Autosomal Recessive Primary Microcephaly (MCPH) and Novel Pathogenic Variants in ASPM and WDR62 Genes.

Introduction: Autosomal recessive primary microcephaly (MCPH) is a disorder characterized by congenital microcephaly and intellectual disability without extra-central nervous system malformation. MCPH is a disease with heterogeneity in genotype and phenotype. For this reason, it is important to determine the genetic causes and genotype-phenotype relationship in MCPH, which causes lifelong impairment. In this study, we aimed to evaluate the clinical, genetic, and brain imaging findings of cases diagnosed with MCPH. Methods: Electroencephalogram and brain magnetic resonance imaging were performed for all cases. We evaluated genetic results of the 39 families including cases with suspected MCPH diagnosis. Results: Genetic diagnosis related to MCPH was provided in 11/39 (28.2%) of these families including 13/41 cases (31.7%). Variants of the WDR62 gene were the most common (61.5%) cause, and variants of the ASPM gene were the second most common cause (38.5%). We have found 6 novel variants and 4 previously reported variants in ASPM and WDR62 genes. Main brain imaging findings in our cases were lissencephaly, polymicrogyria, schizencephaly, pachygyria, and cortical dysplasia. Genetic counseling in 2 families whose genetic diagnosis was determined prevented them from having another child with MCPH. Discussion/Conclusion: Detection and reporting of novel variants is an important step in eliminating this disorder by providing families with appropriate genetic counseling.

MicroRNA Expression Levels in Patients with Hashimoto Thyroiditis: A Single Centre Study.

OBJECTIVE: To determine the circulatory miRNA expression levels in patients with Hashimoto thyroiditis (HT) at the time of diagnosis and follow-up period compared with healthy controls. METHODS: We collected blood samples from 34 patients with HT (4 males and 30 females) at the time of first diagnosis (Group P) and euthyroid period (Group E). Thirty-three healthy controls (Group H) blood samples were also included in the study. Expression levels of five different circulating miRNAs (miR-22, miR-141, miR-155, miR-375, miR-451) were evaluated using real-time polymerase chain reaction. RESULTS: There was a significant difference in miR-375 levels between the groups P and H. Also, for miR-451, there was a significant difference between the P and E groups. Finally, there was a moderate positive correlation between thyroid-stimulating hormone values and miR-22 expression levels for the P group. CONCLUSION: miRNAs have important roles at all stages of the diseases. More studies must be performed in all thyroid diseases and autoimmune diseases, including HT.

Extending the Phenotypic Spectrum of Huntington Disease: Hypothermia.

Huntington disease (HD) is an autosomal dominant progressive neurodegenerative disorder associated with expanded CAG repeat size in the huntingtin gene and usually presenting with movement disorder, psychiatric symptoms, and cognitive decline. Sleep problems, weight loss, and cachexia are also common. Here, we report a patient presenting with hypothermia in late-stage HD. Although thermoregulatory defects were documented in animal models, this is the first report describing HD with hypothermia in humans.

Relevance between clinical status and exhaled molecules related to neutrophilic inflammation in pediatric cystic fibrosis.

INTRODUCTION: Cystic fibrosis (CF) is characterized with chronic inflammation with neutrophil and related cytokines in airway secretions. We aimed to measure the levels of neutrophil related inflammatory markers as nitric oxide, IL-8, IL-17, leukotriene B4 and neutrophil elastase as well as e-cadherin in exhaled breath condensate (EBC), and to determine their relation with clinical findings. METHODS: We consecutively enrolled cystic fibrosis patients into our clinics between the age of six and eighteen years who could cooperate for exhaled breath condensate to this case-control study (n = 30). The age and sex matched control group (n = 26) was enrolled. Spirometry was performed during the stable period and EBC samples were obtained for measurement of the markers. RESULTS: The mean age of the subjects enrolled was 12.1(4.2) years and 40% were positive for P.Aeruginosa in sputum. Subjects who had P.Aeruginosa in sputum cultures had significantly lower FEV1, FVC and FEF 25/75 values compared to the ones without P.Aeruginosa (p = 0.002, p = 0.002 and p = 0.005 respectively). EBC neutrophil elastase levels were significantly higher in the CF patients compared to non-CF controls (3.11 ± 4.71 versus 0.90 ± 2.68, p = 0.04). Nitric oxide, IL-17, IL-8, e-cadherin, neutrophil elastase or leukotriene B4 levels in EBC of CF patients were not related to P.Aeruginosa s infection, FEV1 levels or hospital admission in the last year. CONCLUSION: In our study, neutrophil elastase levels in EBC are higher in CF patients compared to non-CF controls. This is independent of acute infection and is evidence to the persistence of neutrophilic lung injury. However, EBC NO, IL-8, IL-17, e-cadherin, neutrophil elastase and leukotriene B4 levels as inflammatory markers, are not correlated with disease progression or clinical findings.

