Transport, enzymatic activity, and stability of mutant sulfamidase (SGSH) identified in patients with mucopolysaccharidosis type III A

Mucopolysaccharidosis type IIIA (MPSIIIA) is an autosomal recessive lysosomal storage disease caused by mutations in the N-sulfoglucosamine sulfohydrolase gene (SGSH; encoding sulfamidase, also sulphamidase) leading to the lysosomal accumulation and urinary excretion of heparan sulfate. Considerable variation in the onset and severity of the clinical phenotype is observed. We report here on expression studies of four novel mutations: c.318C>A (p.Ser106Arg), c.488T>C (p.Leu163Pro), c.571G>A (p.Gly191Arg), and c.1207_1209delTAC (p.Tyr403del), and five previously known mutations: c.220C>T (p.Arg74Cys), c.697C>T (p.Arg233X), c.1297C>T (p.Arg433Trp), c.1026dupC (p.Leu343fsX158), and c.1135delG (p.Val379fsX33) identified in MPSIIIA patients. Transient expression of mutant sulfamidases in BHK or CHO cells revealed that all the mutants were enzymatically inactive with the exception of c.318C>A (p.Ser106Arg), which showed 3.3% activity of the expressed wild-type enzyme. Western blot analysis demonstrated that the amounts of expressed mutant sulfamidases were significantly reduced compared with cells expressing wild type. No polypeptides were immunodetectable in extracts of cells transfected with the cDNA carrying the c.697C>T (p.Arg233X) nonsense mutation. In vitro translation and pulse-chase experiments showed that rapid degradation rather than a decrease in synthesis is responsible for the low, steady-state level of the mutant proteins in cells. The amounts of secreted mutant precursor forms, the cellular stability, the proteolytic processing, and data from double-label immunofluorescence microscopy suggest that the degradation of the majority of newly synthesized c.220C>T (p.Arg74Cys), c.571G>A (p.Gly191Arg), c.1297C>T (p.Arg433Trp), c.1026dupC (p.Leu343fsX158), and c.1135delG (p.Val379fsX33) mutant proteins probably occurs in the ER, whereas c.488T>C (p.Leu163Pro) mutant protein showed instability in the lysosomes.     

Attention during looking and reaching as assessed by heart rate in 7(1/2)-month-old infants

Attention mediates the acquisition and encoding of information about the world and is central to motor action. Heart rate deceleration and behavioral inhibition are sensitive indices of the attentional process, but it is unknown whether these indices are valid in the context of overt action. The current study investigated the relationship between visual attention, action, and heart rate during reaching in 7(1/2)-month-old infants. We found that infants showed prolonged looking and large heart rate decelerations on reaching and looking trials. We conclude that overt action itself does not prevent the autonomic and behavioral changes that are also seen in attention to simple visual displays and that attention is maintained throughout the act of reaching.     

IgA class antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis and autoimmune hepatitis

Antineutrophil cytoplasmic antibodies (ANCA) of IgG class have been described at high prevalence in autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Data on IgA class ANCA in these diseases are limited. The aim of this study was to determine the prevalence and fluorescence patterns of IgA class ANCA in AIH and PSC and to examine a relationship between the presence of IgA ANCA and clinical characteristics in these patients. Sera from 35 patients with PSC (21 with concomitant inflammatory bowel disease), 40 patients with AIH and 10 healthy controls were studied. ANCA were detected on ethanol-fixed neutrophils using an indirect immunofluorescence technique. ANCA of the IgA class were found in 20% of sera from patients with PSC and in 50% of AIH sera. The majority of AIH patients with IgA class ANCA showed a 'classical' perinuclear staining pattern, whereas the 'classical' and 'atypical' perinuclear fluorescence patterns were distributed equally in PSC. In sera containing IgG and IgA class ANCA simultaneously, IgG class ANCA showed an 'atypical' pANCA fluorescence pattern whereas IgA class ANCA produced a 'classical' perinuclear staining. The presence of IgA class ANCA was not associated with disease-specific clinical characteristics. IgA class ANCA are more frequently detected in sera of patients with AIH than PSC. The diversity of fluorescence patterns points to different target antigens of IgA class ANCA with distinct subcellular localizations.     

