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Language ability and handedness are likely to be associated with asymmetry of the cerebral cortex (grey matter) and connectivity (white matter). Grey matter asymmetry, most likely linked to language has been identified with voxel-based morphometry (VBM) using T(1)-weighted images. Differences in white matter obtained with this technique are less consistent, probably due to the relative insensitivity of the T(1) contrast to the ultrastructure of white matter. Furthermore, previous VBM studies failed to find differences related to handedness in either grey or white matter. We revisited these issues and investigated two independent groups of subjects with diffusion-tensor imaging (DTI) for asymmetries in white matter composition. Using voxel-based statistical analyses an asymmetry of the arcuate fascicle was observed, with higher fractional anisotropy in the left hemisphere. In addition, we show differences related to handedness in the white matter underneath the precentral gyrus contralateral to the dominant hand. Remarkably, these findings were very robust, even when investigating small groups of subjects. This highlights the sensitivity of DTI for white matter tissue differences, making it an ideal tool to study small patient populations.

We used diffusion tensor imaging (DTI) to assess Wallerian degeneration of the pyramidal tract within the first 2 weeks after ischemic stroke, and correlated the extent of Wallerian degeneration with the motor deficit. Nine patients with middle cerebral artery stroke were examined 2-16 days after stroke by DTI and T2-weighted MRI. We measured fractional anisotropy (FA), averaged diffusivity (Dav), eigenvalues of the diffusion tensor and T2-weighted signal in the cerebral peduncle and compared these values between the affected and the unaffected side and between patients and six controls. FA was significantly reduced on the affected side compared to the unaffected side and compared to the control group. The largest eigenvalue was reduced, whereas the smallest eigenvalue was elevated on the affected side. There was no significant difference in T2-weighted signal and Dav. The decrease of anisotropy correlated positively with the motor deficit at the time of DTI study and 90 days after stroke. The reduction of anisotropy mirrors the disintegration of axonal structures, as it occurs in the early phase of Wallerian degeneration. DTI detects changes of water diffusion related to beginning pyramidal tract degeneration within the first 2 weeks after stroke that are not yet visible in conventional T2-weighted or orientationally averaged diffusion weighted MRI. We demonstrated for the first time a correlation of early DTI findings of pyramidal tract damage with the motor deficit. DTI can help prognosing recovery of motor function after stroke within the early subacute phase.

Arabis drummondii, A. holboellii and their hybrid A. x divaricarpa are widespread perennials of open habitats in North America. A phylogenetic analysis based on noncoding chloroplast DNA sequences (trnL intron and trnL/F intergenic spacer) resolved A. drummondii as a monophyletic taxon, but found A. holboellii to bear chloroplast haplotypes from highly diverged evolutionary lineages. This raised the question of a possible polyphyletic origin of A. holboellii. Arabis x divaricarpa was found to be of recent and polytopic origin, a result consistent with its presumed hybrid origin. One hundred and three chloroplast haplotypes were detected within 719 Arabis accessions investigated. The majority of chloroplast-types were estimated to have arisen prior to the Wisconsin glaciation. Phylogeographical analysis using nested clade analysis, suggested for A. holboellii (i). past fragmentation events, partitioning genetic variation in several instances between the Sierra Nevada, the Southern Rocky Mountains and the Colorado Plateau on the one hand and the Central to Northern Rockies of the United States and adjacent Cascades on the other; and for both parental species (ii). recolonization of major areas formerly covered by the Wisconsin glaciation by three haplotypes; and (iii). restricted gene flow indicating isolation by distance in areas south of the last glacial maximum. Arabis x divaricarpa is closely codistributed with its parental species and resampled their haplotypes. The highest genetic diversity was found in the Rocky Mountains from Idaho and Montana south to Utah and Colorado. This area was further hypothesized to have played a major role in the origin of both parental species and probably represented an important glacial refugium. However, evidence for glacial refugia was also found in arctic and boreal regions of Alaska and near the Great Lakes. In comparison to nuclear ribosomal internal transcribed spacer data, chloroplast DNA divergence was very high and evidently predated the origin of A. drummondii and possibly A. holboellii. Divergence of major chloroplast lineages dates back to the middle of the Pleistocene at least. Extensive hybridization is the most likely evolutionary factor working on A. holboellii to explain the revealed discrepancy in nuclear DNA and chloroplast DNA diversification.

A phase I clinical trial was conducted to determine the safety, pharmacokinetic parameters, and efficacy of orally administered isoflavones (genistein and daidzein, potential cancer chemotherapeutic agents) over a 3-mo period in men with prostate neoplasia. Twenty men, ages 40 and above, with stage B, C, or D adenocarcinoma of the prostate were treated with a multiple-dose regimen of a soy isoflavone formulation (delivering approximately 300 or 600 mg/day genistein and half this much daidzein) for 84 days. The delivered dose of isoflavones was more than 10-fold higher than that typically taken by prostate cancer patients. In men with prostate cancer, relatively minor side effects of chronic isoflavone treatment were observed including some estrogenic effects (breast changes, increased frequency of hot flashes). Serum dehydroepiandrosterone was decreased by 31.7% (P = 0.0004) at the end of treatment. Except for those subjects whose prostate-specific antigen (PSA) values were below 0.4 ng/ml, subjects had a history of increasing PSA levels prior to the trial. This increase continued during the trial both while on soy isoflavones and after treatment was discontinued. On average the rate of rise accelerated after soy isoflavones were discontinued, but that difference did not attain statistical significance. Genistein and daidzein were rapidly cleared from plasma and excreted in urine. Pharmacokinetic data for chronic dose administration were similar to single-dose administration for the isoflavones investigated except that we observed slightly longer circulation time for daidzein.

