease mutation involves an increase in the number of CAG repeats within the coding regions of the respective genes. Since CAG triplets encode glutamine in the proteins, diseases caused by CAG repeat expansions are known as “Polyglutamine (polyQ) Diseases”. PolyQ diseases share certain clinical, neuropathological and molecular findings. The most widely studied polyQ disease is HD. In HD and other polyQ diseases, conformational change in the mutant protein causes abnormal folding and proteolysis of the protein, leading to the formation of a toxic polyQ fragment, which aggregates and causes neuronal dysfunction and selective neuronal death in the brain

Oncocytic neoplasms; rare adrenocortical tumours — a report of eleven patients

Introduction: Oncocytomas of adrenal glands are extremely rare and usually present as incidentally detected masses. We aimed to present a series of patients with adrenal oncocytomas and review the literature. Material and methods: Electronic database of patients with adrenal tumours, who were admitted to the internal medicine and endocrinology and metabolism outpatient clinics of Uludag University Medical Faculty between January 2005 and November 2016, were assessed retrospectively. Those who underwent surgery and pathological diagnosis of oncocytoma (n = 11) were included to the study. The demographic, clinical, pathological, radiological, and laboratory features were evaluated. Results: Of these 11 patients, 54.5% (n = 6) were female and 45.5% (n = 5) were male. They aged between 31 and 76 years (45.36 ± 13.68). Five (45.5%) of the masses showed endocrinological activity and were more frequent in women. The masses were 25–130 (57.63 ± 34.04) mm in width and 20–100 (47.82 ± 28.95) mm in length. Seven (63.6%) oncocytomas were classified as benign and the remainder as having uncertain malignant potential according to Lin-Weiss-Bisceglia criteria. Mean duration of follow-up were 24.8 (6–60) months and 38.2 (15–82) months, respectively. Conclusions: Because there are no unique clinical and imaging characteristics differentiating adrenal oncocytomas from other types of adrenal masses, it should be kept in mind in differential diagnosis of adrenal masses, especially large ones and those suspicious for adrenocortical carcinoma

Huntington's Disease - Molecular Pathogenesis and Current Models

Huntington's disease is a progressive neurodegenerative disorder of the brain. It is one of the quite devastating and currently incurable human conditions. Degeneration of specific types of neurons in the brain results in a triad of clinical features: serious behavioral disturbances, uncontrolled movements of body parts, and deterioration of intellectual capabilities. The underlying complex mechanisms and molecular players of the cellular cascades still need to be deciphered in detail despite considerable advances. Once solved, the related molecular mechanisms will not only enlighten the HD story but will also shed light on other polyglutamine diseases and similar brain disorders. This book, Huntington's Disease-Molecular Pathogenesis and Current Models, is planned to cover recent scientific achievements in understanding the cellular mechanisms of HD. The chapters provide comprehensive description of the key issues in HD research. In this regard, this book will serve as a source for clinicians and researchers in the field and also for life science readers in increasing their understanding and awareness of the clinical correlates, genetic aspects, neuropathological findings, and potential therapeutic interventions related to HD

Huntington's Disease - Core Concepts and Current Advances

Huntington's Disease is one of the well-studied neurodegenerative conditions, a quite devastating and currently incurable one. It is a brain disorder that causes certain types of neurons to become damaged, causing various parts of the brain to deteriorate and lose their function. This results in uncontrolled movements, loss of intellectual capabilities and behavioural disturbances. Since the identification of the causative mutation, there have been many significant developments in understanding the cellular and molecular perturbations. This book, ""Huntington's Disease - Core Concepts and Current Advances"", was prepared to serve as a source of up-to-date information on a wide range of issues involved in Huntington's Disease. It will help the clinicians, health care providers, researchers, graduate students and life science readers to increase their understanding of the clinical correlates, genetic aspects, neuropathological findings, cellular and molecular events and potential therapeutic interventions involved in HD. The book not only serves reviewed fundamental information on the disease but also presents original research in several disciplines, which collectively provide comprehensive description of the key issues in the area

