Association between gingival parameters and Oral health-related quality of life in Caribbean adults: a population-based cross-sectional study.

BACKGROUND: Good oral health has been associated with better quality of life and general health. In the Caribbean, there have been no studies regarding the association between oral health conditions and the quality of life of the population. The main purpose of this study was to investigate the association between gingival parameters and oral health-related quality of life (OHRQoL) in Caribbean adults. A secondary aim of the study was to gain more information on factors that impact OHRQoL in this population. METHODS: This cross-sectional, epidemiological, population-based study was conducted in community settings. After the participants with missing Oral Health Impact Profile (OHIP) data were excluded, the sample size was 1821 (weighted according to the age and gender distribution in each target population). OHIP-14 standardized questionnaires were used to collect information. In addition, a medical/oral health questionnaire including sociodemographics, general health, dental visits, oral hygiene habits and knowledge, the frequency of dental visits, prosthesis use/hygiene, and smoking was administered. A multivariate model included predictors that showed significant associations in the univariate models. Odds ratios (ORs) and 95% confidence intervals (CIs) were reported; statistical significance was set at 0.05. RESULTS: In the multivariate analysis, current smokers (OR = 2.34, 95% CI: 1.74-3.14 vs. never smokers), those who visited the dentist only when problems arose (OR = 1.65, 95% CI: 1.13-2.40 vs. those visiting once a year), and participants with any chronic disease/condition (OR = 1.38, 95% CI: 1.06-1.78) had higher odds of being in the highest tertile for OHIP score (poorer health). CONCLUSIONS: The present multicenter study identified potential modifiable risk factors for poor OHRQoL among adults in three Caribbean cities.

Searching for non-B DNA-forming motifs using nBMST (non-B DNA motif search tool).

This unit describes basic protocols on using the non-B DNA Motif Search Tool (nBMST) to search for sequence motifs predicted to form alternative DNA conformations that differ from the canonical right-handed Watson-Crick double-helix, collectively known as non-B DNA, and on using the associated PolyBrowse, a GBrowse-based genomic browser. The nBMST is a Web-based resource that allows users to submit one or more DNA sequences to search for inverted repeats (cruciform DNA), mirror repeats (triplex DNA), direct/tandem repeats (slipped/hairpin structures), G4 motifs (tetraplex, G-quadruplex DNA), alternating purine-pyrimidine tracts (left-handed Z-DNA), and A-phased repeats (static bending). The nBMST is versatile, simple to use, does not require bioinformatics skills, and can be applied to any type of DNA sequences, including viral and bacterial genomes, up to an aggregate of 20 megabasepairs (Mbp).

Mechanism of the chemical step for the guanosine triphosphate (GTP) hydrolysis catalyzed by elongation factor Tu.

Elongation factor Tu (EF-Tu), the protein responsible for delivering aminoacyl-tRNAs (aa-tRNAs) to ribosomal A site during translation, belongs to the group of guanosine-nucleotide (GTP/GDP) binding proteins. Its active 'on'-state corresponds to the GTP-bound form, while the inactive 'off'-state corresponds to the GDP-bound form. In this work we focus on the chemical step, GTP+H(2)O-->GDP+Pi, of the hydrolysis mechanism. We apply molecular modeling tools including molecular dynamics simulations and the combined quantum mechanical-molecular mechanical calculations for estimates of reaction energy profiles for two possible arrangements of switch II regions of EF-Tu. In the first case we presumably mimic binding of the ternary complex EF-Tu.GTP.aa-tRNA to the ribosome and allow the histidine (His85) side chain of the protein to approach the reaction active site. In the second case, corresponding to the GTP hydrolysis by EF-Tu alone, the side chain of His85 stays away from the active site, and the chemical reaction GTP+H(2)O-->GDP+Pi proceeds without participation of the histidine but through water molecules. In agreement with the experimental observations which distinguish rate constants for the fast chemical reaction in EF-Tu.GTP.aa-tRNA.ribosome and the slow spontaneous GTP hydrolysis in EF-Tu, we show that the activation energy barrier for the first scenario is considerably lower compared to that of the second case.

