城市地区结核病高发病率相关因素分析

背景：荷兰鹿特丹地区,1995-2006年。目的：探明城市地区结核病高发病率的相关因素。设计：将研究地分为城市和近郊／农村二类,比较其结核病患者的特征,并按照年龄、移民状况,以及结核菌感染的时间和地点进行分层,分别比较两类地区的结核病登记报告率。结果：城市地区的结核病登记报告率是近郊／农村地区的3．8倍;经出生地分层后,这比率有所下降（移民为1．7,非移民为2．8）。移民在境外获得结核菌感染的比例最高（47％的城市移民患者和62％的近郊／农村地区移民患者）。40％的城市患者和27％的近郊／农村患者是在荷兰境内近期感染结核菌的,以致在城市地区人群中因近期传播所致的患者登记报告率是其他地区的5．7倍。结论：城市地区较高的结核病登记报告率与城市移民较多有关,而这些移民结核病患者常常是因其在境外感染结核菌而发病的。近期传播也是城市地区移民和非移民结核病高发的重要因素。建议对已知的相关因素采取一系列针对性干预措施,以解决城市地区结核病高发的问题。     

Multilocus genetic structure in natural populations of Escherichia coli.

A survey of allozyme variation at 12 enzyme loci in 1,705 clones of the genetic species Escherichia coli (including four species of Shigella) from natural populations revealed 302 unique allele combinations (electrophoretic types). Single-locus diversity estimates fall within the range predicted by the neutral allele theory of molecular evolution, but the combination of alleles in electrophoretic types are highly nonrandom, as indicated by a test of association over all loci and by evidence of complex linkage disequilibria in several four-locus combinations. These linkage disequilibria reflect genetic differentiation of E. coli into three groups of strains. Because of restricted recombination, both the stochastic extinction of lines and selective differences between particular genetic combinations may have contributed to the evolution of subspecific structure in E. coli.     

Synchronous hippocampal bursting reveals network excitability defects in an epilepsy gene mutation.

A mutation at the tottering locus (tg, recessive, on chromosome 8) stimulates noradrenergic locus coeruleus axon terminal outgrowth and predisposes the brain to generalized spike-wave epilepsy in the young mouse. In an isolated synaptic circuit studied in vitro, the hyperinnervated mutant hippocampal pyramidal neurons respond normally when individually activated; however, latent neuronal signaling defects emerge during synchronous network bursting, revealing two conditional excitability phenotypes: a voltage-dependent prolongation of a complex synaptic response, the paroxysmal depolarizing shift, and a beta-adrenoreceptor-linked attenuation of the afterhyperpolarization. In this target brain region, the tg locus transforms neuronal excitability without altering measured intrinsic membrane properties, indicating that gene control of inherited epileptic traits may be mediated in part by activity-dependent modulation of network behavior favoring synchronous neuronal firing.     

Perfect genetic correlation between number of offspring and grandoffspring in an industrialized human population

