Effects of growth hormone treatment on thyroid function in pediatric patients with Prader–Willi syndrome

It is unclear whether hypothyroidism is present in patients with Prader–Willi syndrome (PWS). This study aimed to clarify the state of the hypothalamic–pituitary–thyroid axis and the effects of growth hormone (GH) treatment on thyroid function in pediatric patients with PWS. We retrospectively evaluated thyroid function in 51 patients with PWS before GH treatment using a thyroid‐releasing hormone (TRH) stimulation test (29 males and 22 females; median age, 22 months). We also evaluated the effect of GH therapy on thyroid function by comparing serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid stimulating hormone (TSH) levels at baseline, 1 year, and 2 years after GH therapy. TSH, fT4, and fT3 levels were 2.28 μU/ml (interquartile range [IQR]; 1.19–3.61), 1.18 ng/dl (IQR; 1.02–1.24), and 4.02 pg/dl (IQR; 3.54–4.40) at baseline, respectively. In 49 of 51 patients, the TSH response to TRH administration showed a physiologically normal pattern; in two patients (4.0%), the pattern suggested hypothalamic hypothyroidism (delayed and prolonged TSH peak after TRH administration). TSH, fT4, and fT3 levels did not change significantly during 1 or 2 years after GH treatment. The TSH response to TRH showed a normal pattern in most patients, and thyroid function did not change significantly during the 2 years after initiating GH treatment.     

TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection

To investigate the role of the Toll-like receptor (TLR) family in host defense against Toxoplasma gondii, we infected TLR2-, TLR4- and MyD88-deficient mice with the avirulent cyst-forming Fukaya strain of T. gondii. All TLR2- and MyD88-deficient mice died within 8 days, whereas all TLR4-deficient and wild-type mice survived after i.p. infection with a high dose of T. gondii. Peritoneal macrophages from T. gondii-infected TLR2- and MyD88-deficient mice did not produce any detectable levels of NO. T. gondii loads in the brain tissues of TLR2- and MyD88-deficient mice were higher than in those of TLR4-deficient and wild-type mice. Furthermore, high levels of IFN-gamma and IL-12 were produced in peritoneal exudate cells (PEC) of TLR4-deficient and wild-type mice after infection, but low levels of cytokines were produced in PEC of TLR2- and MyD88-deficient mice. On the other hand, high levels of IL-4 and IL-10 were produced in PEC of TLR2- and MyD88-deficient mice after infection, but low levels of cytokines were produced in PEC of TLR4-deficient and wild-type mice. The most remarkable histological changes with infiltration of inflammatory cells were observed in lungs of TLR2-deficient mice infected with T. gondii, where severe interstitial pneumonia occurred and abundant T. gondii were found.     

Genome-wide detection of human copy number variations using high-density DNA oligonucleotide arrays

Recent reports indicate that copy number variations (CNVs) within the human genome contribute to nucleotide diversity to a larger extent than single nucleotide polymorphisms (SNPs). In addition, the contribution of CNVs to human disease susceptibility may be greater than previously expected, although a complete understanding of the phenotypic consequences of CNVs is incomplete. We have recently reported a comprehensive view of CNVs among 270 HapMap samples using high-density SNP genotyping arrays and BAC array CGH. In this report, we describe a novel algorithm using Affymetrix GeneChip Human Mapping 500K Early Access (500K EA) arrays that identified 1203 CNVs ranging in size from 960 bp to 3.4 Mb. The algorithm consists of three steps: (1) Intensity pre-processing to improve the resolution between pairwise comparisons by directly estimating the allele-specific affinity as well as to reduce signal noise by incorporating probe and target sequence characteristics via an improved version of the Genomic Imbalance Map (GIM) algorithm; (2) CNV extraction using an adapted SW-ARRAY procedure to automatically and robustly detect candidate CNV regions; and (3) copy number inference in which all pairwise comparisons are summarized to more precisely define CNV boundaries and accurately estimate CNV copy number. Independent testing of a subset of CNVs by quantitative PCR and mass spectrometry demonstrated a >90% verification rate. The use of high-resolution oligonucleotide arrays relative to other methods may allow more precise boundary information to be extracted, thereby enabling a more accurate analysis of the relationship between CNVs and other genomic features.     