Conformation dependence of pKa's of the chromophores from the purple asFP595 and yellow zFP538 fluorescent proteins.

Two members of the green fluorescent protein family, the purple asFP595 and yellow zFP538 proteins, are perspective fluorescent markers for use in multicolor imaging and resonance energy-transfer applications. We report the results of quantum based calculations of the solution pKa values for selected protonation sites of the denatured asFP595 and zFP538 chromophores in the trans- and cis-conformations in order to add in the interpretation of photophysical properties of these proteins. The pKa values were determined from the theromodynamic cycle based on B3LYP/6-311++G(2df,2p) calculations of the gas phase free energies of the molecules and the B3LYP/6-311++G(d,p) calculations of solvation energies. The results show that the pKa's of the protonation sites of the chromophore from asFP595 noticeably depend on the isomer conformation (cis- or trans-), while those of zFP538 are much less sensitive to isomerization.

(Salen)Mn(III)-catalyzed epoxidation reaction as a multichannel process with different spin states. Electronic tuning of asymmetric catalysis: a theoretical study.

The (salen)Mn(III)-catalyzed epoxidation reaction mechanism has been investigated using density functional theory (DFT). There is considerable interest in and controversy over the mechanism of this reaction. The results of experimental studies have offered some support for three different reaction mechanisms: concerted, stepwise radical, and metallooxetane mediated. In this paper, a theoretical examination of the reaction suggests a novel mechanism that describes the reaction as a multichannel process combining both concerted and stepwise radical pathways. The competing channels have different spin states: the singlet, the triplet, and the quintet. The singlet reaction pathway corresponds to a concerted mechanism and leads exclusively to a cis epoxide product. In contrast, the triplet and quintet reactions follow a stepwise mechanism and lead to a product mixture of cis and trans epoxides. We show that the experimentally observed dependence of isomer product ratios on electronic effects connected with the substitution of the catalyst ligands is due to changing the relative position and, hence, the relative activities of the channels with different cis-trans yields. Because the results and conclusions of the present work dramatically differ from the results and conclusion of the recent DFT theoretical investigation (Linde, C.; Akermark, B; Norrby, P.-O.; Svensson, M. J. Am. Chem. Soc. 1999, 121, 5083.), we studied possible sources for the deep contradictions between the two works. The choice of the DFT functional and a model has been shown to be crucial for accurate results. Using high level ab initio calculations (coupled cluster-CCSD(T)), we show that the computational procedure employed in this study generates significantly more reliable numerical results. It is also shown that the smaller cationic model without a chlorine ligand that was used by Linde et al. is too oversimplified with respect to our larger neutral model. For this reason, using the cationic model led to a qualitatively wrong quintet reaction profile that played a key role in theoretical postulates in the earlier work.

Behavioral and endocrine responses of hair sheep ewes exposed to different mating stimuli around estrus.

Hair sheep ewes were used to evaluate the influence of various levels of mating stimuli on the duration and timing of estrus and LH concentrations around estrus. Ewes were treated with PGF2alpha (15 mg, im) 10 d apart. At the time of the second PGF2alpha treatment (Day 0) ewes were placed in groups and exposed to different types of mating stimuli. One group of ewes (n = 16) was exposed to an epididymectomized ram (RAM), a second group of ewes (n = 16) was exposed to an epididymectomized ram wearing an apron to prevent intromission (APRON) and a third group of ewes (n = 17) was exposed to an androgenized ovariectomized ewe (T-EWE). Jugular blood samples were collected from ewes at 6-h intervals through Day 5. Plasma was harvested and LH concentration was determined by RIA. The ewes were observed at 6-h intervals to detect estrus. A ewe was considered to be out of estrus when she no longer stood to be mounted by the teaser animal. There was no difference (P > 0.10) in the proportion of ewes expressing estrus (79.6%) or having an LH surge (85.7%) among the treatments. Neither the time to estrus nor the duration of estrus were different (P > 0.10) among APRON, RAM or T-EWE groups (41.6+/-3.8 vs 43.6+/-3.6 vs 46.1+/-3.6 h, respectively, and 26.5+/-2.2 vs 24.8+/-2.3 vs 30.5+/-2.2 h, respectively). The time to LH surge was similar (P > 0.10) among APRON, RAM and T-EWE groups (51.2+/-4.5 vs 51.2+/-4.7 vs 52.7+/-4.5 h, respectively). The magnitude of the LH surge was similar (P > 0.10) in the T-EWE, APRON and RAM ewes (99.7+/-4.9 vs 87.2+/-4.9 vs 85.8+/-5.0 ng/mL, respectively). The time from estrus to the LH surge was not different (P > 0.10) among APRON, RAM or T-EWE ewes (10.1+/-2.2 vs 9.8+/-2.3 vs 11.6+/-2.3 h, respectively). These results show that the expression and duration of estrus are not influenced by different types of mating stimuli in hair sheep ewes. In addition, the timing and the magnitude of LH release does not appear to be influenced by mating stimuli around the time of estrus.

