Loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1) cause a novel,X-linked syndrome of central hypothyroidism and testicular enlargement

BackgroundCongenital central hypothyroidism occurs either as isolated thyroid-stimulating hormone (TSH) deficiency or in conjunction with other pituitary hormone deficits. Undetected central hypothyroidism is associated with developmental delay in children and adverse cardiometabolic sequelae in adults. Hitherto, mutations in the thyrotropin-releasing hormone receptor gene (TRHR) or the TSHb subunit gene (TSHB) are the only known causes of isolated TSH deficiency.MethodsUsing whole exome and candidate gene sequencing, we have studied 11 unrelated families with males exhibiting isolated TSH deficiency, testicular enlargement, and variably low serum prolactin levels.FindingsWe have identified eight distinct mutations and two whole gene deletions disrupting the X-linked immunoglobulin superfamily member 1 gene (IGSF1) in affected males. IGSF1 encodes a pituitary-enriched plasma membrane glycoprotein; disease-associated mutations block trafficking of IGSF1 from the endoplasmic reticulum to the membrane, consistent with loss-of-protein function. Adult male IGSF1 null mice exhibit central hypothyroidism with decreased pituitary TSH content and circulating T3 levels; TSH secretion in response to TRH is blunted and pituitary TRHR mRNA levels are decreased, suggesting that impaired TRH signalling may provide the basis for hypothyroidism.InterpretationOur observations delineate a novel X-linked syndrome in which loss-of-function mutations in IGSF1 cause central hypothyroidism, testicular enlargement, and variable prolactin deficiency, and identify a previously unsuspected role for IGSF1 in hypothalamic-pituitary control of thyroid and testicular function. Variable biochemical penetrance in these families highlights the importance of genetic ascertainment in this syndrome, so that asymptomatic affected individuals can benefit from early initiation of thyroxine treatment.FundingWellcome Trust and National Institute for Health Research Biomedical Research Centre.     

Fourier phase analysis of SPECT equilibrium radionuclide angiography in symptomatic patients with mitral valve prolapse without significant mitral regurgitation: Assessment of biventricular functional abnormalities suggesting a cardiomyopathy

BACKGROUND: Ventricular premature beats are common in patients with mitral valve prolapse (MVP). The purpose of this study was to determine whether symptomatic patients with MVP had certain functional characteristics and if ventricular arrhythmia (VA) could be explained by functional extravalvular abnormalities. Single photon emission computed tomography equilibrium radionuclide angiography with Fourier phase analysis was preferred to the planar radionuclide method. Only patients without significant mitral regurgitation were studied. METHODS AND RESULTS: A total of 23 symptomatic patients with MVP (13 men, 10 women, mean age, 47+/-14 years) without mitral regurgitation underwent single photon emission computed tomography equilibrium radionuclide angiography. Symptoms were present in 20 patients, and VA was present in 14 patients. Ejection fraction, regional wall motion, and Fourier phase analysis were examined in both ventricles and compared with results for normal subjects. Ventricular abnormalities were observed in 20 (87%) patients: decreased left ventricular and right ventricular ejection fractions, increased standard deviations of the mean phase and focal wall motion, and/or delayed phase abnormalities. Abnormalities were less frequent but more marked in the right ventricular free wall, the infundibulum, or the septum compared with left ventricular delayed abnormalities, which were more frequent but limited. In 12 of 14 patients with VA, phase-delayed areas were observed in the ventricle where the origin of ventricular premature beats was suspected on the basis of their electrocardiographic morphologic features. A relation was found between late potentials and delayed-phase areas (right ventricle or septum) and left bundle branch block morphologic features of VA. CONCLUSIONS: Symptomatic patients with MVP frequently have ventricular dysfunction in 1 or both ventricles, sometimes limited but more marked in the presence of severe VA even without significant mitral regurgitation, suggesting structural modification. The use of a sensitive, accurate, and 3-dimensional method such as single photon emission computed tomography equilibrium radionuclide angiography may be of interest for a noninvasive investigation, especially in young symptomatic patients with MVP and VA.     

