Tau protein induces bundling of microtubules in vitro: comparison of different tau isoforms and a tau protein fragment.

Expression of tau protein in non-neuronal cells can result in a redistribution of the microtubule cytoskeleton into thick bundles of tau-containing microtubules (Lewis et al.: Nature 342:498-505, 1989; Kanai et al.: J Cell Biol 109:1173-1184, 1989). We reconstituted microtubule bundles using purified tubulin and tau in order to study the assembly of these structures. Taxol-stabilized tubulin polymers were incubated with various concentrations of recombinant human tau and examined by electron microscopy. With increasing concentrations of tau 3 (tau isoform containing three microtubule binding domains) or tau 4 (isoform containing four microtubule binding domains) the microtubules changed orientation from a random distribution to loosely and tightly packed parallel arrays and then to thick cables. In contrast, tau 4L, the tau isoform containing four microtubule binding domains plus a 58-amino acid insert near the N-terminus, showed minimal bundling activity. tau 4-induced bundling could be inhibited by the addition of 0.5 M NaCl or 0.4 mM estramustine phosphate, conditions which are known to inhibit tau binding to microtubules. A tau construct that contained only the microtubule binding domains plus 19 amino acids to the C-terminus was fully capable of bundling microtubules. Phosphorylation of tau 3 with cAMP-dependent protein kinase had no effect on its ability to induce microtubule bundling. These results indicate that tau protein is directly capable of bundling microtubules in vitro, and suggests that different tau isoforms differ in their ability to bundle microtubule filaments.     

The Lewis blood group--a new genetic marker of ischaemic heart disease.

In a cohort of 3383 men aged 53 to 74 in the Copenhagen Male Study we investigated the association between ischaemic heart disease (IHD) and the Lewis blood group, assigned to chromosome 19. Among men with the Le(a-b-) phenotype, 8% had a history of non-fatal myocardial infarction, among others the frequency was 4%. The corresponding odds ratio was (95% confidence interval: CI) 1.9 (1.2-3.0) P < 0.01, men with Le(a-b-) had a risk-factor profile and pattern of disease resembling that of Reaven's syndrome X. In a subsequent prospective study 343 men with arteriosclerotic stigmas were excluded. The men had their morbidity and mortality recorded over the next 4 years. One-hundred-and-one men suffered IHD; 26 dying from IHD. In total 162 men died. Men with Le(a-b-) had an increased risk of death from IHD compared with others. Adjusted for age, relative risk (RR) (95% CI) was: 4.4 (1.9-10.3), P < 0.001, and for all causes of mortality: RR = 1.6 (1.0-2.6), P < 0.05. Men with the Le(a-b-) phenotype had an increased risk of an IHD event compared to men with other phenotypes (RR = 1.6 (0.9-2.8), P = 0.10) and a significantly higher IHD case fatality rate (RR = 2.8 (1.5-5.2), P = 0.01). The finding that the Le(a-b-) phenotype is a genetic marker of IHD risk may have implications in terms of prevention. The Le(a-b-) phenotype may also contribute to providing an explanation for the substantial ethnic differences found in the incidence of IHD. The similar risk-factor profile and pattern of disease found between Le(a-b-) men and individuals with Reaven's syndrome X is hypothesized to be due to a close genetic relationship on chromosome 19.     

Viridans group streptococci: a reservoir of resistant bacteria in oral cavities

The worldwide spread of erythromycin A-resistant streptococci, including Streptococcus pneumoniae , is of concern. Many studies have demonstrated that the viridans group streptococci can be a reservoir of erythromycin A resistance. Within oral streptoccoci, an important difference in the susceptibility pattern has been noted. The purpose of this short editorial is to highlight the importance of this group of bacteria as a reservoir of resistance to erythromycin A and the possible transfer of resistance to S. pneumoniae and S. pyogenes.     