Dermal Absorption and Metabolism of the Antipsoriatic Drug Dithranol Triacetate

Die perkutane Resorption, die Ausscheidungskinetik und der Metabolismus von Dithranol-triacetat (2) wurden bei Wistar- Ratten untersucht. Durch die Verwendung zweier verschieden markierter Verbindungen - 3H im Anthracen-Teil und 1 4 C in den Acetat-Resten - konnte das Schicksal der verschiedenen Molekülteile verfolgt werden. Nach Injektion wird 2 in großem Umfang durch enzymatische Einwirkung in Acetat und Dithranol gespalten. Die desacetylierten Metaboliten verlieren zur Hälfte die 3H-Markierung unter Bildung von 3H20. Als Stoffwechselprodukte wurden nach iv. Injektion von 3H-2 im Urin l,8-Diacetoxy-9-anthron, 1 - Acetoxy- 8- hydroxy- 9- anthron, Dithranol, 1,8-Dihydroxy- 9,10-anthrachinon und dessen Diacetat gefunden. Bei der dermalen Verabreichung wird unverändertes 2 praktisch nicht resorbiert. Die in der Haut in vitro nachweisbaren Arylesterasen hydrolysieren jedoch 2 zu Dithranol, das unter einem Okklusiv-Verband bis zu 33% resorbiert wird. Dithranol- triacetat erweist damit seine Prodrug-Eigenschaften für die Psoriasis-Behandlung. Percutaneous absorption, excretion kinetics, and metabolism of dithranol triacetate (2) have been investigated in Wistar rats. By the use of two differently labelled molecules - 3H in the anthracene nucleus and 1 4 C in the acetoxy groups of 2, resp. - the fate of the different parts of the dithranol triacetate molecule could be followed. After injection, large amounts of 2 are cleaved under the influence of enzymes into acetate and dithranol. These deacetylated metabolites lose half their 3H label with formation of3H20. In urine, l,8-diacetoxy-9-anthrone, 1-acetoxy-8-hydroxy-9- anthrone, l,8-dihydroxy-9,10-anthraquinone and its diacetate were found as metabolites. After dermal application, unchanged 2 is practically not absorbed at all. Arylesterases which, according to in vitro studies, are present in or on the skin, hydrolyse dithranol triacetate to give free dithranol. Up to 33% of the latter are absorbed from under an occlusive dressing. Dithranol triacetate, therefore, shows pro-drug characteristics for the treatment of psoriasis

Neoliberalism, the Transformation of the Practice of Law and Women Attorneys

Neoliberal politikaların yarattığı dönüşüm hukuk alanına da yansımış ve avukatlık mesleğinin yapılış biçimini değiştirmiştir. Neoliberalizm ile birlikte ortaya çıkan yeni ve karmaşık hukuki sorunların çözümü konusunda uluslararası şirketlerin taleplerine ve beklentilerine cevap verebilecek yeni bir avukatlık yapılanmasına ihtiyaç duyulmuştur. Bu ihtiyaca cevap vermek üzere kurulan büroların ayırt edici özelliği ise şirketlerin farklı alanlardaki hukuki sorunlarına çözüm üretebilmek amacıyla iyi eğitimden geçmiş, birden çok yabancı dile hakim, genç avukatları istihdam etmesidir. Bu bürolarda çalışmak, yüksek maaş ve kariyer imkanları sebebiyle cezbedici olmakla beraber adliyelerle ilişkisi sınırlı, sadece belli alanlarda uzmanlaşmış, dava dosyalarının yalnızca belirli aşamalarıyla ilgilenen yeni bir avukatlık biçiminin doğmasına neden olmaktadır. Çalışmamızın ana eksenini ise ülkemizde faaliyet gösteren bu tür bürolarda çalışan ve yukarıda anılan özellikleri haiz kadın avukatlar oluşturmaktadır. Bahsi geçen büroların çalışma koşullarına içkin olan ve neoliberalizm ile güçlenen rekabet, yabancılaşma, kademelenme gibi unsurların iş yerinde ve iş dışında kadınların yaşamlarına ne şekilde yansıdığı yapılan görüşmeler kapsamında değerlendirilmiştir. Bu bağlamda, adalet sisteminin taşıdığı eril yapının devamı olan bu tür bürolarda, kadın avukatların iş görüşmelerinden işten çıkarılmaya dek maruz kaldıkları cinsiyetçi uygulamalara yer verilmiştir. Ücret ve kariyer bakımından iyi bir statüde bulunan kadın avukatların ev içi işbölümünde yaşadıkları deneyimler yapılan görüşmeler çerçevesinde ele alınmıştırThe transformation created by the neoliberal policies has also affected the field of law and changed the way the law profession is practiced. By implications, neoliberalism brought in a new type of attorneyship that could meet the expectations and fulfill the requirements of international companies with regard to the novel and complex legal issues. The distinguishing characteristic of these law firms which are established to meet such needs is that these firms employ well educated, multilingual young attorneys in order to address the companies' diverse set of legal matters. Given the fact that it is tempting to work for these firms with all their career and six-figure income opportunities, it, however creates a new style of attorneyship that has weak ties with the courthouse--also based on specialized attorneys dealing only with certain instances of a given case. The focus of our article will be on the women attorneys who are working in such law firms, and having acquired the qualifications mentioned above. The reflections of the factors--competition, alienation, pecking order--on the lives of women are evaluated within the context of interviews made whether it concerns their lives in or out of the office. In this sense, a vast array of sexist applications starting from the job interview until the dismissal at these law firms are the extensions of the patriarchal structure inherent to the justice system.. Hence, the division of domestic labor and the related experiences of women attorneys with respectable salaries and careers are discussed in the scope of the interview

