Naratriptan: biological profile in animal models relevant to migraine

The biological profile of naratriptan (N-methyl-3-(1-methyl-4-piperidinyl)-1H-indole-5-ethane-sulphona-mide), a novel 5HT_1B/1D receptor agonist, was investigated in a variety of experimental models of relevance to migraine. Naratriptan has high affinity for human recombinant 5HT_1B and 5HT_1D receptors (pKi = 8.70.03 and 8.30.1, respectively) and causes contractions of dog isolated basilar and middle cerebral artery (EC₅₀ values of 0.11 and 0.07 M, respectively). Naratriptan causes small contractions of human isolated coronary arteries (EC₅₀ value of 0.17 M; maximum contraction equivalent to 33% of 5HT maximum). In anaesthetized dogs, naratriptan causes selective vasoconstriction of the carotid arterial bed (CD₅₀ dose = 193 g kg⁻¹) and, in anaesthetized rats, naratriptan selectively inhibits neurogenic plasma protein extravasation in the dura (ID₅₀ = 4.1 g kg⁻¹). In a variety of antinociceptive tests, naratriptan has no effect even at high doses. In conscious rats and dogs, naratriptan has high oral bioavailability (71% and 95%, respectively). The data show that naratriptan is a selective agonist at 5HT_1B/1D receptors, with a pharmacological profile very similar to that of sumatriptan, albeit 2-3 fold more potent. These observations, coupled with high oral bioavailability in animals, suggest that naratriptan has the profile of an orally effective anti-migraine drug.     

Symptomatic peripheral arterial disease: the value of a validated questionnaire and a clinical decision rule

BACKGROUND: If a validated questionnaire, when applied to patients reporting with symptoms of intermittent claudication, could adequately discriminate between those with and without peripheral arterial disease, GPs could avoid the diagnostic measurement of the ankle brachial index. AIM: To investigate the Edinburgh Claudication Questionnaire (ECQ) in general practice and to develop a clinical decision rule based on risk factors to enable GPs to easily assess the likelihood of peripheral arterial disease. DESIGN OF STUDY: An observational study. SETTING: General practice in The Netherlands. METHOD: This observational study included patients of > or =55 years visiting their GP for symptoms suggestive of intermittent claudication or with one risk factor. The ECQ and the ankle brachial index were performed. The prevalence of peripheral arterial disease, defined as an ankle brachial index <0.9, was related to risk factors using logistic regression analyses, on which a clinical decision rule was developed and related to the presence of peripheral arterial disease. RESULTS: Of the 4790 included patients visiting their GP with symptoms suggestive of intermittent claudication, 4527 were eligible for analyses. The prevalence of peripheral arterial disease in this group was 48.3%. The sensitivity of the ECQ was only 56.2%. The prevalence of peripheral arterial disease in a clinical decision rule that included age, male sex, smoking, hypertension, hypercholesterolemia, and a positive ECQ, increased from 14% in the lowest to 76% in the highest category. CONCLUSION: This study indicates that the ECQ alone has an inadequate diagnostic value in detecting patients with peripheral arterial disease. The ankle brachial index should be performed to diagnose peripheral arterial disease in patients with complaints suggestive of intermittent claudication, although our clinical decision rule could help to differentiate between extremely high and lower prevalence of peripheral arterial disease.     