Estrus synchronization and artificial insemination of hair sheep ewes in the tropics

Hair sheep ewes (St. Croix White and Barbados Blackbelly) were used to evaluate 3 methods of estrus synchronization for use with transcervical artificial insemination (TAl). To synchronize estrus, ewes (n=18) were treated with PGF2alpha (15 mg, im) 10 d apart, with controlled internal drug release (CIDR) devices containing 300 mg progesterone for 12 d (n=18), or with intravaginal sponges containing 500 mg progesterone for 12 d (n=18). On the day of the second PGF2alpha injection or at CIDR or sponge removal, sterile rams were placed with the ewes. Jugular blood samples were collected from the ewes at 6-h intervals until the time of ovulation, and daily for 16 d after estrus (Day 0). Plasma was harvested and stored at -20 degrees C until LH, and progesterone concentrations were determined by RIA. There was no difference (P>0.10) in time to estrus among the CIDR-, PGF2 alpha- or sponge-treated ewes. All of the ewes in the CIDR group and 94.4 percent of the sponge treated ewes exhibited estrus by 36 h after ram introduction, while only 72.2 percent of PGF2alpha-treated ewes showed signs of estrus by this time (P<0.06). The time from ram introduction to ovulation was not different (P>0.10) among CIDR, PGF2alpha- or sponge-treated ewes. The time to preovulatory LH surge was similar (P>0.10) among treatment groups. Hair sheep ewes (n=23) were synchronized using PGF2alpha and bred by TAI using frozen-thawed semen 48 h after the second injection. The conception rate to TAI was 2/23 (8.7 percent) and produced 3 ram lambs. In a subsequent trial, 17 ewes were synchronized with CIDR devices and bred by TAI using frozen-thawed semen 48 h after CIDR removal, resulting in a conception rate of 52.9 percent (9/17). It is possible to synchronize estrus in hair sheep using either CIDRs, sponges or PGF2alpha. Even though there were no significant differences in the timing of ovulation or the LH surge among the treatment groups, a higher concentration rate was achieved in ewes synchronized with CIDR devices during the second trial. This may reflect an increase in the skill level of the TAI technician.(AU)

Estrus synchronization and artificial insemination of hair sheep ewes in the tropics.