SEPTIN12 c.474 G > A polymorphism as a risk factor in teratozoospermic patients

Teratozoospermia is a condition related to poor morphologically normal sperm count below the lower reference limit, which could hinder natural conception. Single nucleotide polymorphisms (SNPs) in the genes involved in sperm production and testicular function are proved to be risk factors, resulting in decreased sperm parameters and defects in sperm morphology. c.474 G > A polymorphism in the SEPTIN12 gene which is one of the testis-specific genes creates a novel splice variant and the resulting truncated protein was previously found to be more prevalent in infertile men. We aimed to investigate the association of SEPTIN12 c.474 G > A polymorphism with male infertility in teratozoospermia patients. Forty-eight teratozoospermic patients, diagnosed according to Kruger's criteria and 164 fertile controls who fathered at least 1 child within 3 years without assisted reproductive technologies were included into our prospective randomized controlled study. PCR-RFLP method was used for genotyping. Although no statistical difference was found between teratozoospermic patients and fertile controls in terms of genotype distributions, significance was identified between the genotypes of all and non-smoking teratozoopermic patients in terms of neck defects. SEPTIN12 c.474 G > A polymorphism was shown to be associated with sperm neck defects in teratozoospermic patients using the dominant statistical model. Smoking was identified as a risk factor for the sperm morphology defects in teratozoospermic A allele carriers

Molecular Biology of Huntington’s Disease

Huntington’s Disease (HD) is the most common among nine known polyglutamine disorders. Its prevalence is estimated to be 3-7/100 000 in populations of Western European descent. HD is an autosomal dominantly inherited neurodegenerative disorder of the central nervous system, characterized by involuntary movements, impaired motor coordination, cognitive loss and various psychiatric abnormalities. The most prominent pathological finding is the selective neuron death in basal ganglia. The disease gene (IT-15), localized to chromosome 4 in 1993 and 180kb long, is composed of 67 exons. The gene product is a 348 kDa protein, called huntingtin, whose function is not known yet. The mutation causing HD is the expansion of the CAG triplet repeat in the first exon of the IT-15 gene. Huntington’s Disease Working Group has identified four repeat intervals: People who carry 26 or less CAG repeats in the IT-15 gene are healthy, alleles with 27-35 repeats may show intergenerational instability, people carrying 36-39 CAG repeats may or may not develop the disease , however 40 or more CAG repeats definitely cause HD, if people live long enough. The molecular diagnosis of HD with direct mutation analysis has been available since 1993. In this method, the CAG repeat region on the IT15 gene is PCR-amplified, and the repeat number is determined using radioactive or non-radioactive methods. Although the genetic mutation leading to HD has been identified ten years ago, the underlying molecular mechanism leading to selective neurodegeneration is not clear yet. Proteolytic cleavage and aggregate formation of the mutant protein, aberrant protein interactions and transcriptional dysregulation are possible pathogenic mechanisms. The understanding of HD pathogenesis will enlighten the way to a cure for several other neurodegenerative disorders, which are thought to share a common mechanism