Hydrosalpinges adversely affect markers of endometrial receptivity

While in-vitro fertilization (IVF) was initially developed in women with tubal factor infertility, recent clinical studies have suggested that the presence of hydrosalpinges lowers implantation and pregnancy rates. We postulated that these hydrosalpinges cause impaired endometrial receptivity. A total of 103 women with hydrosalpinges were prospectively evaluated, and compared with 55 infertile and 44 fertile controls. All women had endometrial biopsies during the window of implantation, analysed by conventional histological criteria, and also stained for three integrin markers of endometrial receptivity (alpha1beta1, alpha4beta1 and alpha vbeta3). Women with hydrosalpinges (cases) expressed significantly less of the alpha vbeta3 integrin compared with controls. There was no difference in expression of alpha1beta1 or alpha4beta1 among groups. A significantly greater number of cases had out of phase histology and missing alpha vbeta3 (type I defects) and absent integrin expression despite normal histological maturation (type II) defects, compared with controls. Of 20 women with impaired endometrial receptivity who were also biopsied after hydrosalpinx surgery, 70% demonstrated increased alpha vbeta3 expression. Seventy-seven percent of type I and 57% of type II defects were corrected postoperatively. Using markers of endometrial receptivity, this study demonstrates that inflammatory hydrosalpinges have an adverse effect on endometrial receptivity, which in some cases may be overcome by surgical treatment of the hydrosalpinx.      

bcl-2 transgene expression promotes survival and reduces proliferation of CD3-CD4-CD8- T cell progenitors

Proliferative expansion and apoptotic cell death play prominent roles in T cell development. The molecular control of cell cycle progression and apoptosis appear to be inter-connected since the Bcl-2 protein can inhibit apoptosis and slow cell cycle progression in cortical thymocytes and mature T cells, particularly during the transition from the quiescent state into the cell cycle. Here the impact of bcl-2 transgene expression on CD3-CD4-CD8- T cell progenitors was assessed. Bcl-2 enhanced the survival of these progenitors at all of the four major differentiation stages, CD25- CD44+ (pro-T1), CD25 + CD44+ (pro- T2), CD25 + CD44- (pro-T3) and CD25-CD44- (pro-T4). However, it reduced cell cycling and slowed turnover only in the pro-T4 subset. From an analysis of bcl-2 transgenic mice expressing a TCR transgene or bearing a mutation in the scid or rag-1 gene we conclude that Bcl-2 inhibits proliferation only of T cell progenitors that are activated via the pre- TCR, not those stimulated via c-Kit and the IL-7 receptor.      

Microduplication of Xp11.23p11.3 with effects on cognition,behavior, and craniofacial development

El‐Hattab AW, Bournat J, Eng PA, Wu JBS, Walker BA, Stankiewicz P, Cheung SW, Brown CW. Microduplication of Xp11.23p11.3 with effects on cognition, behavior, and craniofacial development. We report an ～1.3 Mb tandem duplication at Xp11.23p11.3 in an 11‐year‐old boy with pleasant personality, hyperactivity, learning and visual‐spatial difficulties, relative microcephaly, long face, stellate iris pattern, and periorbital fullness. This clinical presentation is milder and distinct from that of patients with partially overlapping Xp11.22p11.23 duplications which have been described in males and females with intellectual disability, language delay, autistic behaviors, and seizures. The duplicated region harbors three known X‐linked mental retardation genes: FTSJ1, ZNF81, and SYN1. Quantitative polymerase chain reaction from whole blood total RNA showed increased expression of three genes located in the duplicated region: EBP, WDR13, and ZNF81. Thus, over‐expression of genes in the interval may contribute to the observed phenotype. Many of the features seen in this patient are present in individuals with Williams‐Beuren syndrome (WBS). Interestingly, the SYN1 gene within the duplicated interval, as well as the STX1A gene, within the WBS critical region, co‐localize to presynaptic active zones, and play important roles in neurotransmitter release.     

Geographic distribution of schistosomiasis and soil-transmitted helminths in Western Kenya: implications for anthelminthic mass treatment

A survey of 1,246 children 10-12 years old in 32 primary schools in Kenya near Lake Victoria was conducted to determine prevalence and distribution of schistosome and geohelminth infections. Stool and urine samples were collected and examined for eggs of Schistosoma mansoni, S. haematobium, and intestinal helminths. A questionnaire was used to obtain demographic information and to quantify exposure to surface waters. Houses, schools, and water sources were mapped using a geographic information system. The mean school prevalence of S. mansoni infection was 16.3% (range = 0-80%). Proximity to the lake (r = 0.89, P < 0.001) and contact with lake water were associated with infection, as were specific water-related activities including swimming, fishing, and collecting water. Sixty-three percent of students were infected with one or more other geohelminths and these infections were more homogenously distributed. The separate distributions of schistosome and geohelminth infections have important implications for combined mass-treatment programs.     