Hair sheep ewes (St. Croix White and Barbados Blackbelly) were used to evaluate 3 methods of estrus synchronization for use with transcervical artificial insemination (TAI). To synchronize estrus, ewes (n = 18) were treated with PGF2alpha (15 mg, im) 10 d apart, with controlled internal drug release (CIDR) devices containing 300 mg progesterone for 12 d (n = 18), or with intravaginal sponges containing 500 mg progesterone for 12 d (n = 18). On the day of the second PGF2alpha injection or at CIDR or sponge removal, sterile rams were placed with the ewes. Jugular blood samples were collected from the ewes at 6-h intervals until the time of ovulation, and daily for 16 d after estrus (Day 0). Plasma was harvested and stored at -20 degrees C until LH, and progesterone concentrations were determined by RIA. There was no difference (P>0.10) in time to estrus among the CIDR-, PGF2alpha- or sponge-treated ewes. All of the ewes in the CIDR group and 94.4% of the sponge treated ewes exhibited estrus by 36 h after ram introduction, while only 72.2% of PGF2alpha-treated ewes showed signs of estrus by this time (P<0.06). The time from ram introduction to ovulation was not different (P>0.10) among the CIDR-, PGF2alpha- or sponge-treated ewes. The time to the preovulatory LH surge was similar (P>0.10) among CIDR, PGF2alpha and sponge treated ewes. Progesterone levels through Day 16 after the synchronized estrus were not different (P>0.10) among treatment groups. Hair sheep ewes (n = 23) were synchronized using PGF2alpha and bred by TAI using frozen-thawed semen 48 h after the second injection. The conception rate to TAI was 2/23 (8.7%) and produced 3 ram lambs. In a subsequent trial, 17 ewes were synchronized with CIDR devices and bred by TAI using frozen-thawed semen 48 h after CIDR removal, resulting in a conception rate of 52.9% (9/17). It is possible to synchronize estrus in hair sheep using either CIDRs, sponges or PGF2alpha. Even though there were no significant differences in the timing of ovulation or the LH surge among the treatment groups, a higher conception rate was achieved in ewes synchronized with CIDR devices during the second trial. This may reflect an increase in the skill level of the TAI technician.

Protein-binding domains of the tight junction protein, ZO-2, are highly conserved between avian and mammalian species.

The tight junction is composed of many proteins and includes three members of the MAGUK (membrane-associated, guanylate kinase-like) protein family: ZO-1, ZO-2, and ZO-3. ZO-2 was cloned and sequenced from embryonic chicken retina. Antibodies against a short ZO-2 peptide immunolabeled the outer limiting membrane (an adherens junction of the neural retina) and the apical junctional complexes of the retinal pigment epithelium. Each ZO family member contains a homologous series of protein-binding domains: three distinct PDZ domains and src homology 3 (SH3), guanylate kinase-like (GuK), and acidic domains. Compared with human and canine ZO-2s, the PDZ and SH3 domains are the most conserved (90-95% amino acid sequence identity). These domains are only 50-71% identical with the homologous domains of ZO-1 and ZO-3. Although the sequence is less conserved for regions that link the protein-binding domains, the length of those regions is conserved in ZO-2s. The postacidic (C-terminal) region is the least conserved. The evolutionary pressure to maintain the sequence of the protein-binding domains suggests that homologous domains have different functions in ZO-1, ZO-2, and ZO-3.

Occult systemic infection and persistent simian immunodeficiency virus (SIV)-specific CD4(+)-T-cell proliferative responses in rhesus macaques that were transiently viremic after intravaginal inoculation of SIV.

The intact cervicovaginal mucosa is a relative barrier to the sexual transmission of human immunodeficiency virus type 1 (HIV-1). In the simian immunodeficiency virus (SIV) macaque model of HIV infection, seronegative transient viremia (STV; virus isolation positive followed by repeated negative cultures) occurs after intravaginal inoculation of a low dose of pathogenic SIVmac251 (C. J. Miller, M. Marthas, J. Torten, N. Alexander, J. Moore, G. Doncel, and A. Hendrickx, J. Virol. 68:6391-6400, 1994). Thirty-one adult female macaques that had been inoculated intravaginally with pathogenic SIVmac251 became transiently viremic. One monkey that had been culture negative for a year after SIV inoculation became persistently viremic and developed simian AIDS. No other STV monkey developed persistent viremia or disease. Results of very sensitive assays showed that 6 of 31 monkeys had weak SIV-specific antibody responses. SIV-specific antibodies were not detected in the cervicovaginal secretions of 10 STV monkeys examined. Twenty of 26 monkeys had lymphocyte proliferative responses to p55(gag) and/or gp130(env) antigens; 3 of 6 animals, including the monkey that became persistently viremic, had detectable cytotoxic T-lymphocyte (CTL) responses to SIV. At necropsy, lymphoid tissues and vaginal mucosa were virus culture negative, but in 10 of 10 animals, SIV provirus was detected by PCR using gag-specific primer pairs. Fifty percent of the PCR-positive tissue samples were also positive for SIV gag RNA by reverse transcriptase PCR. Thus, transient viremia following intravaginal inoculation of pathogenic SIV is associated with persistent, systemic infection, either latent or very low level productive. Atypical immune responses, characterized by lymphocyte proliferation and some CTL responses in the absence of conventionally detectable antibodies, develop in transiently viremic monkeys.