Reproductive success is widely used as a measure of fitness. However, offspring quantity may not reflect the genetic contribution to subsequent generations if there is nonrandom variation in offspring quality. Offspring quality is likely to be an important component of human fitness, and tradeoffs between offspring quantity and quality have been reported. As such, studies using offspring quantity as a proxy for fitness may yield erroneous projections of evolutionary change, for example if there is little or no genetic variance in number of grandoffspring or if its genetic variance is to some extent independent of the genetic variance in number of offspring. To address this, we performed a quantitative genetic analysis on the reproductive history of 16,268 Swedish twins born between 1915 and 1929 and their offspring. There was significant sex limitation in the sources of familial variation, but the magnitudes of the genetic and environmental effects were the same in males and females. We found significant genetic variation in number of offspring and grandoffspring (heritability = 24% and 16%, respectively), and genetic variation in the two variables completely overlapped—i.e., there was a perfect genetic correlation between number of offspring and grandoffspring. Shared environment played a smaller but significant role in number of offspring and grandoffspring; again, there was a perfect shared environmental correlation between the two variables. These findings support the use of lifetime reproductive success as a proxy for fitness in populations like the one used here, but we caution against generalizing this conclusion to other kinds of human societies.Measuring selection and projecting evolutionary change, including in contemporary human populations (1), relies on validly measuring fitness (i.e., the genetic contribution to future generations). Fitness is usually measured by a metric of reproductive success, i.e., offspring quantity (1, 2). However, offspring quantity may be a poor proxy for fitness when there is nonrandom variation in the reproductive quality of offspring (ref. 3; e.g., due to differences in offsprings’ viability, attractiveness to mates, or intrasexual competitive ability). For example, a female might have few offspring but increase their reproductive quality (and the female’s own fitness) by investing parental care and resources in the offspring, by choosing a mate who invests in the offspring (4), and/or by choosing a mate whose superior (5) or more compatible (6) genetic makeup improves the genetic quality of the offspring. A second female might have more offspring but fewer grandoffspring (and so lower fitness) if she and her mate(s) confer lesser material or genetic benefits to her offspring. The same of course applies to males.Given humans’ exceptionally slow life history (∼15 y to sexual maturity) and high degree of biparental investment in offspring, the quality of those offspring is likely to be an important component of fitness in humans (7, 8), and extended parental investment improves quality of offspring in terms of their reproductive success (9). Research from preindustrial societies provides evidence for a tradeoff between offspring quantity and reproductive quality (e.g., refs. 2, 8, and 10–12), and there is evidence in postindustrial societies that offspring quantity is associated with lower parental investment in each offspring (13) and with detriments in offspring quality measures such as intelligence (14) and childhood growth (15) (see ref. 16 for a review of quantity–quality tradeoffs in humans). Such tradeoffs could mean that number of offspring might be a misleading indicator of longer-range (i.e., better) measures of fitness, e.g., number of grandoffspring.Evolutionary change in a trait (i.e., the shift in population mean over generations) due to selection depends on the trait’s genetic covariation with fitness (17–19). In this way (i.e., using the Robertson–Price identity), recent high-profile studies have projected evolutionary change in human traits (20, 21). However, because they used number of offspring to measure fitness, the projected magnitude or direction of evolutionary change could be wrong. For example, although previous research has revealed genetic variation (39% of the total variation) in number of offspring (22), there might be little or no genetic variation in number of grandoffspring, which would yield little or no long-term evolutionary change. Alternatively, if there is genetic variation in number of grandoffspring, it might not be captured by the genetic variation in number of offspring (e.g., because of the genetic variation in traits relating to maternal investment, mate choice, or mate retention), which would affect the magnitude or direction of the genetic covariation with the trait. However, it could be that the genetic variation in number of grandoffspring completely overlaps (i.e., r_g = 1.0) with the genetic variation in number of offspring, which would validate using number of offspring as a measure of fitness.The classical twin design uses the greater genetic similarity of identical twins (100%) compared with nonidentical twins (50%) to partition traits’ variance and covariance into genetic and environmental sources. Here we examine Swedish twins born between 1915 and 1929 (n = 16,268) and their number of offspring and grandoffspring born, which, for the vast majority of the sample, reflect lifetime reproductive fitness in both generations (Methods). We estimate the genetic variation in these variables and assess whether there are genetic influences on number of grandoffspring that are independent of the genetic influences on number of offspring.     

DNA fingerprinting analysis of parent-offspring conflict in a bee.

Demonstrating the importance of haplodiploidy in the evolution of eusociality among the Hymenoptera (bees, wasps, and ants) requires estimation of four parameters: relatedness between cooperating individuals, effective mating frequency, sex ratio, and rates of worker reproduction. Multilocus DNA fingerprinting techniques permitted the precise determination of these parameters for the primitively eusocial bee Augochlorella striata (Halictidae). DNA fingerprints revealed an unprecedented resolution of genetic relationships within colonies, detecting factors such as intraspecific nest parasitism and diploid males that confounded estimates of relatedness and sex ratio, respectively. Parameter estimates (i) corroborate recent evidence for queen-worker conflict over the sex ratio and (ii) implicate the role of haplodiploidy in the evolution of worker behavior.     

Transmission of tuberculosis between people of different ages in The Netherlands: an analysis using DNA fingerprinting.

SETTING: In the period 1950 to 1980 the risk of tuberculous infection in the Netherlands declined more steeply than tuberculosis incidence. This study aimed at determining whether this might be explained by preferential transmission within age groups. METHODS: Using restriction fragment length polymorphism (RFLP) typing on all Mycobacterium tuberculosis isolates in the Netherlands from 1993 to 1996, clusters with identical fingerprints were identified. The correlation between the ages of people in clusters of two Dutch patients was determined. RESULTS: The mean difference in age between the two people, in 81 clusters of two, was 13.9 years, while the mean age difference between all possible pairs of individuals in this data set was 25.5 years. Fisher's intraclass correlation coefficient was 0.62 (95% confidence interval [CI] 0.46-0.74). CONCLUSION: It is concluded that sources of tuberculosis may preferentially transmit infection to people close to their own age. As the average age of cases has increased in the period 1950-1980, sources may have become less likely to infect children in whom the risk of infection has been measured. The annual risk of infection measured in children and young adults in countries with low levels of tuberculosis may not apply to older members of the population.     