Genetic susceptibility to gluten sensitive enteropathy in Irish setter dogs is not linked to the major histocompatibility complex

Abstract: Gluten sensitive enteropathy (GSE) in Irish setter dogs has been proposed as an animal model for human celiac disease (CD), in which the major histocompatibility complex (MHC) class II alleles HLA DQAl*0501 and DQBl*0201 play an important role. To investigate whether an orthologous MHC class II region is involved in canine GSE, we undertook a linkage study in two large families of gluten sensitive Irish setter dogs. A total of 44 dogs in these pedigrees were genotyped for DQA1, DQB1 and C.2202 alleles, along with 30 unrelated healthy Irish setters. No genetic linkage between the DQ or C.2002 loci and GSE was detected. In contrast to CD, susceptibility to canine GSE does not appear to be determined by variation within the MHC class II gene cluster. Therefore, canine GSE may not be an appropriate model for CD, but nevertheless remains an important disease for advancing knowledge of pathological processes in the intestine.     

High levels of Lp(a) lipoprotein in a family ith cases of severe pre-eclampsia

We report a family with two cases of severe pre-eclampsia/eclampsia in which very high levels of Lp(a) lipoprotein were found. The serum level of Lp(a) lipoprotein is genetically determined and the Lp(a) apolipoprotein has a close homology to plasminogen. Very high levels of Lp(a) lipoprotein might interfere with the fibrinolytic/thrombolytic process in man. A previous report suggested that a high maternal serum Lp(a) lipoprotein level can cause fetal growth retardation, and it is proposed that very high levels might lead to increased deposition of fibrin in the uterine spiral arteries in pregnancy, which is central in the pathogenesis of pre-eclampsia. If confirmed, a very high Lp(a) lipoprotein level could be one risk factor for pre-eclampsia that is genetically determined.     

TMA与TGA检测对甲状腺疾病的临床诊断价值

根据174例疑诊患者的TMA、TGA，T3，T4放射免疫测定结果及其临床表现进行诊断，结果表明桥本氏甲状腺炎和甲亢所占的比例(分别为38．51％及31．61％）显著高于甲减和亚急性甲状腺炎(分别为6．32％和4．02％)，P＜0．05。甲减患者TGA TMA的阳性率（81．82％)显著高于甲亢(50．91％)，桥本氏甲状腺炎(50．75％)及亚急性甲状腺炎(57．14％)，P＜0．05。单项抗体阳性者以TMA较TGA为多。本文结果提示在甲状腺疾病中TMA，TGA的阳性结果存在相互重叠现象，与T3、T4联检并结合临床表现进行综合分析有助于甲状腺疾病的鉴别诊断并正确指导治疗。     

Are thrombocyte membranes altered in Alzheimer''s disease? A morphometric and biochemical study

Morphometric analysis of thrombocytes from patients with Alzheimer's disease, from patients with multi-infarct dementia, and from young and agematched healthy control donors, did not reveal any Alzheimer-related increase in internal membranes. Biochemical analysis showed a reduced cholesterol content of thrombocyte membrane preparations from Alzheimer patients relative to age-matched controls, but not relative to multi-infarct dementia patients. Overall distribution of protein kinase C activity (PKC) between cytosol and membrane, in resting as well as in activated thrombocytes from Alzheimer patients, was similar to that in the control groups. However, both Alzheimer and multi-infarct dementia patients had lower cytosolic levels of basal kinase and PKC activities than age-matched controls, while only Alzheimer patients had lower cytoskeletal PKC activity than controls.     

