水通道：从原子结构到临床医学

阿格雷（Peter Agre）博士，美国杜克大学医学院细胞生物学系教授，约翰斯霍普金斯大学医学院生物化学系客座教授。阿格雷教授其研究成果在于分离出了长期以来所搜寻的特定输送水分子的通道。这一发现开启了针对细菌、植物和哺乳动物水通道的系列生化、生理和遗传研究之门，从而使得研究人员可以仔细跟踪水分子通过细胞膜的过程，并了解为何只有水分子而不是其他小分子能够通过细胞膜，阿格雷博士也因此获得了2003年诺贝尔化学奖。     

BCR-ABL activity and its response to drugs can be determined in CD34+ CML stem cells by CrkL phosphorylation status using flow cytometry.

In chronic myeloid leukaemia, CD34(+) stem/progenitor cells appear resistant to imatinib mesylate (IM) in vitro and in vivo. To investigate the underlying mechanism(s) of IM resistance, it is essential to quantify Bcr-Abl kinase status at the stem cell level. We developed a flow cytometry method to measure CrkL phosphorylation (P-CrkL) in samples with <10(4) cells. The method was first validated in wild-type (K562) and mutant (BAF3) BCR-ABL(+) as well as BCR-ABL(-) (HL60) cell lines. In response to increasing IM concentration, there was a linear reduction in P-CrkL, which was Bcr-Abl specific and correlated with known resistance. The results were comparable to those from Western blotting. The method also proved to be reproducible with small samples of normal and Ph(+) CD34(+) cells and was able to discriminate between Ph(-), sensitive and resistant Ph(+) cells. This assay should now enable investigators to unravel the mechanism(s) of IM resistance in stem cells.     

Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction.

Pre-eclamptic toxaemia (PET) may be associated with both endothelial dysfunction (ED) and sleep-disordered breathing (SDB). It was hypothesised that females with PET would demonstrate both SDB and ED, and that a correlation between these two would suggest a potential causative association. A total of 17 females with PET and 25 matched females with uncomplicated pregnancy were studied. They underwent a nocturnal ambulatory sleep study (using Watch_PAT100) and noninvasive evaluation of endothelial function utilising the reactive hyperaemia test (using Endo_PAT 2000). A higher ratio of post- to pre-occlusion pulse-wave amplitude (endothelial function index (EFI)) indicated better endothelial function. Females with PET had a significantly higher respiratory disturbance index (RDI) and lower EFI than controls (18.4+/-8.4 versus 8.3+/-1.3.h(-1), and 1.5+/-0.1 versus 1.8+/-0.1, respectively). Blood pressure significantly correlated with RDI and with EFI. EFI tended to correlate with RDI. In conclusion, these results suggest that both sleep-disordered breathing and endothelial dysfunction are more likely to occur in females with pre-eclamptic toxaemia than in females with uncomplicated pregnancies. The current authors speculate that respiratory disturbances contribute to the functional abnormality of the blood vessels seen in females with pre-eclamptic toxaemia, although causality cannot be determined based on this study.     

Computed tomography and pulmonary function abnormalities in sickle cell disease.

The aim of this study was to determine whether patients with sickle cell disease (SCD) in steady state had pulmonary abnormalities seen on high-resolution computed tomography (HRCT) and whether any abnormalities correlated with contemporaneously diagnosed lung function abnormalities. A subsidiary question was whether the results of a noninvasive measure of haemolysis (end-tidal carbon monoxide (ETCO) levels) correlated with pulmonary function abnormalities. Thirty three patients with SCD, median (range) age 36 yrs (17-67 yrs) were examined. The degree of lobar volume loss and ground-glass opacification and prominence of central vessels on HRCT were quantitatively assessed. Pulmonary function was assessed by measurements of lung volumes, spirometry, gas transfer and oxygen saturation. ETCO levels were measured using an end-tidal CO monitor. Forced expiratory volume in one second (FEV1), forced vital capacity and total lung capacity significantly correlated with HRCT findings, particularly lobar volume loss. ETCO levels significantly negatively correlated with FEV1, vital capacity measured using a plethysmograph, specific airway conductance and arterial oxygen saturation measured by pulse oxymetry. In conclusion, the present results suggest that high-resolution computed tomography noninvasive assessment of haemolysis might be useful to identify sickle cell disease patients with respiratory function impairment.     