Solid-phase synthesis of oxytocin using iodotrichlorosilane as Boc deprotecting agent

Deprotection of the tert-butoxycarbonyl group during solid-phase synthesis of peptides can be conveniently and efficiently carried out using a neutral reagent, silicon tetrachloride/sodium iodide (iodotrichlorosilane). This simple and rapid method has been advantageously employed during the solid-phase synthesis of the pituitary hormone, oxytocin.     

Effect of dialysis flux and membrane material on dyslipidaemia and inflammation in haemodialysis patients.

BACKGROUND: Dyslipidaemia, inflammation and oxidative stress are prominent risk factors that potentially cause vascular disease in haemodialysis patients. Dialysis modalities affect uraemic dyslipidaemia, possibly by modifying oxidative stress, but the effects of dialyser flux and membrane material on atherogenic remnant particles and oxidized low-density lipoproteins (LDL) are unknown. METHODS: We performed a randomized crossover study in 36 patients on haemodialysis to analyse the effect of dialyser flux and membrane material on plasma lipids, apolipoproteins and markers of inflammation and oxidative stress. Stable patients on low-flux dialysis with polysulphone for >/=6 weeks were assigned to high-flux polysulphone or high-flux modified cellulose with similar dialyser surface area and permeability characteristics and crossed over twice every 6 weeks. RESULTS: Thirty patients completed the study per protocol. Treatments with high-flux polysulphone and modified cellulose lowered serum triglyceride (by 20% and 10%, respectively; P<0.05) and remnant-like particle cholesterol by 32% (P<0.001) and 11% (NS) after the first 6 weeks of treatment. Oxidized LDL decreased significantly with high-flux polysulphone, but not with modified cellulose. Apolipoproteins CII and CIII were reduced, whereas the ratio CII/CIII was increased (all P<0.05). Acute-phase proteins and LDL and high-density lipoprotein cholesterol remained unaffected. CONCLUSIONS: This randomized crossover study demonstrates a potent effect of high-flux haemodialysis on uraemic dyslipidaemia. Polysulphone membrane material showed superiority on oxidatively modified LDL, an indicator of oxidative stress in haemodialysis patients.     

Postgraduate qualifications of British doctors

Among British-qualified doctors of 1974 and 1977, about 80% held postgraduate qualifications of some kind. The commonest qualifications were DRCOG, MRCP and MRCOG. There were considerable differences between medical schools in the numbers of qualifiers taking various examinations. Apart from the MRC Psych, DRCOG and Family Planning Certificate, qualifications were more commonly held by men than women. Tables show the type of work being done 9-13 years after leaving medical school by holders of various postgraduate qualifications; e.g. 60% of MRCP holders were working in medicine or a medical specialty and 84% of FRCS holders in general surgery or a surgical specialty. Discussion deals with the plurality, specificity, variability, perceived necessity, sufficiency, international utility and career significance of British postgraduate qualifications.     

Conditional estimation of sensitivity and specificity from a phase 2 biomarker study allowing early termination for futility

Development of a disease screening biomarker involves several phases. In phase 2 its sensitivity and specificity is compared with established thresholds for minimally acceptable performance. Since we anticipate that most candidate markers will not prove to be useful and availability of specimens and funding is limited, early termination of a study is appropriate, if accumulating data indicate that the marker is inadequate. Yet, for markers that complete phase 2, we seek estimates of sensitivity and specificity to proceed with the design of subsequent phase 3 studies. We suggest early stopping criteria and estimation procedures that adjust for bias caused by the early termination option. An important aspect of our approach is to focus on properties of estimates conditional on reaching full study enrollment. We propose the conditional‐UMVUE and contrast it with other estimates, including naïve estimators, the well‐studied unconditional‐UMVUE and the mean and median Whitehead‐adjusted estimators. The conditional‐UMVUE appears to be a very good choice. Copyright © 2008 John Wiley & Sons, Ltd.     