α2-巨球蛋白基因I1000V多态性与散发阿尔茨海默氏病的关联研究

目的近年来有研究发现α2-巨球蛋白基因(α2-macroglobulin，A2M)Ile1000Val多态与阿尔茨海默氏病(Alzheimer’s disease，AD)发病有关联，但也有相悖的研究结果报道。因此．我们利用较大的样本，观察了A2M基因Ile1000Val多态在广州及成都地区汉族老年人中的分布，并探讨其与散发AD的相关性。方法以广州地区257例散发AD患者和242名正常老年人、成都地区112例散发AD患者和113名正常老年人为对象进行病例一对照研究。用聚合酶链反应一限制性片段长度多态性方法分析A2M基因11000V多态性和载脂蛋白E基因(apolipoprotelnE，apoE)多态性。结果(1)在两地合并样本中，AD患者与对照组中等位基因A2M-1000V的频率分别为7．7％与8．7％，广州与成都地区AD患者与对照组中A2M基因I1000V多态的分布差异无统计学意义。(2)散发AD无论按是否伴有apoE—ε4或按发病年龄分成不同亚组后，A2M基因I1000V多态的分布在病例组与对照组之间差异无统计学意义。结论广州与成都汉族人群中A2M基因I1000V多态与散发AD不具有关联。     

老年冠心病慢性闭塞病变的介入治疗探讨

目的探讨老年冠心病患者采用经皮冠状动脉介入(PCI)治疗的中短期疗效。方法对102例住院老年患者采用股动脉穿刺后,行球囊扩张,造影显示扩张满意后植入合适支架。术后随访6-32个月。结果102例患者术后临床症状均完全或基本完全缓解。本组患者有19例多支病变患者至少有一支慢性完全闭塞血管经努力而未能开通,无法植入支架。102例患者通过随访6-32个月,其中32例患者接受了冠脉造影复查,有17例患者分别于术后6个月至16个月又出现胸痛、胸闷症状。超声心动图检查射血分数(EF),心功能术后较术前明显改善,P<0.05。结论对冠状动脉慢性完全闭塞的老年患者,无论核素或超声检查是否存在存活心肌,均应尽量进行闭塞病变的介入治疗,以期改善患者的远期预后。     

Interaction of sensory and cognitive processes during visual recognition: The role of the associative areas of the cerebral cortex

The first part of the present study used a model of Alzheimers disease in two groups of animals (three monkeys in each), given injections of neurotoxins (monkeys of group I) and physiological saline (monkeys of group II). Before injections, all monkeys were trained to discriminate stimuli containing different types of information (spatial frequency grids and geometrical figures of different colors and with different spatial relationships between objects) and to perform spatial selection. The dynamics of impairments in the characteristics of working memory were identified using delayed differentiation tasks in monkeys of both groups before injections and every two months after injections. Quantitative measures of impairments were made using the entropy of visual recognition, which characterizes uncertainty in decision-taking. The development of Alzheimers disease in rhesus macaques was characterized by a deficit of working memory, resulting from lesions to the two component processes of memory. Impairments of the first of these in monkeys of group I were manifest as a significant increase in entropy, which is associated with correct decision-taking. The magnitude of the increase depended on the type of visual information. Impairments of the second component were characterized by increases in entropy associated with refusals to take decisions and were independent of the delay duration and the type of visual information. Monkeys given injections of physiological saline showed no significant changes in these characteristics. The features of working memory were also studied in the second part of the investigation, using four groups of Rhesus macaques: intact, those with bilateral extirpation of the sulcus principalis or field 7 or both: degradation again identified two components. Entropy associated with this was increased significantly for most of the stimuli tested on monkeys of all extirpation groups as compared with intact animals. Significant differences were found in these characteristics for a number of stimuli, which depended on the location of the structures removed. The characteristics of impairments of the components of working memory resulting in the development of Alzheimers disease showed that the cholinergic mechanisms responsible for sensory processing differ from those involved in decision-taking. The structural-functional organization of the interaction of sensory and cognitive processes controlled by the motivation and attention systems is discussed, as is the role of the associative areas of the cortex.Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 89, No. 10, pp. 1226–1239, October, 2003.