心理群体干预对缓解体外受精妇女焦虑作用的随机对照研究

目的：评价东部身体-智力-精神（EBMS）群体干预对进行体外受精（IVF）的中国妇女焦虑缓解的作用。设计：随机对照研究。机构：三级辅助生殖机构。受试者：227例接受第1个IVF周期治疗的妇女。干预：干预组（n=69）接受4次EBMS群体咨询，而对照组（n=115）无任何干预。主要观察指标：状态-特质焦虑问卷。结果：与对照组相比，干预组在干预后状态焦虑平均分显著下降。每组移植同样数目的卵子，但干预组没有明显更高妊娠率的倾向。     

The Impact of Community Diversity and Consolidated Inequality on Dropping Out of High School

Abstract: Data from the National Education Longitudinal Study were combined with census data at the zip code level to examine the impact of neighborhood racial and ethnic diversity and consolidated inequality, in addition to individual, family, and school factors, on the likelihood of dropping out of high school. Results indicate that while the effects for diversity and consolidated inequality did not support the stated hypotheses, main effects for family risk and prior academic achievement were significant and in the stated direction. Also, when controlling for individual, family, school, and neighborhood characteristics, African Americans were less likely than White students to drop out of school. Implications for contextual effects research and educational outcomes are discussed.     

A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease,seizures and cotton wool plaques,but not spastic paraparesis

Over 100 mutations in the presenilin‐1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. Aβ was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family.     

A profile of invasive cutaneous malignant melanoma in Malta: 1993–2002

BACKGROUND: The incidence of malignant melanoma of the skin has risen in every part of the world where reliable cancer registration data are found. OBJECTIVE: Our study aims to describe the changing incidence of and survival from invasive cutaneous malignant melanoma in Malta, by analysing the data from the 211 cases that were registered at the Malta National Cancer Registry between 1993 and 2002. RESULTS: The age standardized incidence rates for invasive cutaneous malignant melanoma rose from 3.7 per 100,000 population per year for males and 5.1 for females in the first 5-year period, to 8.0 per 100,000 population per year for males and 5.9 for females in the second 5-year period. In both sexes, numbers of thin (< or = 1.0 mm) invasive melanomas increased significantly between 1993 and 2002; males also registered a significant increase in intermediate-thickness (1.01-4.0 mm) melanomas. The increase in numbers of thin and intermediate-thickness melanomas between the two 5-year periods was greatest in patients aged 60 years and over. The overall absolute 5-year survival rate for the first period was 74% and for the second period 92%. CONCLUSION: Numbers of reported cases of invasive cutaneous malignant melanoma in Malta have more than doubled during the 10-year study period. This is mostly due to a marked rise in the diagnosis of thin melanomas in both sexes, occurring mainly in patients aged 60 years and over. As thin melanomas are of low metastasizing potential, this has resulted in an increase in survival between the two 5-year study periods.     

PET imaging of the dopamine transporter with 18F-FECNT: a polar radiometabolite confounds brain radioligand measurements.

18F-2beta-Carbomethoxy-3beta-(4-chlorophenyl)-8-(2-fluoroethyl)nortropane (18F-FECNT), a PET radioligand for the dopamine transporter (DAT), generates a radiometabolite that enters the rat brain. The aims of this study were to characterize this radiometabolite and to determine whether a similar phenomenon occurs in human and nonhuman primate brains by examining the stability of the apparent distribution volume in DAT-rich (striatum) and DAT-poor (cerebellum) regions of the brain. METHODS: Two rats were infused with 18F-FECNT and sacrificed at 60 min. Extracts of brain and plasma were analyzed by high-performance liquid chromatography (HPLC) and liquid chromatography-mass spectrometric (LC-MS) techniques. Two human participants and 3 rhesus monkeys were injected with 18F-FECNT and scanned kinetically, with serial arterial blood analysis. RESULTS: At 60 min after the injection of rats, 18F-FECNT accumulated to levels about 7 times higher in the striatum than in the cortex and cerebellum. The radiometabolite was distributed at equal concentrations in all brain regions. The LC-MS techniques identified N-dealkylated FECNT as a major metabolite in the rat brain, and reverse-phase HPLC detected an equivalent amount of radiometabolite eluting with the void volume. The radiometabolite likely was 18F-fluoroacetaldehyde, the product expected from the N-dealkylation of 18F-FECNT, or its oxidation product, 18F-fluoroacetic acid. The distribution volume in the cerebellum increased up to 1.7-fold in humans between 60 and 300 min after injection and 2.0 +/- 0.1-fold (mean +/- SD; n = 3) in nonhuman primates between 60 and 240 min after injection. CONCLUSION: An 18F-fluoroalkyl metabolite of 18F-FECNT originating in the periphery confounded the measurements of DAT in the rat brain with a reference tissue model. Its uniform distribution across brain regions suggests that it has negligible affinity for DAT (i.e., it is an inactive radiometabolite). Consistent with the rodent data, the apparent distribution volume in the cerebellum of both humans and nonhuman primates showed a continual increase at late times after injection, a result that may be attributed to entry of the radiometabolite into the brain. Thus, reference tissue modeling of 18F-FECNT will be prone to more errors than analysis with a measured arterial input function.