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Biomedical subjects

T Warren

Publications and source records attributed to T Warren.

At least 19 recordsLinked to original sources
PubMed2006

Sexual behaviour and condom use among individuals with a history of symptomatic genital herpes.

OBJECTIVES: This study describes the differences in sexual behaviour in individuals with genital herpes (GH) during "symptomatic" and "asymptomatic" periods of the disease. METHODS: A cross sectional questionnaire was undertaken by 1193 individuals attending clinics between 1998 and 2001. All participants in this analysis were in heterosexual, monogamous partnerships, self identified with a history of symptomatic GH and with confirmed HSV-2 infection. RESULTS: Sexual activity reported during asymptomatic v symptomatic periods of GH was 98% v 40% (p<0.001), 76% v 29% (p<0.001), and 25% v 11% (p<0.001) for vaginal, oral, and anal intercourse, respectively, while "always" condom use during asymptomatic and symptomatic periods was 20% v 35% (p<0.001), 2% v 7% (p<0.001), and 10% v 15% (p = 0.131), respectively. The proportion of individuals who either abstained from vaginal intercourse or "always" used condoms was 21% v 74% (p<0.001), for asymptomatic v symptomatic periods. Multivariable analyses indicated that factors associated with engaging in intercourse during symptomatic periods of GH included current intrauterine device use (adjusted odds ratio (aOR) = 2.96, 95% confidence interval (CI) = 1.46 to 6.02); living in Latin America (aOR = 2.16, CI = 1.19 to 3.91) or Europe (aOR = 1.67, CI = 1.21 to 2.28), compared with North America; previous sexually transmitted disease (aOR = 1.42, CI = 1.08 to 1.89); a higher number of sexual acts per month (aOR = 1.09, CI = 1.06 to 1.11); and a higher number of GH recurrences per year (aOR = 1.08, CI = 1.03 to 1.12). CONCLUSIONS: These data indicate that the majority of people with GH either abstained from intercourse or "always" used condoms during symptomatic periods of GH. However, condom use was relatively low during asymptomatic periods in comparison with symptomatic periods. These results highlight that further education on GH prevention is warranted, particularly for symptomatic periods.

Adult↗
PubMed2002

Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2).

Streptomyces coelicolor is a representative of the group of soil-dwelling, filamentous bacteria responsible for producing most natural antibiotics used in human and veterinary medicine. Here we report the 8,667,507 base pair linear chromosome of this organism, containing the largest number of genes so far discovered in a bacterium. The 7,825 predicted genes include more than 20 clusters coding for known or predicted secondary metabolites. The genome contains an unprecedented proportion of regulatory genes, predominantly those likely to be involved in responses to external stimuli and stresses, and many duplicated gene sets that may represent 'tissue-specific' isoforms operating in different phases of colonial development, a unique situation for a bacterium. An ancient synteny was revealed between the central 'core' of the chromosome and the whole chromosome of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae. The genome sequence will greatly increase our understanding of microbial life in the soil as well as aiding the generation of new drug candidates by genetic engineering.

Bacterial Proteins↗
PubMed2002

The genome sequence of Schizosaccharomyces pombe.

We have sequenced and annotated the genome of fission yeast (Schizosaccharomyces pombe), which contains the smallest number of protein-coding genes yet recorded for a eukaryote: 4,824. The centromeres are between 35 and 110 kilobases (kb) and contain related repeats including a highly conserved 1.8-kb element. Regions upstream of genes are longer than in budding yeast (Saccharomyces cerevisiae), possibly reflecting more-extended control regions. Some 43% of the genes contain introns, of which there are 4,730. Fifty genes have significant similarity with human disease genes; half of these are cancer related. We identify highly conserved genes important for eukaryotic cell organization including those required for the cytoskeleton, compartmentation, cell-cycle control, proteolysis, protein phosphorylation and RNA splicing. These genes may have originated with the appearance of eukaryotic life. Few similarly conserved genes that are important for multicellular organization were identified, suggesting that the transition from prokaryotes to eukaryotes required more new genes than did the transition from unicellular to multicellular organization.

Base Sequence↗
PubMed2001

Divergent therapeutic and immunologic effects of oligodeoxynucleotides with distinct CpG motifs.

Immune stimulatory oligodeoxynucleotides (ODN) with unmethylated CpG motifs are potent inducers of both innate and adaptive immunity. It initially appeared that a single type of optimal CpG motif would work in all applications. We now report that specific motifs of CpG ODN can vary dramatically in their ability to induce individual immune effects and that these differences impact on their antitumor activity in different tumor models. In particular, a distinct type of CpG motif, which has a chimeric backbone in combination with poly(G) tails, is a potent inducer of NK lytic activity but has little effect on cytokine secretion or B cell proliferation. One such NK-optimized CpG ODN (1585) can induce regression of established melanomas in mice. Surprisingly, no such therapeutic effects were seen with CpG ODN optimized for activation of B cells and Th1-like cytokine expression (ODN 1826). The therapeutic effects of CpG 1585 in melanoma required the presence of NK but not T or B cells and were not associated with the induction of a tumor-specific memory response. In contrast, CpG 1826, but not CpG 1585, was effective at inducing regression of the EL4 murine lymphoma; this rejection was associated with the induction of a memory response and although NK cells were necessary, they were not sufficient. These results demonstrate that selection of optimal CpG ODN for cancer immunotherapy depends upon a careful analysis of the cellular specificities of various CpG motifs and an understanding of the cellular mechanisms responsible for the antitumor activity in a particular tumor.