During the past decade, important advances have been made in the humane care and use of laboratory animals used in toxicology studies, and there is strong international interest by the pharmaceutical sector in continuing with this progress. Because of the potential influence on human health, safety studies are highly regulated, and implementing refinements in laboratory animal care and use may require an initial validation study to demonstrate a lack of effect on study outcome. This paper provides an overview of issues surrounding implementation of animal care refinements in toxicology laboratory settings, including regulatory constraints, conducting validation studies, current progress in refinements, and areas for future consideration.

Proteins are modularly built from a limited set of approximately 1000 structural domains. The evolutionary relationship within a domain family suggests that the knowledge about a common fold structure can be exploited for the design of small molecule libraries in the development of inhibitors and ligands. This principle has been used for the synthesis of inhibitors for kinases sharing the same fold. It can also be applied for proteins which share the same fold architecture yet belong to different functional classes. Bestatin--originally known as an aminopeptidase inhibitor--was employed as guiding structure for the development of leukotriene A4 hydrolase inhibitors. A combinatorial approach helped to identify inhibitors for sulfotransferases which share structural similarity with nucleotide kinases using a kinase inhibitor core structure as guiding principle.

This paper gives an overview of the recent literature on methodological developments of functional magnetic resonance imaging (fMRI) and recent trends in clinical applications. With the recent introduction of high-field systems and methodological developments leading to more robust signal behavior, fMRI is in a transition state from a research modality for use by experts to a standard procedure with useful applications in patient management. Compared to the use in neuroscientific research, which is often based on BOLD techniques alone, the application in patients is distinguished by a multiparametric characterization of the brain using a combination of several techniques. Neuronal fiber tracking based on diffusion anisotropy measurements, in particular, has already turned out to provide relevant supplementary information to the BOLD-based cortical activation maps., (Copyright 2003 Wiley-Liss, Inc.)

Background: Genistein may be useful in the prevention or treatment of prostate cancer; however, it causes genetic damage in cultured human cells., Objective: The objective was to assess the potential genotoxicity of a purified soy unconjugated isoflavone mixture in men with prostate cancer., Design: Twenty patients with prostate cancer were treated with 300 mg genistein/d for 28 d and then with 600 mg/d for another 56 d. In peripheral lymphocytes, DNA strand breaks were assessed as nuclear tail moment, chromosomal damage was assessed as micronucleus frequency (MF), and translocations of the MLL gene (11q23) were assessed by using fluorescence in situ hybridization. Values are also reported for 6 healthy men. The studies were performed under Investigational New Drug application no. 54 137 at a tertiary referral academic medical center., Results: No changes in group average or individual nuclear tail moment and MF were observed. We observed a single elevated MF value in one subject that exceeded a clinical threshold set before we initiated the study. A significant decrease in average COMET tail moment was observed on day 28 relative to day 0. We detected no genistein-induced rearrangements of the MLL gene in the 3 subjects we studied with this technique. MF increased significantly in lymphocytes exposed in vitro to unconjugated genistein at concentrations > or = 100 micromol/L. Total genistein never exceeded a peak concentration of 27.1 micro mol/L, and unconjugated genistein never exceeded a peak concentration of 0.32 micromol/L., Conclusion: Although isoflavones are capable of inducing genetic damage in vitro, a similar effect was not observed in subjects treated with a purified soy unconjugated isoflavone mixture.

DNA sequence variation of the internal transcribed spacer (ITS) region of nuclear ribosomal DNA from Arabis holboellii, A. drummondii, and its putative hybrid A. divaricarpa was analyzed to study hybrid speciation in a species system geographically covering nearly the entire North American continent. Based on molecular systematics the investigated species are better combined under the genus Boechera. Multiple intraindividual ITS copies were detected in numerous accessions of A. divaricarpa, and, to a minor extent, in the parental taxa. Comparative phylogenetic analysis demonstrates that reticulate evolution is common. Consequently, concerted evolution of ITS regions resulted in different types of ITS fragments not only in hybrid populations but also in one of the parental taxa, A. holboellii. Hybrid formation often occurred independently at different sites and at different times, which is reflected by ITS copies resampling the original parental sequence variation in different ways. Some biogeographic structuring of genetic diversity is apparent and mirrors postglacial migration routes. Hybridization, reticulation, and apomixis are assumed to be the major forces driving speciation processes in this species complex. Analysis of conserved regions and secondary structures of the ITS region provided no evidence that, in this system, hybrid ITS evolution is predominantly driven in a particular direction. However, two regions in the ITS1 and ITS2, respectively, show higher mutation rates than expected from outgroup comparisons. Strong evidence for the occurrence of apomixis in A. holboellii and A. divaricarpa has come from pollen size measurements and estimations of pollen quality, which favor the hypothesis that A. drummondii served as paternal hybridization partner more frequently than A. holboellii.