既往疾病史和胆道癌关系的全人群病例对照研究

目的　研究分析既往疾病史和胆道癌 (包括胆囊癌、肝外胆管癌和壶腹部癌 )的关系。方法　自 1997年 6月～ 2 0 0 1年 5月 ,在上海市区开展了一项大规模的基于全人群的胆道癌的病例对照研究 ,共收集、调查了 6 6 4例胆道癌新病例和 894例人群对照。结果　研究发现既往有胆囊炎疾病史者患胆囊癌、肝外胆管癌的危险性升高 ,调整的比数比分别为 2 .2 (95 %CI =1.3～ 3.6 )和 1.9(95 %CI=1.0～ 3.3)。糖尿病患者患胆囊癌的危险性增加 ,调整的比数比为 1.5 (95 %CI=0 .9～ 2 .5 ) ,在非胆结石者中调整的比数比为 2 .0 (95 %CI=0 .9～ 4 .5 ) ;此外 ,研究还发现肝硬化者患肝外胆管癌的危险性明显增加 ,调整的比数比为 3.0 (95 %CI=1.0～ 9.1) ,在非胆结石者中调整的比数比为 4 .9(95 %CI=1.2～ 19.8)。结论　该项研究为论证胆囊炎症增加患胆道癌的危险性提供了依据 ,研究还提示糖尿病和肝硬化分别提高患胆囊癌和肝外胆管癌的危险性。     

Whole body protein metabolism in children with cancer

Whole body protein synthesis and catabolism were measured using the [ring-2H5]phenylalanine and [1-13C]leucine primed constant infusion technique in 32 paediatric patients with cancer at different stages of treatment. Rates of synthesis (S) and catabolism (C) derived from the [ring-2H5]phenylalanine and [1-13C]leucine models were 4.7 (SD 1.3) (S) and 6.0 (1.5) (C) g/d/kg, and 5.5 (0.8) (S) and 6.8 (1.2) (C) g/d/kg, respectively. These results show that these two tracer techniques give similar results in this study population. Comparison of these values with results previously reported for groups of control children using the [ring-2H5]phenylalanine model (S = 3.69 and 3.93; C = 4.09 and 4.28 g/d/kg) and the [1-13C]leucine model (S = 4.32; C = 4.85 g/d/kg) show that rates of synthesis and catabolism were higher in cancer patients than in controls. Thus whole body protein turnover is increased in children under treatment for cancer. Other indices of metabolism such as plasma amino acids and intermediary metabolites were also measured and showed that, although subjects were in isotopic steady state, there were significant metabolic changes during the course of the primed constant infusions used to measure protein turnover.     

Creatinine related reference ranges for urinary homovanillic acid and vanillylmandelic acid at 6 months of age

The relationship between homovanillic acid (HVA), vanillylmandelic acid (VMA), and creatinine in the urine of 6 month old babies has been studied and reference ranges in the form of centiles constructed for HVA and VMA against creatinine. Over 10,000 urine samples were collected from babies in four health districts in the north of England. HVA and VMA concentration, either independently or when divided by creatinine concentration, were dependent upon the absolute concentration of creatinine in the sample. After adjustment for creatinine significant differences in the mean concentration of HVA were found between sexes. No such differences were found for VMA. HVA and VMA were also found to be age dependent. Centiles were constructed using a procedure which makes no distributional assumptions about the data. The net effect of utilising these centiles was to increase the predictive value of a positive screening test from 20% to 40% without any increase in the false negative rate.