Induction of bone formation in biphasic calcium phosphate scaffolds by bone morphogenetic protein‐2 and primary osteoblasts

Bone tissue engineering strategies mainly depend on porous scaffold materials. In this study, novel biphasic calcium phosphate (BCP) matrices were generated by 3D‐printing. High porosity was achieved by starch consolidation. This study aimed to characterise the porous BCP‐scaffold properties and interactions of osteogenic cells and growth factors under in vivo conditions. Five differently treated constructs were implanted subcutaneously in syngeneic rats: plain BCP constructs (group A), constructs pre‐treated with BMP‐2 (group B; 1.6 µg BMP‐2 per scaffold), seeded with primary osteoblasts (OB) (group C), seeded with OB and BMP‐2 (group D) and constructs seeded with OB and pre‐cultivated in a flow bioreactor for 6 weeks (group E). After 2, 4 and 6 weeks, specimens were explanted and subjected to histological and molecular biological analyses. Explanted scaffolds were invaded by fibrovascular tissue without significant foreign body reactions. Morphometric analysis demonstrated significantly increased bone formation in samples from group D (OB + BMP‐2) compared to all other groups. Samples from groups B‐E displayed significant mRNA expression of bone‐specific genes after 6 weeks. Pre‐cultivation in the flow bioreactor (group E) induced bone formation comparable with group B. In this study, differences in bone distribution between samples with BMP‐2 or osteoblasts could be observed. In conclusion, combination of osteoblasts and BMP‐2 synergistically enhanced bone formation in novel ceramic scaffolds. These results provide the basis for further experiments in orthotopic defect models with a focus on future applications in orthopaedic and reconstructive surgery. Copyright © 2012 John Wiley & Sons, Ltd.     

放射疗法在经典型皮肤卡勃基氏肉瘤治疗中的应用

目的探讨放射疗法在经典型皮肤卡勃基氏肉瘤（Ｋａｐｏｓｉｓｓａｒｃｏｍａ,ＫＳ）这种罕见肿瘤治疗中的有效性。方法１９８６年６月～１９９６年１２月,法国巴黎第十二大学亨利·孟德尔医院肿瘤科共收治经典型皮肤ＫＳ５例。所有病人均接受４５～７０ＫＶＸ线局部放射治疗,共设４８个照射野,剂量均＜３０Ｇｙ。放疗方式为：第１周１０Ｇｙ,２．５Ｇｙ／次×４,休息１０～１５天后再行第２阶段放疗,追加剂量１５～２０Ｇｙ。结果完全缓解率１００％。皮肤对放射的耐受良好,不影响美观。２例出现射野外新病灶,其中１例行放疗而另１例行长春花碱治疗,均完全缓解。结论放射疗法对ＫＳ可以提供有效的局部控制率并保持皮肤的完整美观,剂量２０～３０Ｇｙ足以使经典型皮肤ＫＳ完全缓解。     

腺病毒介导RA538及反义c-myc在不同细胞系中作用及其机制

目的比较重组RA538,反义c-myc及LacZ腺病毒(adenovirus,AV)对不同靶细胞的转染效率、生物学特性并探讨其作用的分子机制.方法以人胃癌细胞(SGC7901)、食管癌细胞(EC109)及人胚肺二倍体细胞(2BS)系为靶细胞,采用LacZ基因转染X-gal染色、形态学观察、MTT,RT-PCR等方法,研究重组RA538,反义c-myc及LacZ AV对上述细胞的转染效率,生物学作用及其分子机制.结果 AV-LacZ进行重组腺病毒转导效率检测显示其对SGC7901,2BS细胞具有很高的转导效率,对EC109细胞转导效率较低.AV-RA538及AV-ASc-myc对SGC7901细胞能产生明显的生长抑制效应并诱导凋亡,其生长抑制率分别为76.3%和44.1%.AV-RA538及AV-ASc-myc对SGC7901细胞内源性c-myc,bcl-2基因的表达具有抑制作用.AV-RA538及AV-ASc-myc对EC109细胞及2BS细胞无明显的生长抑制及凋亡诱导作用,AV-RA538对EC109及2BS细胞中内源性c-myc,bcl-2基因的表达无调节作用.结论 AV载体转导效率很高,能实现目的基因在转导细胞中的高水平表达,但对不同靶细胞的转染效率存在差别.AV-RA538,AV-ASc-myc对SGC7901的生长抑制及凋亡诱导作用可能是通过AV的高效转导及抑制c-myc,bcl-2的表达而实现的.AV-RA538,AV-ASc-myc对食管癌、2BS细胞系无类似作用可能与其对上述细胞的转导的作用及内源性基因表达的作用有关.