The main impact of functional neuroimaging has been its ability to locate neuronal activity either directly (EEG, MEG) or through the hemodynamic response caused by neuronal activity (PET, fMRI). In the past decade functional neuroimaging has been extended to investigate how brain regions interact, using the concepts of functional and effective connectivity. These concepts are further strengthened by estimates of anatomical connectivity of the same subject. A tool to determine anatomical connectivity in vivo may be provided by diffusion tensor imaging (DTI) methods. These can be used to determine the orientation of fiber bundles in white matter on the basis of the diffusion characteristics of water. Commonly, DTI data are acquired using echo planar imaging which suffers from susceptibility artifacts in orbitofrontal and inferior temporal cortex. Here we demonstrate the use of an alternative pulse sequence, diffusion-weighted single-shot STEAM, for assessing fiber orientation in orbitofrontal cortex and the cranial nerves. The scope of DTI needs to be extended to these structures to investigate psychiatric disorders in which orbitofrontal pathology or temporo-frontal disconnection have been postulated.

Background: The neuronal basis of persistent developmental stuttering is unknown. The disorder could be related to a reduced left hemisphere dominance, which functional neuroimaging data suggest might lead to right hemispheric motor and premotor overactivation. Alternatively, the core deficit underlying stuttering might be located in the speech-dominant left hemisphere. Furthermore, magnetoencephalography study results show profound timing disturbances between areas involved in language preparation and execution in the left hemisphere, suggesting that persistent developmental stuttering might be related to impaired neuronal communication, possibly caused by a disruption of white matter fibre tracts. We aimed to establish whether disconnection between speech-related cortical areas was the structural basis of persistent developmental stuttering., Methods: We analysed the speech of 15 people with persistent developmental stuttering and 15 closely matched controls for the percentage of syllables stuttered. We used diffusion tensor imaging to assess participants' brain tissue structure, and used and two-sample t test to compare diffusion characteristics between groups., Findings: Diffusion characteristics of the group with persistent developmental stuttering and controls differed significantly immediately below the laryngeal and tongue representation in the left sensorimotor cortex (mean difference in fractional anisotropy 0.04 [95% CI 0.03-0.05])., Interpretation: Our findings show that persistent developmental stuttering results from disturbed timing of activation in speech-relevant brain areas, and suggest that right hemisphere overactivation merely reflects a compensatory mechanism, analogous to right hemisphere activation in aphasia.

This article examines functional and anatomical connectivity in healthy human subjects measured with magnetic resonance imaging methods. Anatomical connectivity in white matter is obtained from measurements of the diffusion tensor. A Monte-Carlo simulation determines the probability that a particle diffuses between two points, with the probability of a jump in a particular direction from a given voxel being based on the local value of the diffusion tensor components. Functional connectivity between grey matter pixels is assessed without recourse to a specific activation paradigm, by calculating the correlation coefficient between random fluctuations in the blood oxygenation level-dependent signal time course in different pixels. The methods are used to examine the anatomical and functional connectivities between crowns of adjacent gyri. A high functional connectivity was found between grey matter pixels, with white matter displaying only very low correlation. A comparison of the measurements of anatomical and functional connectivity found that there is no simple correlation between these measures, except that low values of functional connectivity were not found together with high values of anatomical connectivity. Furthermore pairs of regions situated around the central sulcus indicated a dependence of the two connectivity measures on each other. These results are in accordance with an interpretation that regions which are clearly directly linked by white matter fiber tracts should show high functional connectivity, but that the inverse need not be true as functional connectivity may also be indirectly mediated via more distant grey matter regions., (2002 Elsevier Science (USA).)

Background: Soy isoflavones are potential cancer chemoprevention treatments., Objective: We conducted safety studies of purified unconjugated genistein, daidzein, and glycitein, and defined pharmacokinetic parameters for their absorption and metabolism., Design: Thirty healthy men ingested a single dose of 1 of 2 isoflavone preparations purified from soy. The delivered doses of genistein (1, 2, 4, 8, or 16 mg/kg body wt) were higher than those previously administered to humans. Formulation A was composed of 90 +/- 5% genistein, 10% daidzein, and 1% glycitein. Formulation B was composed of 43% genistein, 21% daidzein, and 2% glycitein., Results: We observed no clinically significant behavioral or physical changes after treatment. We observed elevations in lipoprotein lipase and hypophosphatemia that were possibly related to the treatment but that were associated with no clinical toxicity. Considerable quantities of isoflavones were excreted in urine as conjugates. The terminal elimination rate, elimination half-life, area under the curve, maximum plasma concentration, apparent systemic clearance, and volume of distribution were estimated for genistein and daidzein. The mean elimination half-lives with both formulations were 3.2 h for free genistein and 4.2 h for free daidzein. The mean pseudo half-lives were 9.2 h for total genistein and 8.2 h for total daidzein., Conclusions: Dietary supplements of purified unconjugated isoflavones administered to humans in single doses exceeding normal dietary intake manyfold resulted in minimal clinical toxicity. Genistein and daidzein (free and total) were rapidly cleared from plasma and excreted in urine.

