Finding bald spots on chromosome 20p11

A genome-wide association scan identifies new susceptibility variants for male pattern baldness on chromosome 20p11
Hillmer et al. (2008)
Nature Genetics 40: 1279–1281
Male-pattern baldness susceptibility locus at 20p11
Richards et al. (2008)
Nature Genetics 40: 1282–1284     

Eating Behavior as a Prognostic Factor for Weight Loss after Gastric Bypass

BACKGROUND: Binge-eating disorder (BED) may be associated with unsatisfactory weight loss in obese patients submitted to bariatric procedures. This study aims to investigate whether the presence of binge eating before Roux-en-Y gastric bypass (RYGBP) influences weight outcomes. METHODS: In a prospective design, 216 obese patients (37 males, 178 females, BMI=45.9 +/- 6.0 kg/m2) were assessed for the lifetime prevalence of BED and classified at structured interview into 3 subgroups: no binge eating (NBE=43), sub-threshold binge eating (SBE=129), and binge-eating disorder (BED=44). All patients were encouraged to take part in a multidisciplinary program following surgery, and weight loss at follow-up was used as the outcome variable. RESULTS: At 1-year follow-up, NBE patients (n=41) showed percent excess BMI loss (%EBL) significantly higher than SBE patients (n=112) (P=0.027), although this effect was not significantly different between NBE and BED patients (n=44). At 2-year follow-up, NBE patients (n=33) showed %EBL higher than SBE (n=64) (P=-0.003) and BED patients (n=34) (P<0.001). Nevertheless, we found no significant weight loss differences between SBE (subclinical) and BED (full criteria) patients at any period of follow-up. Preliminary results at 3-year follow-up suggest that such an effect may be enduring. CONCLUSION: The presence of a history of binge eating prior to treatment is associated with poorer weight loss in obese patients submitted to RYGBP. Because BED is highly prevalent in obese patients seeking bariatric surgery, its early recognition and treatment may be of important clinical value.     

Expression of integrins and examination of their adhesive function in normal and leukemic hematopoietic cells

Adhesion of hematopoietic progenitor cells to marrow-derived adherent cells has been noted for erythroid, myeloid, and lymphoid precursors. In this report, we have characterized very late antigen (VLA) integrin expression on normal CD34+ marrow progenitors, on leukemic cell lines, and on blasts from patients with acute myelogenous or monocytic leukemias. CD34+ progenitor cells expressed the integrin beta 1 chain (CD29), VLA-4 alpha (CD49d), and VLA-5 alpha (CD49e). The myeloid lines KG1 and KG1a also expressed CD49d and CD49e as did the Mo7e megakaryoblastic line. CD29, CD18, and CD11a were also present on each of these cell lines. Only the Mo7e line expressed the cytoadhesins GPIIbIIIa or GPIb. Binding of KG1a to marrow stroma was partially inhibited by antibodies to CD49d and its ligand, vascular cell adhesion molecule (VCAM-1). The majority of leukemic blasts studied expressed CD49d and CD49e as well. Blasts from patients with acute myelomonocytic leukemia consistently bound to stroma at levels greater than 20%, and adhesion to stroma could in some cases be partly inhibited by anti- CD49d. No role for glycosylphosphatidyl-inositol (GPI)-linked structures was demonstrated in these binding assays because the adhesion of leukemic blasts to stroma was not diminished after treatment with phosphatidylinositol-specific phospholipase C (PI-PLC). These studies indicate that CD34+ myeloid progenitors, myeloid leukemic cell lines, and leukemic blasts possess a similar array of VLA integrins. Their functional importance individually or in combination with other mediators of attachment in adhesion, transendothelial migration, and differentiation has yet to be fully elucidated.     

4-酰硫基-4-脱氧-4-去甲表鬼臼毒素衍生物的合成和抗肿瘤活性

为研究4’-去甲表鬼臼毒素的C₄位不同原子及不同取代基类型同活性之间的关系,寻找活性高、毒性低的抗肿瘤新药,合成了11个4-酰硫基-4-脱氧-4’-去甲表鬼臼毒素,衍生物并进行了抗肿瘤活性试验。4-巯基-4-脱氧-4’-去甲表鬼臼毒素和不同的羧酸在二乙氧基磷酰氰酯存在下得相应的硫酯。该类化合物在L1210白血病细胞和KB细胞的体外抑制试验中普遍表现出抑制活性。化合物10的活性与依托泊甙相当。其余活性比依托泊甙差。与相应的C₄位酰氨基的4’-去甲表鬼臼毒素衍生物相比,活性明显弱。提示氮取代的衍生物活性更好。     

Heparin-induced thrombocytopenia: studies with a new low molecular weight heparinoid, Org 10172

Studies were performed to determine the cross-reaction rate of the heparin-dependent antibody with Org 10172, a new low molecular weight heparinoid, and to investigate the effect of Org 10172 on platelet activation induced by the antibody. The plasmas of 17 patients with thrombocytopenia induced by standard heparin were shown, by platelet aggregation studies, to contain the heparin-dependent antibody. Of these 17 patient plasmas, only three cross-reacted with the heparinoid, producing a cross-reaction rate of 18%. When Org 10172 was added to a reaction mixture containing normal platelet-rich plasma, patient plasma, and standard heparin with non-cross-reacting plasmas, it inhibited platelet aggregation and thromboxane B2 production induced by the antibody, provided that the ratio of Org 10172 concentration (anti- Xa U/mL) to standard heparin concentration (IU/mL) exceeded 2.5 to 5.0. This inhibitory effect was observed only with platelet activation mediated by the antibody, but not by collagen (2 micrograms/mL) or ADP (5.0 mumol/L). Additionally, three of 17 patients with serious thrombosis, whose plasma showed no cross-reaction with the heparinoid, received Org 10172 treatment with a good response in each case. These findings suggest that Org 10172 may be a useful drug for the treatment of heparin-induced thrombocytopenia.     