The Additional Diagnostic Value of the Three-dimensional Volume Rendering Imaging in Routine Radiology Practice.

Three-dimensional volume rendering (3DVR) is useful in a wide variety of medical-imaging applications. The increasingly advanced capabilities of CT and MRI to acquire volumetric data sets with isotropic voxels have resulted in the increased use of the 3DVR techniques for clinical applications. The two most commonly used techniques are the maximum intensity projection (MIP) and, more recently, 3DVR. Several kinds of medical imaging data could be reconstructed for 3D display, including CT, MRI, and ultrasonography (US). In particular, the 3D CT imaging has been developed, improved, and widely used of late. Understanding the mechanisms of 3DVR is essential for the accurate evaluation of the resulting images. Although further research is required to detect the efficiency of 3DVR in radiological applications, with wider availability and improved diagnostic performance, 3DVR is likely to enjoy widespread acceptance in the radiology practice going forward.

Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss.

The genetics of both syndromic (SHL) and non-syndromic hearing loss (NSHL) is characterized by a high degree of genetic heterogeneity. We analyzed whole exome sequencing data of 102 unrelated probands with apparently NSHL without a causative variant in known NSHL genes. We detected five causative variants in different SHL genes (SOX10, MITF, PTPN11, CHD7, and KMT2D) in five (4.9%) probands. Clinical re-evaluation of these probands shows that some of them have subtle syndromic findings, while none of them meets clinical criteria for the diagnosis of the associated syndrome (Waardenburg (SOX10 and MITF), Kallmann (CHD7 and SOX10), Noonan/LEOPARD (PTPN11), CHARGE (CHD7), or Kabuki (KMT2D). This study demonstrates that individuals who are evaluated for NSHL can have pathogenic variants in SHL genes that are not usually considered for etiologic studies.

Multidetector computed tomographic assessment of the normal diameters for the thoracic aorta and pulmonary arteries in infants and children.

BACKGROUND: Knowledge of the normal size of the thoracic aorta and pulmonary arteries is important regarding the detection of the abnormal and valuable in the treatment of patients with congenital and acquired cardiovascular diseases. PURPOSE: To determine the normal diameters of the thoracic vascular structures of pediatric participants on contrast-enhanced multidetector computer tomography (MDCT) scans. MATERIAL AND METHODS: Between July 2010 and July 2014, the MDCT examinations obtained from 520 participants (age range, 0-18 years; mean age, 8.49 years ± 5.54 [standard deviation]; male:female ratio, 1.6:1) with normal cardiovascular examinations were retrospectively evaluated. Patients were divided into six groups according to their age. Diameters of the ascending aorta (AA), descending aorta (DA), main pulmonary artery (MPA), right pulmonary artery (RPA), and left pulmonary artery (LPA) were measured. RESULTS: The diameters of the thoracic vascular structures increased with age and the statistical difference among the age groups and genders were significant. The vascular structures in male patients tended to have higher dimensions than female patients. The LPA demonstrated higher mean values than the RPA in each age group. The mean ratio PA (MPA/AA) is 0.93 ± 0.08 for pediatric participants and it is slightly higher in girls compared to boys (0.93 ± 0.07 and 0.92 ± 0.07, respectively). The level of pulmonary artery bifurcation moves caudally with increasing age with thoracal 6 vertebra being the most common for all age groups (53.3%). CONCLUSION: We believe that the results of our study can serve as a potential reference in differentiating the normal from the abnormal size of the aorta and pulmonary arteries on chest MDCT studies in the pediatric population.

The effects of suplatast tosilate treatment and prophylaxis on lung histopathology in a mouse model of chronic asthma.