DNA sequence variations of chalcone synthase (Chs) and Apetala3 gene promoters from 22 cruciferous plant species were analyzed to identify putative conserved regulatory elements. Our comparative approach confirmed the existence of numerous conserved sequences which may act as regulatory elements in both investigated promoters. To confirm the correct identification of a well-conserved UV-light-responsive promoter region, a subset of Chs promoter fragments were tested in Arabidopsis thaliana protoplasts. All promoters displayed similar light responsivenesses, indicating the general functional relevance of the conserved regulatory element. In addition to known regulatory elements, other highly conserved regions were detected which are likely to be of functional importance. Phylogenetic trees based on DNA sequences from both promoters (gene trees) were compared with the hypothesized phylogenetic relationships (species trees) of these taxa. The data derived from both promoter sequences were congruent with the phylogenies obtained from coding regions of other nuclear genes and from chloroplast DNA sequences. This indicates that promoter sequence evolution generally is reflective of species phylogeny. Our study also demonstrates the great value of comparative genomics and phylogenetics as a basis for functional analysis of promoter action and gene regulation.

We analyzed sequence variation for chalcone synthase (Chs) and alcohol dehydrogenase (Adh) loci in 28 species in the genera Arabidopsis and Arabis and related taxa from tribe Arabideae. Chs was single-copy in nearly all taxa examined, while Adh duplications were found in several species. Phylogenies constructed from both loci confirmed that the closest relatives of Arabidopsis thaliana include Arabidopsis lyrata, Arabidopsis petraea, and Arabidopsis halleri (formerly in the genus Cardaminopsis). Slightly more distant are the North American n = 7 Arabis (Boechera) species. The genus Arabis is polyphyletic-some unrelated species appear within this taxonomic classification, which has little phylogenetic meaning. Fossil pollen data were used to compute a synonymous substitution rate of 1.5 x 10 substitutions per site per year for both Chs and Adh. Arabidopsis thaliana diverged from its nearest relatives about 5 MYA, and from Brassica roughly 24 MYA. Independent molecular and fossil data from several sources all provide similar estimates of evolutionary timescale in the Brassicaceae.

The New Jersey Substance Abuse Treatment Campus was funded to assess the feasibility of establishing a new model for delivering substance abuse treatment services and to serve as a research laboratory for conducting comparative evaluations of those services. The 350-bed campus was designed to improve treatment effectiveness by providing special services needed by underserved populations, and reduce treatment costs by serving large numbers of clients, centralizing services, and sharing facilities. First-time clients who met preliminary eligibility requirements during phone screening were randomly assigned to therapeutic community and chemical dependency programs. We used data collected on 1,573 adults who were ultimately accepted for admission to analyze treatment refusals and attrition during the 25 days after admission. Only 6.4% of the clients refused admission when informed of their treatment assignment. Planned duration of the residential phase of treatment, gender, and language spoken (English/Spanish) interacted with one another and differentially predicted treatment refusal/attrition. These findings may be useful for understanding treatment refusal and attrition in substance abuse treatment programs.

Enteritis is a potential complication of antimicrobial agent use, particularly in certain species of rodents. The organism most frequently implicated in this disease is Clostridium difficile. Anecdotal information suggests that administration of yogurt or other Lactobacillus-containing products in conjunction with antimicrobial agents will prevent or minimize the effects of antibiotic-associated enteritis. We wanted to determine whether a single subcutaneous injection of clindamycin phosphate could induce enteritis in guinea pigs and whether a commercial Lactobacillus preparation would ameliorate the clinical effects of antibiotic administration in these animals. Juvenile male guinea pigs were divided into three treatment groups. Group 1 guinea pigs (n=8) received a single saline injection followed by an oral Lactobacillus preparation twice daily; group 2 (n=8) received a single antibiotic injection followed by an oral Lactobacillus preparation twice daily; group 3 (n=8) received a single antibiotic injection. Attitude, body temperature, body weight, and feed and water consumption were recorded for each guinea pig 7 days prior to and after treatment. Fecal samples were collected and necropsies performed on each guinea pig at the time of euthanasia. C. difficile and other enteric pathogens were not isolated from any group before or after treatment, although some guinea pigs receiving the antibiotic developed enteritis. There were no significant clinical differences between guinea pigs receiving antibiotics with the oral Lactobacillus preparation, and those receiving antibiotics alone. The results of this study suggest that a single injection of clindamycin phosphate can induce enteritis in guinea pigs and that oral administration of a Lactobacillus-containing product is ineffective in preventing clinical disease in guinea pigs administered clindamycin phosphate.

To evaluate the effectiveness of a physician-based intervention to promote smoking cessation during pregnancy, we conducted this randomized controlled trial in the resident-staffed prenatal clinics at the University of North Carolina Women's Hospital . Two hundred fifty prenatal patients who smoked were enrolled at their first visit and randomly assigned to the intervention or the usual-care group. Resident physicians provided self-help materials to intervention subjects and used a script to set goals with them at each prenatal visit. Subjects who set quit dates were contacted by volunteer cessation counselors. To verify smoking status, subjects provided a self-report and breath carbon monoxide (CO) sample at each visit. Controls were similarly assessed at enrollment and at three additional predetermined intervals. Twenty percent of intervention subjects and 10% of controls reported cessation, which was verified by CO level (P = .052). Fifty-one percent of subjects reduced their consumption by half or more, compared with 30% of controls (P = .002). The intervention is effective in promoting smoking cessation and reduction. In addition, this technique is inexpensive, readily accepted by staff, and efficient.