Mucosal phenotype of antiviral cytotoxic T lymphocytes in the vaginal mucosa of SIV-infected rhesus macaques.

CD8+ T lymphocytes are present in the vaginal epithelium and submucosa of women and female rhesus macaques. Antiviral cytotoxic T lymphocyte precursors were detected in the vaginal intraepithelial lymphocyte (IEL) population of SIV-infected monkeys. Monoclonal antibodies to adhesion molecules distinguish lymphocytes that recirculate through peripheral lymphoid tissues (e.g., L-selectin) from mucosal lymphocytes that traffic through peripheral blood to the gut (e.g., the integrins alpha4beta7 and alphaEbeta7). Cytolytic CD8+ T cell lines from either peripheral blood or the vaginal epithelium of SIV-infected monkeys were stained with antibodies against these molecules. Three of three vaginal epithelial cell lines had the phenotype: alpha4beta7+/alphaEbeta7+/L-selectin-. Two of three peripheral blood cell lines had this phenotype and the other was positive for all three molecules. These results suggest that cytolytic vaginal IELs have the same mucosal phenotype as has been described for human and murine gut IELs, and that their precursors are destined to traffic through peripheral blood and return to the vaginal mucosa.

Evaluation of sexual behavior of hair sheep rams in a tropical environment.

We evaluated sexual behavior of St. Croix White (SC; n = 5) and Barbados Blackbelly hair (BB; n = 4) rams under two environmental conditions in the tropics. Sexually naive rams were individually exposed for 15 min to a restrained, ovariectomized ewe, three times during a 3-wk period in June, in a pen with shade (SHADE; 33.1+/-.3 degrees C) or without shade (SUN; 38.3+/-.3 degrees C). Rectal temperature (RT) of rams was measured before and after each test. Sexual behaviors were recorded by observers outside the pens. The number of mounts and ejaculations were similar (P > .10) between the SUN (12.1+/-2.8 and 3.6 +/-.5, respectively) and SHADE (10.7+/-2.9 and 3.4+/-.4, respectively) tests. There was no breed x test pen interaction for any of the behaviors recorded (P > .10). The BB rams mounted the ewe more (P < .04) than did the SC rams (15.7+/-2.8 vs 7.3+/-2.7 mounts, respectively). The overall level of activity (foreleg kicks, attempted mounts, mounts, and ejaculations) was similar (P > .10) between BB and SC rams (64.9 +/-8.5 vs 45.4+/-8.5 events, respectively). Rectal temperature before testing was similar (P > .10) in BB and SC rams (39.4+/-.1 vs 39.4+/-.1 degrees C, respectively). The change in RT of rams was not different (P > .10) between SUN and SHADE tests (.6 +/-.1 vs .8+/-.1 degrees C), but BB rams had a greater (P < .02) change in RT than SC rams (.9+/-.1 vs .5+/-.1 degrees C, respectively). The change in RT was positively correlated with time to first service (r = .39, P < .01) and number of mounts (r = .52, P < .001) and negatively correlated with number of services (r = -.47, P < .0008). These results show that under tropical conditions, hair sheep rams exhibit a full repertoire of sexual behaviors. There does not seem to be a negative influence of elevated ambient temperature during testing on the level of sexual behavior of these rams.

The effect of ram exposure on uterine involution and luteal function during the postpartum period of hair sheep ewes in the tropics.