INTRODUCTION: Suplatast tosilate is a medication that inhibits TH2-type cytokines. We aimed to investigate the effects of suplatast tosilate treatment and prophylaxis on lung histopathology and cytokine levels in a mouse model of chronic asthma. MATERIALS AND METHODS: Forty-two BALB/c mice were divided into 6 groups: group I (control), group II (vehicle control), group III (dexamethasone), group IV (prophylaxis with suplatast tosilate), group V (treatment with suplatast tosilate), and group VI (prophylaxis and treatment with suplatast tosilate). All of the groups, except for the control and vehicle control groups, were sensitized and challenged with ovalbumin. The mice in the study groups, except those in the group receiving suplatast tosilate for prophylaxis only, were treated with study drugs. After the mice were killed, IL-4, IL-5, and interferon-γ levels were quantified in the lung tissue, which were examined histologically by light and electron microscopy. RESULTS: There were significant improvements in all histopathological parameters in the group treated with suplatast tosilate compared with the vehicle control group. Similar improvements were observed when the group receiving prophylaxis and treatment with suplatast tosilate was compared with the vehicle control as well. There were no significant differences between the group receiving only prophylaxis with suplatast tosilate and the vehicle control group. Cytokine levels were significantly higher in the vehicle control group when compared with the control group. Although all of the groups had lower cytokine levels than those of the vehicle control group, the differences were not statistically significant. CONCLUSIONS: Treatment with suplatast tosilate was effective in improving all histopathological parameters in a mouse model of chronic asthma. It was observed that the use of prophylactic suplatast tosilate was ineffective and had no additional effects when administered together with treatment.

The effect of rupatadine on lung histopathology in a murine model of chronic asthma.

INTRODUCTION: Rupatadine is a new second-generation antihistamine with H(1) receptor antagonist activity and platelet-activating factor antagonist properties. This study aimed to investigate the effect of rupatadine on histologic changes in the lungs in a murine model of chronic asthma. MATERIALS AND METHODS: Thirty-five BALB/c mice were divided into five groups of seven mice each: group I (control), group II (placebo [saline]), group III (dexamethasone 1 mg · kg(-1)·d(-1)), group IV (rupatadine 3 mg·kg(-1) d(-1)), and group V (rupatadine 30 mg·kg(-1)·d(-1)). Groups II through V were sensitized and challenged with ovalbumin and treated once per day via the oral route (gavage). Animals were sacrificed 24 h after the last treatment was administered. Airway histopathology was evaluated using light and electron microscopy in all groups. RESULTS: There were no significant differences observed in any of the histologic parameters between groups II and IV. There were significantly thinner basement membrane, subepithelial smooth muscle layer, and epithelia were significantly thinner in group V than in group II (p < .05). There were no statistically significant differences in the thicknesses of the basement membrane, subepithelial smooth muscle layer and epithelia between groups III and V. CONCLUSION: Rupatadine had a beneficial effect on histologic changes in a chronic murine model of asthma.

An unusual cause of mediastinal widening: bilateral innominate vein aneurysms.

We present a case of aneurysm of bilateral innominate veins and vena cava superior. Chest X-ray, computed tomography, and 3D contrast enhanced magnetic resonance angiography findings are described. The etiology of venous aneurysms is reviewed and clinical management options are discussed.

Preparation of new catalysts by the immobilization of palladium(II) species onto silica: an investigation of their catalytic activity for the cyclization of aminoalkynes.

Silica-immobilized palladium catalysts are readily prepared by treating partially dehydroxylated silica with solutions of the palladium(II) complexes, cis-[PdMeXL2] (X = Me, L2 = dmpe; X = Cl, L2 = dmpe, dppe, phen, bipy, 2PMe3), trans-[PdMeXL2] (X = Cl, NO3, OTf, L = PMe3; X = Cl, L = PPh3), or [PdPh(OH)L]2 (L = PPh3, PCy3), at room temperature. A chemisorption reaction is presumed to occur on the surface Si-OH groups, with elimination of 1 equiv of methane, benzene, or water and the initial formation of a covalent Pd-O bond to the silica surface. The amount of chemisorbed material is strongly dependent on the nature of the complex employed, and the Pd content of the materials, determined by ICP analysis, was found to vary widely (from 1.47 to 0.021 wt %). It appears that the complexes stabilized by more basic ligands undergo a more facile reaction with the surface. The catalytic activity of the materials was first tested in the cyclization of 6-aminohex-1-yne. Higher conversions were found for those catalysts containing more basic ligands, due to the higher loadings, and for those complexes containing more weakly coordinating anions. Silica/trans-[PdMe(NO3)(PMe3)2] was identified as the best catalyst and was used to test the generality of the catalytic cyclization method with two other alkynes, namely, 5-phenyl-4-pentyn-1-amine and 6-phenyl-5-hexyn-1-amine. The catalysts prepared here show rates comparable to, or greater than, those found for homogeneous late transition metal complexes, including their molecular precursors. Furthermore, the supported catalysts are only slightly air-sensitive and can be recycled, after filtration in air, with only moderate loss of activity.