We compared the efficacy of very-low-intensity oral anticoagulation (OA) with that of the recommended standard low-intensity oral anticoagulation, using international normalized ratios (INRs). We enrolled 101 patients into a pilot study--51 patients in the very-low-intensity anticoagulation arm (INR 1.4 to 2.0) and 50 in the standard low-intensity anticoagulation arm (INR 2.0 to 3.0). They were monitored for thrombotic/embolic and hemorrhagic complications for an average follow-up of 1.5 years. Two thrombotic/embolic events occurred in the very-low-intensity group; no thrombotic/embolic events occurred in the standard low-intensity group. No major bleeding occurred in the very-low-intensity group; one major hemorrhagic event occurred in the standard low-intensity group. These findings did not achieve a statistically significant difference in major complications between the two groups. It appears that very-low-intensity OA (INR 1.4 to 2.0) is as effective in preventing thromboses as standard low-intensity OA (INR 2.0 to 3.0).

Objective: To confirm the effectiveness of misoprostol as a labour-induction agent., Design and Setting: One hundred and ten consecutive second- and third-trimester hospital patients. Patients with intra-uterine deaths (group A) received 100 micrograms misoprostol 4-hourly and those with live fetuses (group B) 50 micrograms misoprostol 4-hourly until labour commenced., Subjects: Forty-eight patients in group A (group A1 second trimester 27, group A2 third trimester 21); 62 mainly hypertensive patients in group B., Outcome Measures: These were the amount of misoprostol required to induce labour; duration of induction and labour; success and completeness of vaginal delivery; neonatal outcome; and cost., Results: In group A1, labour was successfully induced in 21/27 (77.8%) patients with 157.4 micrograms misoprostol; and in 19/21 (90.5%) patients in group A2 with 128.9 micrograms misoprostol. Cost per successful induction was R0.55 and R0.44 respectively. Mean induction times were 13.2 hours and 13.4 hours respectively. All patients delivered vaginally but incompletely in 7/21 group A1 and 1/19 group A2 patients. In group A2, the mean duration of labour was 5.97 hours. In group B induction was successful in 51/62 (82%) with 95.1 micrograms of misoprostol; the mean cost was R0,32. Twelve out of 51 (23%) received oxytocin and 44/51 delivered vaginally. Mean duration of induction was 11.4 hours and of labour 5.4 hours. Two babies had low Apgar scores. There were two stillbirths (perinatal mortality rate 39.2/1000), both apparently unrelated to misoprostol., Conclusions: Misoprostol is an effective, easy to use, apparently safe and cheap drug for the induction of labour.

We investigated the role of nitric oxide, an endothelium-derived relaxing factor, in the hemodynamic response to acute hemorrhage in conscious rabbits. Chronically instrumented rabbits were treated with the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) or vehicle and hemorrhaged until mean arterial pressure fell below 40 mmHg. Control animals were treated with L-NAME or vehicle but not subjected to hemorrhage. L-NAME increased mean arterial pressure and decreased heart rate in control animals. Hindquarters and mesenteric blood flow velocity and conductance were reduced by L-NAME. Nitric oxide synthase inhibition also produced significant changes in the hemodynamic response to hypotensive hemorrhage. Mean arterial pressure was higher and regional vascular conductances were lower throughout hemorrhage and during recovery. L-NAME treatment significantly (but in some cases, subtly) altered the characteristic pattern of changes in vascular conductance associated with acute hypotensive hemorrhage and recovery. Similar experiments with other arginine analogues or phenylephrine infusion showed that L-NAME's effects during hemorrhage were due to nitric oxide synthase inhibition. We conclude that nitric oxide plays a role in the hemodynamic response to acute hemorrhage in the rabbit and is essential for the full expression of the vasodilation associated with hypotensive hemorrhage.

Within a prospective study of the course of HIV-infection in women, 80 HIV-infected women without AIDS were delivered of 80 children between 1985 and September 1992. The median of the age of gestation was 38 weeks. Until 1988 Caesarean section was chosen as mode of delivery (45 women). Later when the mode of delivery appeared to have no influence on the frequency of maternofetal HIV transmission, vaginal delivery was preferred (35 women). None of the infants was breastfed. Three infants --delivered vaginally--died within the first 6 months of life before their infection status could be determined. Seventy-seven children could be observed for 18 months or longer regularly every three months. 10 of the 77 children were found to be HIV- infected by serological, virological and clinical criteria. Taking into account the mode of delivery, of 32 children who were delivered vaginally or by emergency Caesarean section 8 were found to be HIV-infected. None of 26 children delivered by elective Caesarean section after an uneventful pregnancy is infected. In 19 women Caesarean section was performed within 2 hours after onset of labour or after episodes of preterm labour which required hospital admission for treatment. Two children of these women are infected. No differences of CD4+ cell counts and p24 antigenaemia could be determined between the mothers of the three groups. The risk of fetal HIV infection was increased by preterm labour (p < 0.01) and the mode of delivery (p < 0.01). A correlation between loss of CD4 cells in the mother and increased risk of infection for the child is seen in children born spontaneously or delivered by emergency Caesarean section (p < 0.001). No correlation was found between the length of labour at delivery, the time of the rupture of membranes before birth as well as of the parity and the risk of fetal infection in that group. These findings point to labour as an important factor which increases the risk of maternofetal transmission of HIV. The onset of labour is accompanied by dramatic immunological alterations as a sudden increase of chemotactics and inflammatory cytokines at the maternofetal interface. The accumulation and stimulation of maternal immune cells will--if these cells are carriers of HIV--result in production and release of infectious HIV. This virus may accumulate in the maternofetal interface or gain access to the amniotic cavity. Since amniotic fluid is swallowed by the fetus, the largest potential port of entry for HIV in the fetus are the fetal lungs and the gastrointestinal tract. For the prevention of maternofetal transmission of HIV delivery before onset of labour or alternatively the protection of the fetus during parturition by means of potent antiviral compounds can be considered.