St. Croix White hair sheep ewes lambing in July (n = 20) or November (n = 26) were used to evaluate the effect of ram exposure on uterine involution and postpartum luteal function. Ewes were exposed to an epididymectomized ram (EXPOSED) beginning on d 7 after lambing (d 0) or kept isolated from rams (CONTROL) through d 63. The width of each uterine horn was measured using transrectal ultrasonography at 3.5-d intervals beginning within 3 d after lambing. Jugular blood samples were also collected at these times, and plasma was harvested for progesterone (P4) analysis. Days to first estrus postpartum was not different (P > .10) between EXPOSED ewes that lambed in July or November (39.3 +/- 3.1 vs 44.2 +/- 3.8 d, respectively). Cross-sectional area of uterine horns was not different (P > .10) between EXPOSED and CONTROL ewes, ewes bearing one or two lambs, or ewes that lambed in November or July. Cross-sectional area of uterine horns in EXPOSED and CONTROL ewes had decreased to < 30% of initial values by 28 d postpartum (P < .0001). Ewes exposed to rams had a P4 concentration greater than 1 ng/mL sooner postpartum (P < .006) than CONTROL ewes (32.4 +/- 2.4 vs 42.1 +/- 2.3 d, respectively). The P4 concentration in the first sample greater than 1 ng/mL was greater (P < .06) in EXPOSED ewes than in CONTROL ewes (3.3 +/- .4 vs 2.3 +/- .4 ng/mL, respectively). In July, ewes exposed to rams had greater (P < .03) P4 concentrations than CONTROL ewes during the 63 d after parturition, but this difference was not apparent (P > .10) in ewes that lambed in November. Ram exposure did not hasten uterine involution in hair sheep ewes in the tropics. Luteal function, determined by plasma P4 concentrations, was enhanced by ram exposure during July but not during November. The lack of seasonality of hair sheep in the tropics does not seem to totally inhibit the response of ewes to ram exposure.

Structure-based subsite specificity mapping of human cathepsin D using statine-based inhibitors.

Human cathepsin D is a lysosomal aspartic protease that has been implicated in breast cancer metastasis and Alzheimer's disease. Based on a crystal structure of a human cathepsin D-pepstatin A complex, a series of statine-containing inhibitors was designed, synthesized, and tested for inhibitory activity toward the enzyme in vitro. The compounds were modified systematically at individual positions (P4, P3, P2, P1, and P2t) with the aim of mapping the cathepsin D subsite preferences. The experimentally obtained SAR data were correlated on the basis of molecular modeling. Side-chain preferences for the peptidomimetic inhibitors differed from those found previously using peptide substrates (Scarborough PE et al., 1993, Protein Sci 2:264-276). In addition, the effects of single side-chain modifications were often nonadditive. Structure-activity relationships, modeling, and thermodynamic analysis indicated that entropy plays a major stabilizing role in inhibitor binding to cathepsin D.

A comparison of two methods of oestrous synchronisation of hair sheep in the tropics.

Two trials were conducted to evaluate the efficacy of oestrous synchronisation procedures in St. Croix White, Barbados Blackbelly hair and Florida Native wool ewes. In Trial 1 (conducted in June), 27 ewes were treated with controlled internal drug release (CIDR) devices for 12 days (CIDR1) and 29 untreated ewes served as controls (CONT). The CIDR devices were removed on the same day that intact rams equipped with marking harnesses were placed with the ewes. Time to oestrus after ram introduction was shorter (P < 0.0001) in CIDR1 than CONT ewes. Within 3 days of ram introduction 100% of CIDR1 ewes but only 37.9% of CONT ewes had been in oestrus (P < 0.0001). Conception rate at first oestrus after ram introduction was 74.1% overall, with no effect (P > 0.10) of treatment, but days to conception were shorter (P < 0.001) in CIDR1 than CONT ewes. Ovulation rate at first oestrus after ram introduction was not different (P > 0.10) between CIDR1 and CONT ewes. The CIDR1 ewes lambed earlier (P < 0.004) in the lambing season than CONT ewes, but there was no difference in the number of lambs born per ewe (P > 0.10). In Trial 2 (conducted in October), 14 St. Croix White ewes were treated with CIDRs as in Trial 1 (CIDR2) and 14 St. Croix White ewes were given two i.m. injections (15 mg) of prostaglandin F2 alpha (PGF) 10 days apart. Intact rams were introduced on the day of CIDR removal or the second PGF injection. The CIDR2 ewes exhibited oestrus earlier (P < 0.01) than PGF treated ewes. The conception rate to breeding at the synchronised oestrus was similar (P > 0.10) between CIDR2 and PGF treated ewes. Progesterone concentration on Day 10 after the synchronised oestrus was not different (P > 0.10) between CIDR2 and PGF treated ewes. These results indicate that oestrous synchronisation procedures can be used in sheep in the tropics without adversely affecting fertility. Due to a lack of seasonal anoestrous these procedures have the potential to be used during all times of the year.