Preservation of somatostatin secretion in cystic fibrosis patients with diabetes

Immunohistochemical studies of pancreatic tissue from patients with cystic fibrosis associated with diabetes mellitus (CFDM) show increased numbers of somatostatin secreting delta cells. To look for a possible functional correlate to this finding basal and arginine stimulated plasma somatostatin and serum C peptide concentrations in eight insulin treated patients with cystic fibrosis and eight normal male controls were measured. Mean basal somatostatin concentrations were not different in the two groups. Mean peak somatostatin concentrations were significantly higher in the group with CFDM: 11.60 pmol/l v 7.14 pmol/l in controls. Mean peak C peptide concentrations were significantly lower in the group with cystic fibrosis: 0.89 nmol/l v 4.27 nmol/l in controls. This observation provides a physiological correlate to the pathological finding of increased somatostatin content in pancreatic tissue from patients with CFDM. Selective preservation of somatostatin secretion in patients with cystic fibrosis may further complicate pancreatic endocrine insufficiencies through paracrine inhibition of insulin and glucagon secretion.     

Low O6-alkylguanine DNA-alkyltransferase activity in normal colorectal tissue is associated with colorectal tumours containing a GC-->AT transition in the K-ras oncogene

O6-alkylguanine DNA-alkyltransferase (ATase) provides protection against the toxic, mutagenic and carcinogenic effects of alkylating agents, principally by removing the promutagenic lesion O6-alkylguanine from DNA. Differences in ATase activity in human tissue may thus determine mutational susceptibility. As GC-->AT transitions, which can be induced by O6-alkylguanine in DNA, are commonly observed in the K- ras oncogene of alkylating agent induced animal tumours and in human colorectal tumours, we have examined whether differences in ATase activity may affect the risk of K-ras mutations in humans with colorectal tumours. NTase activity in normal tissue from individuals with a K-ras mutation in colorectal tissue and more specifically a GC-- >AT transition (but not a transversion mutation) was significantly lower than that in individuals without a mutation (P < 0.01). Thus, individuals with low ATase activity in normal tissue (i.e. below the median) were at increased risk of having a transition (OR 10.1; 95% CI 1.9-99.0), but not a transversion mutation (OR 1.7; 95% CI 0.3-12.2). There were no significant differences in tumour ATase activity in individuals with or without a mutation. These results suggest that ATase can protect colorectal tissue against the mutagenic effects of alkylating agents and furthermore, that alkylating agent exposure plays a role in the aetiology of colorectal tumours containing a GC-->AT transition in the K-ras oncogene.      

Lack of PPCA expression only partially coincides with lysosomal storage in galactosialidosis mice: indirect evidence for spatial requirement of the catalytic rather than the protective function of PPCA

Protective protein/cathepsin A (PPCA) is a pleiotropic lysosomal enzyme that complexes with beta-galactosidase and neuraminidase, and possesses serine carboxypeptidase activity. Its deficiency in man results in the neurodegenerative lysosomal storage disorder galactosialidosis (GS). The mouse model of this disease resembles the human early onset phenotype and results in severe nephropathy and ataxia. To understand better the pathophysiology of the disease, we compared the occurrence of lysosomal PPCA mRNA and protein in normal adult mouse tissues with the incidence of lysosomal storage in PPCA(-/-) mice. PPCA expression was markedly variable among different tissues. Most sites that produced both mRNA and protein at high levels in normal mice showed extensive and overt storage in the knockout mice. However, this correlation was not consistent as some cells that normally expressed high levels of PPCA were unaffected in their storage capability in the PPCA(-/-) mice. In addition, some normally low expressing cells accumulated large amounts of undegraded products in the GS mouse. This apparent discrepancy may reflect a requirement for the catalytic rather than the protective function of PPCA and/or the presence of cell-specific substrates in certain cell types. A detailed map showing the cellular distribution of PPCA in nomal mouse tissues as well as the sites of lysosomal storage in deficient mice is critical for accurate assessment of the effects of therapeutic interventions.      

精液叶酸、维生素B_(12)、活性氧水平与精子质量关系研究

目的 :　检测人精液叶酸、维生素 B12 ( VB12 ) ,及活性氧 ( ROS)的含量 ,探讨三者与精子质量的关系。方法 :　收集经证实配偶已怀孕的新加坡籍健康成年男性 1 76名的精液 ,根据WHO推荐方法检测精子质量各项指标 ,并测定精液叶酸和 VB12 含量及 ROS水平。结果 :　平均精液量、精子浓度和其活力都在正常范围内。而精子存活率 ( 73.0 6% )略低于 WHO标准 (≥ 75% ) ,形态异常的精子 ( 77.0 6% )高于 WHO标准 ( 70 % )。精液的叶酸含量与 ROS水平呈显著负相关 ( r=- 0 .2 5,P=0 .0 0 3) ;VB12 与 ROS呈负相关 ( r=- 0 .2 5,P=0 .0 0 2 ) ,与精子形态异常也呈负相关( r=- 0 .1 5,P=0 .0 4 8) ,但与精子浓度呈正相关 ( r=0 .31 ,P<0 .0 0 1 )。ROS与精子形态异常呈正相关 ( r=0 .2 5,P=0 .0 0 2 ) ,与精子活力也呈正相关 ( r=0 .1 9,P=0 .0 1 9)。结论 :　 VB12 对精子生成和维持精子正常功能是必需的 ,ROS水平与精子功能缺陷有关 ,VB12 和叶酸可能通过降低 ROS以维持精子的正常功能。