A multipurpose survey in a representative sample of the german population was conducted to obtain sociodemographic data together with data on blood donation history and acceptance of HIV antibody tests. A self-administered questionnaire was used to gather information on sexual behaviour. This questionnaire was completed by 62.2% of the participants between 18 and 64 years of age. Comparison between donors and nondonors shows that donors are typically members of the more "socially active" groups: they are younger, gainfully employed, and have attained higher educational levels. The analysis of the data on sexual behaviour reveals that donors are on the average sexually more active than nondonors. Blood donors are a suitable sentinel population to monitor sexually transmitted diseases in the population outside the risk groups for HIV infection.

Objective: To evaluate whether the use of immunological markers in addition to CD4+ lymphocyte count can improve the prediction of the probability of developing AIDS within a given period., Design and Setting: Prospective multicentre cohort study of homosexual men., Patients: A total of 447 HIV-positive homosexual men followed prospectively at 6-month intervals (median time of observation, 47 months)., Methods: Estimation of AIDS-free time using lifetable plots by Cutler and Ederer and Weibull parametric models. A stepwise multivariate regression analysis was used to calculate the optimal combination of the parameters studied., Results: In general CD4+ lymphocyte counts are most important for the prediction of AIDS-free time. The use of serum levels of beta 2-microglobulin (beta 2M), immunoglobulin A (IgA) and erythrocyte sedimentation rate (ESR) can significantly improve the predictive value of CD4+ lymphocyte counts. However, the usefulness of these parameters depends on the stage of HIV disease. In patients with a CD4+ lymphocyte count > 500 x 10(6)/l, only IgA level had a significant predictive value; none of the other parameters significantly improved the model. In patients with a CD4+ lymphocyte count < 500 x 10(6)/l, the absolute number of CD4+ cells itself was the most important single predictive parameter, but the prediction of AIDS was significantly improved by the addition of the other parameters investigated. The most powerful combination of parameters in this group was CD4+ count, beta 2M and ESR., Conclusion: Determination of serum IgA, beta 2M and ESR in addition to CD4+ lymphocyte count may aid the choice of specific therapeutic regimens or systems of care for HIV-positive individuals.

Background: Protocol 019 of the AIDS Clinical Trials Group is a multicenter, double-blind, placebo-controlled trial of zidovudine (3'-azido-3'-deoxythymidine; formerly AZT) in human immunodeficiency virus-infected asymptomatic individuals. The initial results in the stratum of subjects entering with CD4+ cell counts of 0.50 x 10(9)/L or less have been reported, but without a detailed analysis of toxic effects., Methods: This detailed and updated report analyzes the toxic effects that occurred in 1567 subjects (91% men; 89% white) in this stratum of protocol 019 who received placebo (494 subjects), a 500-mg daily dose of zidovudine (544 subjects), or a 1500-mg daily dose of zidovudine (529 subjects). Hematologic, hepatic, and renal effects and patient-reported symptoms and clinical signs were monitored., Results: Severe anemia (hemoglobin level, < 80 g/L) was associated with both the 500-mg zidovudine group and the 1500-mg group compared with placebo. The estimated 18-month risks of severe anemia were 0.4%, 2.0%, and 9.7% for the placebo, 500-mg zidovudine, and 1500-mg zidovudine groups, respectively. Predictive baseline measures were lower hemoglobin level in the 1500-mg group and the two zidovudine groups combined and lower platelet count in the 500-mg zidovudine group. The risk of a first severe anemia developing was greatest in months 3 through 8 of treatment. Of the 44 subjects with severe anemia in the zidovudine groups, 18 (41%) progressed from mild anemia (hemoglobin level, 95 to 109 g/L) to severe anemia on consecutive visits (usually 2 to 4 weeks apart). Severe neutropenia (absolute neutrophil count, < 750 x 10(6)/L) did not occur significantly more often in the 500-mg zidovudine group but did in the 1500-mg zidovudine group. Moderate neutropenia (absolute neutrophil count, < 1300 x 10(6)/L) did develop significantly more often in the 500-mg zidovudine group (165 subjects) than in the placebo group (71 subjects). Mild (or worse) elevations of bilirubin levels were uncommon but occurred more often with zidovudine. Severe nausea (and/or vomiting) was rare (2.8% of subjects) but was associated with zidovudine. Milder patient-reported events were common, and a number were associated with zidovudine., Conclusion: Zidovudine at the 500-mg/d dosage appears to be tolerable in many patients with asymptomatic human immunodeficiency virus infection and CD4+ cell counts of 0.50 x 10(9)/L or less. Increased clinical surveillance for anemia may be warranted in certain patients.