Cilostazol, a phosphodiesterase inhibitor, prevents no-reflow and hemorrhage in mice with focal cerebral ischemia

Background and PurposeThe Cilostazol Stroke Prevention Study II has shown a similar efficacy in stroke prevention but markedly fewer hemorrhagic events with the phosphodiesterase inhibitor cilostazol versus aspirin. The purpose of this study is therefore to investigate how cilostazol affects cerebral hemodynamics and whether it prevents hemorrhagic transformation induced by recombinant tissue plasminogen activator (rtPA) in a mouse model of focal ischemia/reperfusion. Particular emphasis will be placed on the plasma-microvessel interface.MethodsAfter receiving food containing 0.3% cilostazol or standard food for 7 days, adult C57BL/6 J mice were subjected to middle cerebral artery occlusion/reperfusion with or without rtPA (10 mg/kg) intravenously administered prior to reperfusion. Cerebral blood flow was monitored at several time points by laser speckle imaging in the 24 hour period post reperfusion, before neurobehavioral and histological assessment. The long-term effect of cilostazol on cerebral ischemia was analyzed in the non-rtPA cohort.ResultsIn the non-rtPA cohort, pretreatment by cilostazol significantly decreased the endothelial expression of adhesion molecules (P-selectin and intercellular adhesion molecule-1) and prevented platelet aggregation and leukocyte plugging in the microvessels after cerebral ischemia/reperfusion in the acute phase. Cilostazol significantly reduced mortality rate and improved motor function at 7 days post-ischemia/reperfusion. In the rtPA cohort, cilostazol significantly suppressed edema formation and hemorrhagic transformation with reduced density of microglial cells positive for matrix metalloproteinase-9 in the cerebral cortex and the striatum. In both cohorts, cilostazol significantly suppressed focal no-reflow, mitigated cerebral infarct, and improved neurological outcome.ConclusionsCilostazol may possess protective properties against cerebral ischemic injury by preventing no-reflow and hemorrhagic transformation, via maintenance of microvascular integrity.     

Correlates of Mental Health Service Use and Type Among Asian Americans

This study uses data from the National Latino and Asian American Study to investigate correlates of mental health service use among Asian Americans with mental health needs. Our study contributes to the extant literature by: (1) differentiating between mental health service use types; and (2) examining a broader swatch of Asian Americans with mental health needs, ranging from mild to severe cases. Multinomial logistic regression analyses revealed heterogeneity in service use patterns by ethnicity, age, marital status, English proficiency, and generation status. Unmet mental health needs continue to be a problem despite treatments that could improve the quality of life of Asian Americans. Our study provides a more nuanced understanding of mental health service utilization patterns in this understudied population.     

A novel SCN1A mutation in a cytoplasmic loop in intractable juvenile myoclonic epilepsy without febrile seizures

Generalised (genetic) epilepsy with febrile seizures plus (GEFS+) is a familial epilepsy syndrome with various phenotypes. The majority of individuals with GEFS+ have generalised seizure types, in addition to febrile seizures (FS) or febrile seizures plus (FS+), defined as either continued FS after 6 years of age or afebrile seizures following FS. A 27‐year‐old man with no history of FS/FS+ experienced intractable generalised convulsive seizures. The patient's father had a history of similar seizures during puberty and the patient's siblings had only FS. No individual in the family had both generalised seizures and FS/FS+, although GEFS+ might be considered to be present in the family. Analysis of SCN1A, a sodium channel gene, revealed a novel mutation (c.3250A>T [S1084C]) in the cytoplasmic loop 2 of SCN1A in both the patient and his father. Most previously reported SCN1A mutations in GEFS+ patients are located in the conserved homologous domains of SCN1A, whereas mutations in the cytoplasmic loops are very rare. SCN1A gene analysis is not commonly performed in subjects with generalised seizures without FS. SCN1A mutation may be a clinically‐useful genetic marker in order to distinguish GEFS+ patients from those with classic idiopathic generalised epilepsy, even if they present an atypical clinical picture.     

Improved quantification of amyloid burden and associated biomarker cut-off points: results from the first amyloid Singaporean cohort with overlapping cerebrovascular disease

European Journal of Nuclear Medicine and Molecular Imaging - The analysis of the [11C]PiB-PET amyloid images of a unique Asian cohort of 186 participants featuring overlapping vascular diseases...