Innovative synthesis of 4-carbaldehydepyrrolin-2-ones by zwitterionic rhodium catalyzed chemo- and regioselective tandem cyclohydrocarbonylation/CO insertion of alpha-imino alkynes.

The tandem cyclohydrocarbonylative/CO insertion of alpha-imino alkynes employs CO, H(2), and catalytic quantities of zwitterionic rhodium complex (eta(6)-C(6)H(5)BPh(3))(-)Rh(+)(1,5-COD) and triphenyl phosphite affording aldehyde substituted pyrrolinones in 67-82% yields. This unique transformation is readily applied to imino alkynes containing alkyl, alkoxyl, vinyl, and aryl substituents. The ability to prepare highly functionalized pyrrolinones makes this an attractive route to these important and versatile pharmaceuticals.

First examples of enantioselective palladium-catalyzed thiocarbonylation of prochiral 1,3-conjugated dienes with thiols and carbon monoxide: efficient synthesis of optically active beta,gamma-unsaturated thiol esters.

A catalyst system based on [Pd(OAc)(2)]/(R,R)-DIOP has been found to effect asymmetric thiocarbonylation of certain prochiral 1,3-dienes to produce good yields of optically enriched beta,gamma-unsaturated thiol esters. The reaction was performed under an atmosphere of carbon monoxide (400 psi) at 110 degrees C in methylene chloride for 60 h. The asymmetric thiocarbonylation proceeded with good to excellent enantioselectivities (up to 89% ee). The stereoselectivity is strongly influenced by the structure of the chiral phosphine ligands and substrates, as well as by the reaction conditions. The enantiodetermination step is assumed to be CO insertion to a pi-allylpalladium intermediate.

Synthesis of beta-lactones by the regioselective, cobalt and Lewis acid catalyzed carbonylation of simple and functionalized epoxides.

The PPNCo(CO)(4) and BF(3) x Et(2)O catalyzed carbonylation of simple and functionalized epoxides in DME gives the corresponding beta-lactones regioselectively in good to high yields. The carbonylation occurred selectively at the unsubstituted C-O bond of the epoxide ring, and this reaction tolerates various functional groups such as alkenyl, halide, hydroxy, and alkyl ether.

Remarkable synthesis of 2-(Z)-6-(E)-4H-[1,4]-thiazepin-5-ones by zwitteronic rhodium-catalyzed chemo- and regioselective cyclohyrocarbonylative ring expansion of acetylenic thiazoles.

Cyclohydrocarbonylative ring expansion of acetylenic thiazoles in the presence of CO, H(2), and catalytic quantities of the zwitterionic rhodium complex (eta(6)-C(6)H(5)BPh(3))(-)Rh(+)(1,5-COD) and triphenyl phosphite affords thiazepinones in 61 to 90% yields. This novel transformation of a 5- to a 7-membered heterocycle is readily applied to acetylenic thiazoles containing hydro, alkyl, alkyl halide, vinyl, and benzo substitutents in positions 4 and 5 of the thiazole ring in addition to alkyl-, ether-, ester-, vinyl-, and aryl-substituted alkynes at position 2.

Palladium-catalyzed cyclization reactions of 2-vinylthiiranes with heterocumulenes. Regioselective and enantioselective formation of thiazolidine, oxathiolane, and dithiolane derivatives.

The first palladium-catalyzed ring-expansion reaction of 2-vinylthiiranes with heterocumulenes to form sulfur-containing five-membered-ring heterocycles is described. This regioselective reaction requires 5 mol % of Pd(2)(dba)(3).CHCl(3) and 10 mol % of bidendate phosphine ligand (dppp, BINAP), at 50-80 degrees C, in THF. The reaction of 2-vinylthiiranes with carbodiimides, isocyanates, and ketenimines affords 1,3-thiazolidine derivatives, whereas the reaction with diphenylketene or isothiocyanates results in the formation of 1,3-oxathiolane or 1,3-dithiolane compounds in good to excellent isolated yields and in up to 78% ee.