Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

تحضير جسيمات دقيقة حاوية على الميتفورمين باستخدام طريقة التهلم الشاردي

داء السكري هو اضطراب استقلابي مزمن متمثل بارتفاع مستويات الغلوكوز في الدم. الميتفورمين هيدروكلورايد هو دواء فعّال وأمن يستخدم على نطاق واسع كخط أول لعلاج السكري النمط الثاني. له مشاكل عديدة (على سبيل المثال انخفاض توافره الحيوي عن طريق الفم، قصر عمره النصفي، وتسببه بآثار جانبية معدية معوية). تم تطوير صيغ مضبوطة التحرر من الميتفورمين لزيادة تحمّله وبالتالي تحسين مطاوعة المريض. الهدف من هذا البحث هو تحضير وتقييم جسيمات دقيقة حاوية على الميتفورمين باستخدام طريقة التهلّم الشاردي باعتبارها طريقة بسيطة، منخفضة التكلفة وصديقة للبيئة، بهدف ضبط تحرر الميتفورمين. تم تحضير الجسيمات الدقيقة باستخدام مادة الكيتوزان كبوليمر طبيعي وثلاثي فوسفات الصوديوم TPP كعامل للتصليب، وتبع ذلك دراسة تأثير المتغيرات المختلفة على خصائص الجسيمات الدقيقة. هذه المتغيرات هي تركيز الكيتوزان ٪، تركيز TPP ٪، تركيز الدواء ٪، سرعة التحريك، وزمن التحريك. تم تقييم الجسيمات الدقيقة المحضرة من حيث شكل وأبعاد الجسيمات، فعالية التمحفظ، المردود المئوي، مشعر الانتباج عند التوازن، وتحرر الدواء في الزجاج. أظهرت الصور تحت المجهر أن الجسيمات الدقيقة كان لها شكل كروي وتراوحت أبعادها بين (539-1063) ميكرومتر. وجد أن الصيغة رقم 15 التي تحتوي على (1.5٪ كيتوزان، 1.5٪ TPP ، 1٪ دواء، بسرعة تحريك 600 دورة في الدقيقة، و زمن تحريك 45 دقيقة) تملك بعد وسطي يقدر بـ (827 ميكرومتر)، أعلى فعالية تمحفظ (50%)، ومردود مئوي يقدر بـ (34٪)، كان لهذه الصيغة القدرة على ضبط انتباج الجسيمات الدقيقة وبالتالي ضبط تحرر الدواء في وقاء يحاكي بيئة الجهاز الهضمي.

Multibacillary Leprosy Presenting as Anetoderma in a Young Teenager

Anetoderma presents as a circumscribed area of slack skin. It can present as either primary or secondary, if associated with other conditions. Leprosy is one of the causes of secondary anetoderma, but it is not commonly reported, especially in multibacillary leprosy. Here, we report a case of a 16-year-old young girl who presented with fever, joint pain, and only three anetodermic plaques. A slit skin smear from the lesion showed multiple acid-fast bacilli with a bacillary index of 3+, thus confirming the diagnosis of leprosy. This case is unique since multibacillary leprosy presented with only few anetoderma lesions in a young teenager girl from a leprosy-eliminated country

Syrian crises effect on specialty choice and the decision to work in the country among residents of six major hospitals in Syria, Damascus.

Assessing the impact of war on medical residents' specialty choices and migration decisions is critical to ensure the sustainability of healthcare systems worldwide. This study aimed to evaluate the effect of the Syrian crisis on specialty choices, related factors, and decisions to work in Syria among residents of six major university hospitals in Damascus. A cross-sectional study was conducted using a validated questionnaire from 20/4/2022 to 20/5/2022, including all eligible residents with no missing data. The questionnaire was comprised of 68 items, and residents were divided into two groups: group 1 included residents who made their specialty choice after the end of the military war in Damascus 2018, while group 2 included residents who made their specialty choice (the point of submitting their lists and applying for residency) during the war. A total of 370 residents were included, with 38.4% females and 61.6% males. Our findings revealed that 30% of residents preferred working in Syria, while 43.5% preferred working abroad. The factor of a "safer and more stable life" was significantly higher in Group 1 than in Group 2 (3.86>3.5, p-value = 0.026). Additionally, Group 1 residents were more likely to choose radiology, pathology, laboratory, and psychiatry specialization as their specialties, while choosing surgical specializations and hematology decreased compared to Group 2 (p-value2.21, Standard deviation = 0.22, p-value = 0.033). The Syrian crisis and its economic aftermath have influenced residents' specialty choices and practice locations. Even after the war's end, the high level of migration intentions could negatively affect the quality of provided healthcare services

Structural Optimization of Non-Nucleoside DNA Methyltransferase Inhibitor as Anti-Cancer Agent

Inhibition of DNA methyltransferase 1 (DNMT1) can reverse the malignant behavior of cancer cells by restoring expression of aberrantly silenced genes that are required for differentiation, senescence, and apoptosis. Clinically used DNMT1 inhibitors decitabine and azacitidine inhibit their target by covalent trapping after incorporation into DNA as azacytidine analogs. These nucleoside compounds are prone to rapid enzymatic inactivation in blood, posing challenges to the development of purely epigenetic dosing schedules. Non-nucleoside compounds that suppress expression or function of DNMT1 may overcome this problem. Using a high-throughput PCR-based site specific chromatin condensation assay, we identified a compound that reactivated Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A) in myeloma cells and suppressed expression of DNMT1 from a library of 5120 chemically diverse small molecules. Lead optimization was performed to generate 26 new analogs with lung cancer proliferation and DNMT1 expression as activity readout. Two of the new derivatives showed 2 fold improvement of growth inhibiting potency and also decreased DNMT1 protein levels in lung cancer cells

Participants’ specializations distribution and sample calculation.

Participants’ specializations distribution and sample calculation.</p

This questionnaire aims to collect data about factors affecting the choice of medical specialty.

This questionnaire aims to collect data about factors affecting the choice of medical specialty.</p

Means of the influencing factors on the residents’ desirable specialty (group 1 and 2) and their association with group 1 and group2.

Means of the influencing factors on the residents’ desirable specialty (group 1 and 2) and their association with group 1 and group2.</p

Factors affecting on residents’ decision in choosing the work place after specialization and its association with group 1 and 2.

Factors affecting on residents’ decision in choosing the work place after specialization and its association with group 1 and 2.</p