Objectives: Analysis of changes in the spectrum of AIDS-defining conditions and their correlation with CD4+ lymphocyte counts in different risk groups associated with HIV transmission., Methods: Review of data from all adult AIDS cases reported in Germany between 1986 and 1991., Results: Among AIDS cases diagnosed between 1986 and 1991, the proportion of cases with lymphoma and wasting syndrome increased, while the proportion of Kaposi's sarcoma decreased. Homosexual men, but not intravenous drug users, showed a decrease in the proportion of cases in Pneumocystis carinii pneumonia and an increase in the proportions with toxoplasmosis and cytomegalovirus infection. The median CD4+ lymphocyte count at time of AIDS diagnosis decreased from 73 x 10(6)/l in 1986 (25 and 75 percentiles, 28 and 212) to 47 x 10(6)/l in 1990 (25 and 75 percentiles, 20 and 120; P less than 0.01). This decrease was the result of reduced CD4+ lymphocyte counts of individuals presenting with opportunistic infections; there was no corresponding change for individuals with non-infectious AIDS-defining conditions., Conclusions: AIDS diagnosis is now occurring at a later time in the natural history of HIV infection than in 1986, and the relative frequency of specific AIDS-defining conditions has changed. Most pronounced is a decrease of Pneumocystis carinii pneumonia. Changes in the natural history of HIV infection due to therapeutic and prophylactic interventions must be considered when interpreting epidemiological data in the course of the AIDS epidemic. These changes also have implications for the planning and execution of medical care.

Since 1982, voluntary anonymous reports that meet the criteria of the WHO/CDC-AIDS definition are being collected by the Federal Health Office. By December 31st, 1989 a total of 4,306 AIDS cases has been registered. More than 80% of the reported cases are homo- and bisexual men and injection drug-users. The remaining cases are divided between hemophiliacs, persons who get infected by heterosexual contacts, blood transfusion recipients, and children infected pre- or perinatally. In 16% of all cases AIDS was diagnosed only on the basis of a Kaposi's sarcoma (KS) and in another 6% on the basis of KS and an opportunistic infection (OI). KS occurred mostly in homo- and bisexual men. The relative proportion of KS has steadily decreased from 30% up to 1986 to less than 20% in 1989. The overall incidence of KS decreased mainly due to the decrease of KS in homosexual men with AIDS. OI were diagnosed in 70% of the cases. Pneumocystis-carinii-pneumonia is most frequent (47%), followed by candida-oesophagitis (19%) and toxoplasmosis of brain in 9.5%. A malignant lymphoma was diagnosed in 3% of the cases. Furthermore, HIV-encephalopathy was seen in 2.8% and HIV-wasting-syndrome in 1.6% of cases. There is a different spectrum of diseases at the first manifestation of AIDS diagnosed in injecting drug-users. The reasons for this may be due to different life-style in this group.

On the basis of an analysis of the data from the mandatory reporting of detected HIV infections and the reports to the central AIDS case registry an attempt is made to determine the total number of HIV infected individuals in the FRG. Results of surveys of testing behaviour in different risk groups were included in the calculations. For the calculation different estimates were used as to the total number of detected HIV infections, distribution of infections and percentage of detected infections in different risk groups. Depending on the estimates chosen a "best case" calculation yields 29,515 and the "worst case" calculation 81,949 HIV infected persons at the end of 1990. A synoptic analysis by the AIDS Center of the Federal Health Office resulted in an estimate of 50,000 to 60,000 HIV infected individuals in the FRG which is well between the "best" and "worst case" estimates.

Cytologic and histologic investigations of the uterine cervix and studies of the lymphocyte functions were performed in human immunodeficiency virus-infected and human immunodeficiency virus antibody-negative women to study possible linkages between human papillomavirus-induced dysplasia and degree of human immunodeficiency virus-induced immunosuppression. Cytologic smears of the uterine cervix of 111 human immunodeficiency virus-infected women were compared with findings in 76 female intravenous drug users negative for human immunodeficiency virus antibodies and in a group of 526 women of the outpatient population of the hospital. Cervical dysplasia-neoplasia (including five cases of invasive carcinoma) was seen in 41% of the human immunodeficiency virus-infected patients. In human immunodeficiency virus-negative intravenous drug users dysplasia-neoplasia was seen in 9%, and in the sample from outpatients in 4%, including two cases of invasive carcinoma (p less than 0.01). Cytologic features that were attributable to infection with human papillomavirus were observed in human immunodeficiency virus-infected women four times more often than in the sample from the outpatient population (p less than 0.01). Frequency and severity of dysplasia appear to increase with diminishing numbers of CD4+ helper/inducer T lymphocytes and correlated significantly (p less than 0.01) with a loss of blastogenic response to phytohemagglutinin, pokeweed mitogen, and tetanus toxoid. These results suggest an increased risk for the development of dysplasia of the uterine cervix in women with human immunodeficiency virus infection, which is related to the degree of immunosuppression.