DNA fingerprinting in the epidemiology of African serogroup A Neisseria meningitidis.

The restriction endonuclease (RE) technique was used to compare 172 meningococcal group A strains collected between 1969 and 1990, mainly from countries of the so-called African Meningitis Belt, the Gambia and Ethiopia. The 64 strains from various African countries (Niger, Chad, Burkina Faso, Cameroon, Morocco, Djibouti) were distributed within 3 main restriction enzyme patterns (REPs); the 77 Gambian strains fell into 5 REPs and the 24 Ethiopian strains into 2 such patterns. Several of the main REPs were formed by clusters of closely related clones. Clones, very similar to dominating REPs of the 1960s in Niger, Burkina Faso and Cameroon, were in the 1980s found to be strongly represented in the Gambia to the extreme west of the Meningitis Belt. One of the Gambian clones from 1983-86 was identical to an Indian clone recovered in New Delhi 1986-87. Another clone was detected in 1983 in the Gambia, in 1989 again in the Gambia as well as in Ethiopia, and in 1990 in Tanzania. Our results are largely in line with those of previous studies based on modern techniques of protein and isoenzyme electrophoresis. The RE method is useful mainly for the exact genotypic differentiation of closely related clones, and seems to be a valuable complement to phenotypic tools for epidemiological mapping of Group A meningococcal infection.     

DNA "fingerprinting" reveals high levels of inbreeding in colonies of the eusocial naked mole-rat.

Using the technique of DNA fingerprinting, we investigated the genetic structure within and among four wild-caught colonies (n = 50 individuals) of a eusocial mammal, the naked mole-rat (Heterocephalus glaber; Rodentia: Bathyergidae). We found that DNA fingerprints of colony-mates were strikingly similar and that between colonies they were much more alike than fingerprints of non-kin in other free-living vertebrates. Extreme genetic similarity within colonies is due to close genetic relationship (mean relatedness estimate +/- SE, r = 0.81 +/- 0.10), which apparently results from consanguineous mating. The inbreeding coefficient (F = 0.45 +/- 0.18) is the highest yet recorded among wild mammals. The genetic structure of naked mole-rat colonies lends support to kin selection and ecological constraints models for the evolution of cooperative breeding and eusociality.     

Aceruloplasminemia in an asymptomatic patient with a new mutation. Diagnosis and family genetic analysis

A 39-year-old asymptomatic man showed elevated serum ferritin levels, mild hypertransaminasemia and serum ceruloplasmin almost undetectable. There was histological iron accumulation within the hepatocytes and also in the central nervous system (MRI). A genetic analysis revealed a new missense mutation in the ceruloplasmin gene. Two of the other four siblings were also affected by this mutation.     

DNA指纹技术方法学的建立及在结核分支杆菌菌株鉴定中的应用

目的探讨结核分支杆菌ＤＮＡ指纹技术的方法学及其在结核分支杆菌菌株鉴定中的应用。方法以结核分支杆菌染色体ＤＮＡ插入序列ＩＳ６１１０为基础,根据不同来源的结核分支杆菌菌株ＤＮＡ相异的ＩＳ６１１０拷贝数和相对分子质量,应用增强化学发光标记技术对结核分支杆菌ＤＮＡ酶切产物进行杂交和检测。结果不同来源的５０例结核患者临床分离株具有相异的ＤＮＡ指纹图谱。同一患者痰和膝关节脓培养阳性的结核分支杆菌菌株ＤＮＡ指纹图谱有较大的差异。人工诱导的结核分支杆菌Ｈ３７Ｒｖ氧氟沙星耐药株和敏感株有一致的ＤＮＡ指纹图谱。结论应用ＤＮＡ指纹技术进行结核分支杆菌株水平的鉴定是完全可行的     

Short-range genetic structure of Drosophila melanogaster populations in an Afrotropical urban area and its significance.

Alcohol dehydrogenase (Adh) (alcohol:NAD+ oxidoreductase, EC 1.1.1.1) gene frequencies and ethanol tolerance in Drosophila melanogaster are known to exhibit long-range latitudinal variations on different continents; this has led to the argument that the clines are adaptive. Accordingly, tropical populations are characterized both by a low frequency of Adh-F and by a low ethanol tolerance. In the urban area of Brazzaville (Congo) under an equatorial African climate, an original genetic structure of local populations has been found: Adh-F frequency varies from 3% to 90% when countryside and brewery populations are compared. This variation is accompanied by an increase of ethanol tolerance (from 6% to 13% alcohol). Such differences, which have remained stable for the past 3 years, were observed between collection sites less than 1 km apart. Two other enzyme loci exhibited a correlated variation with Adh-F--i.e., an increase of the S allele of glycerol-3-phosphate dehydrogenase (NAD+) (sn-glycerol-3-phosphate:NAD+ 2-oxidoreductase, EC 1.1.1.8) and of the F allele of glucose-6-phosphate dehydrogenase (D-glucose-6-phosphate:NADP+ 1-oxidoreductase, EC 1.1.1.49). Such observations suggest very strong selective pressures exerted by environmental ethanol that oppose the gene flow due to adult dispersal between contiguous habitats. A functional relationship between the polymorphisms of the three enzyme loci seems likely, and a metabolic interaction involving NAD and NADP cofactors is proposed.     