Fetal or neonatal infection with attenuated simian immunodeficiency virus results in protective immunity against oral challenge with pathogenic SIVmac251.

We have reported that infection of fetal or neonatal rhesus macaques with attenuated SIVmac1A11 results in transient viremia, anti-SIV antibody responses, weak or absent cytotoxic T-lymphocyte responses, and no clinical disease. In light of these results, we hypothesized that congenital infection with SIVmac1A11 produced immune tolerance to SIV. To test this hypothesis, at approximately 1 year of age, five rhesus macaques infected with SIVmac1A11 as fetuses (n = 3) or newborns (n = 2) and five naive juvenile rhesus macaques were challenged orally with pathogenic SIVmac251. The five naive animals became persistently viremic after oral SIVmac251 inoculation. In contrast, one of three monkeys inoculated with SIVmac1A11 in utero and one of two animals inoculated with SIVmac1A11 at birth were virus culture negative. Virus was isolated from PBMC of the other animals infected with SIVmac1A11 in utero or at birth. However, one animal had a substantially lower viral load than the control animals. These results suggest that SIV-specific immunity rather than tolerance results from congenital infection with attenuated SIVmac and that this immunity is sufficient to provide some protection from pathogenic virus challenge. These results also demonstrate that SIV can be transmitted orally in 6- to 17-month-old rhesus monkeys.

Virus-induced immunosuppression is linked to rapidly fatal disease in infant rhesus macaques infected with simian immunodeficiency virus.

Six newborn rhesus macaques were experimentally infected with pathogenic Simian immunodeficiency virus of macaques (SIVmac251), and three newborn macaques were infected with avirulent SIVmac1A11. The former developed rapidly fatal simian AIDS and died within 26 wk of age, whereas the latter remained clinically normal. Infant monkeys that developed rapidly progressive disease had rapid declines in CD4+ cells and were unable to mount IgG and IgA antibody responses to SIV or to an unrelated antigen, tetanus toxoid. IgM antibody responses were near normal to both SIV-specific and nonspecific antigens. Cytotoxic T lymphocyte (CTL) responses to SIV envelope were observed in animals infected with either virulent or avirulent SIV. These studies demonstrated that virulent SIVmac infection induced a rapid immunosuppression that was both SIV-specific and nonspecific in nature. The observation that virulent strains of SIV can rapidly induce a global immunosuppression provides one explanation for the rapid disease course in some HIV-infected children and supports the strategy of early and vigorous antiviral drug therapy to alter the disease course even if this does not prevent infection.

Flap opening in HIV-1 protease simulated by 'activated' molecular dynamics.

We have used an 'activated' molecular dynamics approach to simulate flap opening in HIV-1 protease. An initial impulse for flap opening was provided by applying harmonic constraints to non-flap residues. After an initial 'melting' phase, the two beta-hairpin structures that constitute the flaps opened to a 25 A gap within 200 ps of simulation. Analysis of backbone torsion angles suggests that flap opening is related to conformational changes at Lys 45, Met 46, Gly 52 and Phe 53. In contrast, similar molecular dynamics simulations on the M46I mutant, which is associated with drug resistance, indicates that this mutation stabilizes the flaps in a closed conformation.

Seizures and other neurologic manifestations of allergy.

Numerous disease entities affecting the nervous system can be attributed at least in part to immune responses. Neurons have been shown to have receptors from many of the vasoactive neurotransmitter and neuromodulator molecules first studied as mediators of inflammation and immediate hypersensitivity (Type 1 response). Immune responses have now been proven to affect CNS and peripheral neurons. In the diagnostic workup, consideration should be given to the possibility of immune-related causes for seizures and some other neurologic disorders.