胰岛素样生长因子1对新生大鼠缺氧缺血性脑损伤保护机制的研究

目的　建立单侧缺氧缺血性脑损伤 (HIBD)动物模型 ,研究胰岛素样生长因子 1(IGF 1)对HIBD的影响和可能机制。　方法　选择健康 7日龄Wistar大鼠 12 0只 ,建立HIBD模型 ,随机分成假手术组、HIBD组、HIBD后 0 .2mg/kg人基因重组IGF 1干预组 (RH IGF 1组 )、0 .0 6 6mg/kg人基因重组IGF 1干预组 (SRH IGF 1组 )及盐水对照组 (对照组 )。各组按观察时段进一步分为 2 4、4 8、72h组 ,每组 8只。各组于规定时刻观测脑形态学改变、谷氨酸 (Glu)含量、凋亡细胞计数、Bcl 2蛋白表达。　结果　 (1)HIBD 4 8h组Glu(116 2 .2± 10 8.1)mg/kg ,较假手术组(75 0 .9± 5 3.4 )mg/kg明显升高 (P <0 .0 5 ) ;HIBD组凋亡细胞计数 [2 4h :(7.6± 1.9) % ,4 8h(12 .6±1.2 ) % ,72h :(13.8± 0 .9) % ],较假手术组 [2 4h(2 .0± 0 .2 ) % ,4 8h(2 .0± 0 .3) % ,72h(2 .0±0 .2 ) % ]明显增加 (P均 <0 .0 5 )。 (2 )与对照组相比 ,RH IGF 1组脑组织病变减轻 ;干预 4 8h组Glu[SRH IGF 1组 (781.4± 5 4 .2 )mg/kg ,RH IGF 1组 (74 0 .5± 4 6 .6 )mg/kg],较对照组 (112 6 .6± 4 8.0 )mg/kg明显降低 (P均 <0 .0 5 ) ;RH IGF 1组凋亡细胞计数 [2 4h :(3.6± 0 .9) % ,4 8h(8.2± 2 .2 ) % ,72h(9.4± 1.4 ) % ],较对     

Effects of self-management training in Type 2 diabetes: a randomized, prospective trial.

AIMS: The efficacy of three education programmes for Type 2 diabetic patients was tested in a randomized trial. A didactic-oriented training programme (treatment A) was compared with a self-management-oriented programme delivered in group sessions (treatment B). The latter programme was compared with a more individualized approach (treatment C). METHODS: One hundred and eighty-one Type 2 diabetic patients (age 55.6 +/- 6.3 years, diabetes duration 6.6 +/- 6.2 years, HbA(1c) 7.8 +/- 1.6%, female 49.7%) took part. Efficacy was assessed 3 months (t1) after baseline (t0) and at a follow-up 15 months (t2) after baseline. RESULTS: The fall in HbA(1c) in treatment B at t1 was sustained at t2 (t0 8.1 +/- 1.8%, t1 7.3 +/- 1.7%, t2 7.4 +/- 1.9%). In treatment A, HbA(1c) was unchanged throughout (t0 7.6 +/- 1.5%, t1 7.5 +/- 1.3%, t2 7.7 +/- 1.7%; treatment A vs. treatment B; P < 0.05). With the more individualized approach of treatment C, there was a fall in HbA(1c) at t1, but this was not sustained at t2 (t0 7.8 +/- 1.6%, t1 7.1 +/- 1.3%, t2 7.6 +/- 1.6%; treatment B vs. treatment C; P = 0.73). There were also significant benefits in treatment B subjects compared with treatment A in further medical (body mass index and fasting blood glucose), psychological (control, irritability and hunger dependency of eating behaviour, and trait anxiety) and behavioural (exercise) variables. There were no significant benefits of the more individualized treatment C compared with group treatment B. No significant differences were found regarding triglyceride levels, high-density lipoprotein, diabetes-related knowledge, negative well-being, urine or blood glucose levels or foot care. CONCLUSION: Self-management training had a significantly higher medium-term efficacy than didactic diabetes education. The group sessions were more effective than a more individualized approach.