Investigation of tuberculosis transmission in Canadian Arctic Inuit communities using DNA fingerprinting.

OBJECTIVE: To understand the transmission of tuberculosis in Inuit communities in the Baffin region of the Canadian Arctic. METHODS: Twenty-one isolates of Mycobacterium tuberculosis from 19 Inuit patients diagnosed with tuberculosis between February 1991 and September 1993 were analyzed by DNA fingerprinting. The DNA fingerprints were achieved by the standard restriction fragment length polymorphism (RFLP) technique, with subsequent probing using the repetitive insertion segment IS6110. RESULTS: The isolates could be divided into three DNA types. The DNA types generally corresponded to the geographic origins of the patients. In most instances only one DNA type of M. tuberculosis was identified in each community. This suggests that a single case was the start of each of the three clusters, most likely due to reactivation. CONCLUSIONS: The results show that molecular typing of M. tuberculosis was useful in determining the mode of transmission of tuberculosis in a remote area of the Canadian Arctic where the disease is endemic. In addition, the information provides useful information for planning interventions in this setting.     

A constant rate of spontaneous mutation in DNA-based microbes.

In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by approximately 6500-fold. Their average mutation rates per base pair vary by approximately 16,000-fold, whereas their mutation rates per genome vary by only approximately 2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.     

Epidemiology and characterization of leptospirosis at an urban and provincial site in Thailand

Patients with FUOs at the Children's Hospital in Bangkok and the Chao Phya Abhai Bhu Bejhr Hospital in Prachinburi were screened for leptospirosis by blood and urine culture in addition to microagglutination testing of their serum. Animal populations in urban and periurban areas of Bangkok were surveyed for evidence of leptospira infection. Three rural sites near the Prachinburi Provincial Hospital were also surveyed. The rodents' and domestic animals' blood, urine, and/or kidney cell samples were cultured for leptospira. Sera from these animals were also tested for leptospira antibody. The bataviae serovar was the most commonly detected leptospiral agent in both man and animals. Presenting symptoms varied with age with children showing primarily fever, vomiting, headache, abdominal and generalized muscle pain and diarrhea whereas adults had fever, headache, anorexia, muscle pain and constipation. Blood samples from patients suspected of having leptospirosis were tested for antibody by the MAT and cultured in EMJH media. The following serogroups were identified: bataviae, autumanalis, javanica, hebdomadis, and pyrogens. Leptospirosis incidence in humans was much higher in the rainy/flooding year of 1983 compared to the relatively dry year of 1984. Results of our animal surveillance studies indicate that in addition to rats, which have previously been mentioned, dogs, bandicoots, cattle and pigs could be the source of human leptospirosis infection in both urban and provincial locations in Thailand.     

Patient-derived C-terminal mutation of FANCI causes protein mislocalization and reveals putative EDGE motif function in DNA repair

Fanconi anemia (FA) is a rare familial genome instability syndrome caused by mutations in FA genes that results in defective DNA crosslink repair. Activation of the FA pathway requires the FA core ubiquitin ligase complex-dependent monoubiquitination of 2 interacting FA proteins, FANCI and FANCD2. Although loss of either FANCI or FANCD2 is known to prevent monoubiquitination of its respective partner, it is unclear whether FANCI has any additional domains that may be important in promoting DNA repair, independent of its monoubiquitination. Here, we focus on an FA-I patient-derived FANCI mutant protein, R1299X (deletion of 30 residues from its C-terminus), to characterize important structural region(s) in FANCI that is required to activate the FA pathway. We show that, within this short 30 amino acid stretch contains 2 separable functional signatures, a nuclear localization signal and a putative EDGE motif, that is critical for the ability of FANCI to properly monoubiquitinate FANCD2 and promote DNA crosslink resistance. Our study enable us to conclude that, although proper nuclear localization of FANCI is crucial for robust FANCD2 monoubiquitination, the putative FANCI EDGE motif is important for DNA crosslink repair.     