Up to June 1991 a total of 6,604 AIDS cases were reported to the central AIDS-registry at the Federal Health Office. As typical for "pattern I" countries most of the AIDS-cases are homo/bisexual men (70%), followed by i.v. drug users (IDU, 13%). However, the proportion of homo/bisexual men is constantly decreasing since 1986 while the proportion of IDU's is increasing. As also observed in other industrialized countries a flattening off in the AIDS incidence curve is seen since 1989. Probable reasons for this observation are a decrease of new infections since 1984/85 (due to early saturation of the populations at highest risk and to the early onset of prevention campaigns in these populations) and improved therapeutic strategies in the prevention of AIDS indicating diseases. However, since about 60,000 people are estimated to be HIV infected in the FRG today AIDS incidence will remain on a stable level for the next years regardless the number of new infections occurring today. Since 1988 major changes in the distribution of AIDS indicating diseases are seen. While Kaposi's sarcoma is constantly decreasing non Hodgkin lymphomas, HIV encephalopathy and wasting syndrome are increasing. Due to the effective primary prophylaxis of pneumocystis carinii pneumonia (PCP) by pentamidine the proportion of PCP as AIDS-indicating opportunistic infection decreased from more than 60% in 1988 to 41% in 1991. The second most frequent opportunistic infection is now toxoplasmosis (19%). The changes in the distribution of AIDS-indicating diseases and the increasing proportion of IDU's have major implications on patient care as well as diagnostic and therapeutic procedures.

The prevalence of intestinal spirochaetosis was investigated in 39 HIV-positive homosexual males (mean age 39 [24-65] years) in different stages of HIV infection (3 with the lymphadenopathy syndrome, 8 with AIDS-related complex and 28 with AIDS). Biopsies for cultural and histological demonstration of spirochaetes were obtained during routine ileoscopies. At the time of examination 35 of the 39 patients had intestinal symptoms. 27 patients had had no previous antimicrobial treatment. In 12 of the 27 previously untreated patients with intestinal symptoms spirochaetes were demonstrated, to different extent, from the terminal ileum to the rectum, while the treated group of eight and the control group of four were negative. There were no significant inflammatory changes histologically. Treatment with metronidazole in most cases improved symptoms. In their ultrastructure the microorganisms showed several complete convolutions, cone-shaped cell endings, cell length of 4-18 microns, cell diameter of 0.21-0.35 microns and five subterminal flagella. Morphological considerations favour the inclusion of these microorganisms in the genus Treponema rather than Brachyspira.

Zidovudine (AZT) is a potent inhibitor of the replication of the human immunodeficiency virus (HIV), and it has been shown to improve survival in advanced HIV disease. We conducted a randomized, double-blind trial in adults with asymptomatic HIV infection who had CD4+ cell counts of fewer than 500 per cubic millimeter on entry into the study. The subjects (92 percent male) were randomly assigned to one of three treatment groups: placebo (428 subjects); zidovudine, 500 mg per day (453); or zidovudine, 1500 mg per day (457). After a mean follow-up of 55 weeks (range, 19 to 107), 33 of the subjects assigned to placebo had the acquired immunodeficiency syndrome (AIDS), as compared with 11 of those assigned to receive 500 mg of zidovudine (P = 0.002; relative risk, 2.8; 95 percent confidence interval, 1.4 to 5.6) and 14 of those assigned to receive 1500 mg of zidovudine (P = 0.05; relative risk, 1.9; 95 percent confidence interval, 1.0 to 3.5). In the three treatment groups, the rates of progression (per 100 person-years) to either AIDS or advanced AIDS-related complex were 7.6, 3.6, and 4.3, respectively. As compared with those assigned to placebo, the subjects in the zidovudine groups had significant increases in the number of CD4+ cells and significant declines in p24 antigen levels. In the 1500-mg zidovudine group, severe hematologic toxicity (anemia or neutropenia) was more frequent than in the other groups (P less than 0.0001). In the 500-mg zidovudine group, nausea was the only toxicity that was significantly more frequent (in 3.3 percent) than in the placebo group (P = 0.001). We conclude that zidovudine is safe and effective in persons with asymptomatic HIV infection and fewer than 500 CD4+ cells per cubic millimeter. Additional study will be required to determine whether such treatment will ultimately improve survival for persons infected with HIV.

Ultrathin section and surface replica electron microscopy were applied in combination with immunoelectron microscopy to elucidate the fine structure of HIV. The shell of the tubular core shows p24 antigenicity, while p17 is located at the inner leaflet of the lipid membrane. The virus particle is studded with 70-80 protrusions. These knobs have a diameter of 15 nm, a height of 9 nm, and are probably arranged in a T = 7 I symmetry. The major envelope protein gp120 is spontaneously shed from the viral surface. A possible role of released gp120 in pathogenesis is discussed.

A case of primary hepatocellular carcinoma (HCC) in a 17-year-old pregnant primigravida diagnosed during the 32nd week of pregnancy is presented. A live infant was delivered after induction of labour during the 33rd week. The mother, although still alive 3 months postpartum, had ongoing spread of the malignancy. Only 7 cases of primary liver cancer in pregnancy have been reported to date, with 100% maternal mortality and only 3 live infants. The literature and the diagnosis and management are discussed.