Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism.

The choroid plexuses (CPs) form a protective interface between the blood and the ventricular cerebrospinal fluid (CSF). To probe into the pathways by which CPs provide brain protection, we sought to evaluate the efficiency of glutathione conjugation in this barrier as a mechanism to prevent the entry of blood-borne electrophilic, potentially toxic compounds into the CSF, and we investigated the fate of the resulting metabolites. Rat CPs, as well as human CPs from both fetal and adult brains, displayed high glutathione-S-transferase activities. Using an in vitro model of the blood-CSF barrier consisting of choroidal epithelial cells cultured in a two-chambered device, we showed that glutathione conjugation can efficiently prevent the entry of 1-chloro-2,4-dinitrobenzene (CDNB) into the CSF, a model for electrophilic compounds. The duration of this enzymatic protection was set by the concentration of CDNB to which the epithelium was exposed, and this barrier effect was impaired only on severe epithelial intracellular glutathione and cysteine depletion. The conjugate was excreted from the choroidal cells in a polarized manner, mostly at the blood-facing membrane, via a high-capacity transport process, which is not a rate-limiting step in this detoxification pathway, and which may involve transporters of the ATP-binding cassette c(Abcc) and/or solute carrier 21 (Slc21) families. Supplying the choroidal epithelium at the blood-facing membrane with a therapeutically relevant concentration of N-acetylcysteine sustained this neuroprotective effect. Thus, glutathione conjugation at the CP epithelium coupled with the basolateral efflux of the resulting metabolites form an efficient blood-CSF enzymatic barrier, which can be enhanced by pharmacologically increasing glutathione synthesis within the epithelial cells.     

Risk factors of influenza transmission in households.

BACKGROUND: Influenza transmission in households is a subject of renewed interest, as the vaccination of children is currently under debate and antiviral treatments have been approved for prophylactic use. AIMS: To quantify the risk factors of influenza transmission in households. DESIGN OF STUDY: A prospective study conducted during the 1999 to 2000 winter season in France. SETTING: Nine hundred and forty-six households where a member, the index patient, had visited their general practitioner (GP) because of an influenza-like illness were enrolled in the study. Five hundred and ten of the index patients tested positive for influenza A (subtype H3N2). A standardised daily questionnaire allowed for identification of secondary cases of influenza among their household contacts, who were followed-up for 15 days. Of the 395 (77%) households that completed the questionnaire, we selected 279 where no additional cases had occurred on the day of the index patient's visit to the GP. METHODS: Secondary cases of influenza were those household contacts who had developed clinical influenza within 5 days of the disease onset in the index patient. Hazard ratios for individual clinical and demographic characteristics of the contact and their index patient were derived from a Cox regression model. RESULTS: Overall in the 279 households, 131 (24.1%) secondary cases occurred among the 543 household contacts. There was an increased risk of influenza transmission in preschool contacts (hazard ratio [HR] = 1.85, 95% confidence interval [CI] = 1.09 to 3.26) as compared with school-age and adult contacts. There was also an increased risk in contacts exposed to preschool index patients (HR = 1.93, 95% CI = 1.09 to 3.42) and school-age index patients (HR = 1.68, 95% CI = 1.07 to 2.65), compared with those exposed to adult index cases. No other factor was associated with transmission of the disease. CONCLUSION: Our results support the major role of children in the dissemination of influenza in households. Vaccination of children or prophylaxis with neuraminidase inhibitors would prevent, respectively, 32-38% and 21-41% of secondary cases caused by exposure to a sick child in the household.     

Gender differences in condom-related behaviors and attitudes among Mexican adolescents living on the U.S.-Mexico border.

Adolescents are at increasing risk for HIV infection in Mexico. Research on gender differences in risk behaviors and determinants is needed to develop effective HIV prevention interventions targeting Mexican adolescents. This study examined gender differences in the likelihood of unprotected sex and theoretical correlates among high school students in the border city of Tijuana. Three hundred seventy high-school students completed a face-to-face interview and a self-administered survey. Differences in sexual initiation, condom use, intentions to use condoms in the future, and attitudes towards condoms in this population were assessed. Although male students initiated sexual practices earlier than females, females were more likely to have unprotected sex. Females perceived themselves as more likely to avoid unprotected sex in the future and held more favorable attitudes about condoms. The results suggest that stereotypical gender roles and communication barriers place Tijuana female high school students at higher risk for HIV infection than their male peers.     

Increased circulating interleukin-7 levels in HIV-1-infected women

Sex-based differences in CD4 T-cell (CD4) counts are well recognized, but the basis for these differences has not been identified. Conceivably, homeostatic factors may play a role in this process by regulating T-cell maintenance and repletion. Interleukin (IL)-7 is essential for normal T-cell production and homeostasis. We hypothesized that differences in IL-7 might contribute to sex-based differences in CD4 counts. Circulating IL-7 levels were analyzed in 299 HIV-1-infected women and men. Regression analysis estimated that IL-7 levels were 40% higher in women than in men (P = 0.0032) after controlling for CD4 count, age, and race. Given the important role of IL-7 in T-cell development and homeostasis, these findings suggest that higher IL-7 levels may contribute to higher CD4 counts in women.     

Identification of two point mutations and a one base deletion in exon 19 of the dystrophin gene by heteroduplex formation

Two thirds of the Duchenne muscular dystrophy population haveeither gene deletions or duplications. The nondeletion/duplicationcases are most likely the result of point mutations or smalldeletions and duplications that cannot be easily identifiedby current strategies. The major obstacle in identifying smallmutations is due to the large size of the dystrophin gene. Weselectively screened 5 DMD exons containing CpG dinucleotidesin 110 DMD patients without detectable deletions or duplications.Nonsenses mutations are frequently due to a C- to -T transitionwithin a CG dinucleotide pair. To screen for the nonsense mutations,we used the heteroduplex method. Utilizing this approach, weidentified 2 different nonsense mutations and a single basedeletion all occurring in exon 19. This is the first reportof a clustering of small mutations in the the dystrophin gene.     

Decreased infectivity despite unaltered C3 binding by a DeltahbhA mutant of Mycobacterium tuberculosis

HbhA of Mycobacterium tuberculosis is a multifunctional binding protein, binding to both sulfated sugars such as heparin and to human complement component C3. HbhA may therefore interact with host molecules and/or host cells during M. tuberculosis infection and play a role in the pathogenesis of this bacterium. The purpose of this study was to use allelic exchange to create an M. tuberculosis strain deficient in expression of HbhA to determine whether this protein's C3-binding activity plays a role in the pathogenesis of M. tuberculosis. An in-frame, 576-bp unmarked deletion in the hbhA gene was created using sacB as a counterselectable marker. Southern blotting and PCR analyses confirmed deletion of hbhA in the DeltahbhA mutant. The DeltahbhA mutant strain grew at a rate similar to that of the parent in broth culture and in J774.A1 murine macrophage-like cells but was deficient in growth compared to the parent strain in the lungs, liver, and spleen of infected mice. In addition, the DeltahbhA mutation did not reduce binding of M. tuberculosis to human C3 or to J774.A1 cells in the presence or absence of serum, suggesting that in the absence of HbhA, other molecules serve as C3-binding molecules on the M. tuberculosis surface. Taken together, these data indicate that HbhA is important in the infectivity of M. tuberculosis, but its ability to bind C3 is not required for mycobacterial adherence to macrophage-like cells. Using the DeltahbhA mutant strain, a second M. tuberculosis C3-binding protein similar in size to HbhA was identified as HupB, but the role of HupB as a C3-binding protein in intact organisms remains to be determined.