Transmission in NFS/N mice of the heritable spongiform encephalopathy associated with the gray tremor mutation.

It has been shown that the autosomal recessive mutation, gray tremor (gt) was associated in the homozygous state (gt/gt) with a rapidly fatal spongiform encephalopathy. Heterozygotes (+/gt) developed mild asymptomatic spongiform brain lesions as did recipient inbred mice inoculated with gt/gt brain homogenates, some of whom also showed behavioral abnormalities [Sidman, R. L., Kinney, H. C. & Sweet, H. O. (1985) Proc. Natl. Acad. Sci. USA 82, 253-257]. In these studies, inbred NFS/N mice inoculated intracerebrally at birth or as adults with gt/gt or first passage gt brain homogenates developed a progressive disease characterized by tremor, ataxia, and spasticity. The symptoms were milder and more slowly progressive than in the gt/gt homozygote, in the paralytic syndrome that followed neonatal inoculation of NFS/N mice with a wild murine leukemia virus (Cas-Br-M MuLV), or in the rapidly progressive ataxia and terminal bradykinesia that followed scrapie inoculation of NFS/N mice. The noninflammatory spongiform encephalopathy in affected NFS/N mice resembled that observed in gt/gt homozygotes, +/gt heterozygotes, and asymptomatic recipient inbred mice inoculated with gt/gt brain homogenates. Neither infectious MuLV nor MuLV proteins were detected in gt/gt brain homogenates or in affected recipient mouse brains. Scrapie-associated fibrils, readily identifiable in subcellular fractions of brains from scrapie-inoculated NFS/N mice, were not detected in similar brain fractions from NFS/N mice inoculated with gt brain homogenates. These results confirm and extend the suggestion that gt spongiform encephalopathy has both heritable and transmissible properties. Moreover, the transmissible agent of gt disease differs from both Cas-Br-M MuLV and scrapie in its disease-inducing properties in NFS/N mice. The capacity of NFS/N mice to express transmitted gt encephalopathy as clinical disease, to rapidly express Cas-Br-M MuLV spongiform encephalomyelopathy, and to develop mouse-adapted scrapie after a very short incubation time suggest a distinct sensitivity of NFS/N mice to transmissible spongiform encephalopathy.     

荷兰结核病在不同年龄人群间的传染：应用DNA指纹法的分析

背景1950年至1980年间荷兰结核病感染率的下降比发病率的下降快得多。本研究的目的在于确定这一现象是否能用年龄组内的不同传播所解释。方法应用RFLP法将荷兰1993～1996年所有菌株进行分型,同一指印的菌株被鉴定为同一来源,由此确定2个荷兰患者年龄上的相关性。结果两簇人群81对菌株患者年龄的平均差异是13.9岁。而所有可能配对患者资料的年龄平均差异是25.5岁。Fisher氏检验相关系数为0.62(95％可信区间[CI]值为0.46～0.74)。结论结核病传染源更易传染给和他们年龄相近的人群。由于在1950～1980年间,病例的平均年龄在增加。传染源可能对过去常观测年感染率的儿童的感染更少。在低结核国家中儿童、青少年结核病的年感染率的资料不适于该人群中的老年者。     

Targeted mutation reveals a central role for SR-BI in hepatic selective uptake of high density lipoprotein cholesterol

Scavenger receptor BI (SR-BI) is a cell surface receptor that binds high density lipoproteins (HDL) and mediates selective uptake of HDL cholesteryl esters (CE) in transfected cells. To address the physiological role of SR-BI in HDL cholesterol homeostasis, mice were generated bearing an SR-BI promoter mutation that resulted in decreased expression of the receptor in homozygous mutant (designated SR-BI att) mice. Hepatic expression of the receptor was reduced by 53% with a corresponding increase in total plasma cholesterol levels of 50–70% in SR-BI att mice, attributable almost exclusively to elevated plasma HDL. In addition to increased HDL-CE, HDL phospholipids and apo A-1 levels were elevated, and there was an increase in HDL particle size in mutant mice. Metabolic studies using HDL bearing nondegradable radiolabels in both the protein and lipid components demonstrated that reducing hepatic SR-BI expression by half was associated with a decrease of 47% in selective uptake of CE by the liver, and a corresponding reduction of 53% in selective removal of HDL-CE from plasma. Taken together, these findings strongly support a pivotal role for hepatic SR-BI expression in regulating plasma HDL levels and indicate that SR-BI is the major molecule mediating selective CE uptake by the liver. The inverse correlation between plasma HDL levels and atherosclerosis further suggests that SR-BI may influence the development of coronary artery disease.