Adjuvants, Immunologic↗
PubMed2001

Effect of condoms on reducing the transmission of herpes simplex virus type 2 from men to women.

CONTEXT: Herpes simplex virus type 2 (HSV-2) is one of the most common sexually transmitted infections in the United States. No prospective study has shown the ability of condoms to reduce transmission of HSV-2. OBJECTIVE: To evaluate risk factors for HSV-2 acquisition and efficacy of condoms in prevention of HSV-2 transmission. DESIGN: Analysis of data from a randomized, double-blind, placebo-controlled trial conducted December 13, 1993, to June 28, 1996, of an ineffective candidate HSV-2 vaccine with 18 months of follow-up. SETTING: Eighteen clinical trial centers in the United States. PARTICIPANTS: A total of 528 monogamous couples discordant for HSV-2 infection, including an HSV-2-susceptible population of 261 men and 267 women. MAIN OUTCOME MEASURE: Acquisition of HSV-2 infection by susceptible partners, compared with those remaining free of HSV-2 with regard to demographic characteristics, sexual activity, and condom use. RESULTS: Twenty-six women (9.7%) vs 5 men (1.9%) acquired HSV-2, for a rate per 10 000 sex acts (episodes of sexual intercourse) of 8.9 vs 1.5, respectively (P<.001). In multivariable analysis, younger age (adjusted hazard ratio [HR] per 5 years, 1.57; 95% confidence interval [CI], 1.22-2.04), seropositivity for HSV-1 and HSV-2 vs HSV-2 alone in the source partner (adjusted HR, 2.34; 95% CI, 1.14-4.82), and more frequent sexual activity (adjusted HR per additional sex act per week, 1.10; 95% CI, 1.01-1.19) were associated with higher risk of HSV-2 acquisition. Condom use during more than 25% of sex acts was associated with protection against HSV-2 acquisition for women (adjusted HR, 0.085; 95% CI, 0.01-0.67) but not for men (adjusted HR, 2.02; 95% CI, 0.32-12.50). Risk of HSV-2 transmission declined from 8.5 per 100 person-years in the initial 150-day interval to 0.9 per 100 person-years in the final 150-day interval (P =.002 for trend), concurrent with a decrease in sexual activity and proportion of sex acts occurring when the source partner had genital lesions. CONCLUSIONS: Condom use offers significant protection against HSV-2 infection in susceptible women. Changes in sexual behavior, correlated with counseling about avoiding sex when a partner has lesions, were associated with reduction in HSV-2 acquisition over time. These data suggest that identification of discordant couples can reduce transmission of HSV-2, especially for heterosexual couples in which the male partner has HSV-2 infection.

Acyclovir↗
PubMed2000

Reactivation of genital herpes simplex virus type 2 infection in asymptomatic seropositive persons.

BACKGROUND: Most persons who have serologic evidence of infection with herpes simplex virus (HSV) type 2 (HSV-2) are asymptomatic. Historically, it has been assumed that these persons have less frequent viral reactivation than those with symptomatic infection. METHODS: We conducted a prospective study to investigate genital shedding of HSV among 53 subjects who had antibodies to HSV-2 but who reported having no history of genital herpes, and we compared their patterns of viral shedding with those in a similar cohort of 90 subjects with symptomatic HSV-2 infection. Genital secretions of the subjects in both groups were sampled daily and cultured for HSV for a median of 94 days. RESULTS: HSV was isolated from the genital mucosa in 38 of the 53 HSV-2-seropositive subjects (72 percent) who reported no history of genital herpes, and HSV DNA was detected by the polymerase-chain-reaction assay in cultures prepared from genital mucosal swabs in 6 additional subjects. The rate of subclinical shedding of HSV in the subjects with no reported history of genital herpes was similar to that in the subjects with such a history (3.0 percent vs. 2.7 percent). Of the 53 subjects who had no reported history of genital herpes, 33 (62 percent) subsequently reported having typical herpetic lesions; the duration of their recurrences in these subjects was shorter (median, three days vs. five days; P<0.001) and the frequency lower (median, 3.0 per year vs. 8.2 per year; P<0.001) than in the 90 subjects with previously diagnosed symptomatic infection. Only 1 of these 53 subjects had no clinical or virologic evidence of HSV infection. CONCLUSIONS: Seropositivity for HSV-2 is associated with viral shedding in the genital tract, even in subjects with no reported history of genital herpes.

Adult↗
PubMed2000

The lower hydrolysis of ATP by the stress protein GroEL is a major factor responsible for the diminished chaperonin activity at low temperature.

The chaperonins GroEL and GroES were shown to facilitate the refolding of urea-unfolded rhodanese in an ATP-dependent process at 25 or 37 degrees C. A diminished chaperonin activity was observed at 10 degrees C, however. At low temperature, GroEL retains its ability to form a complex with urea-unfolded rhodanese or with GroES. GroEL is also able to bind ATP at 10 degrees C. Interestingly, the ATPase activity of GroEL was highly decreased at low temperatures. Hydrolysis of ATP by GroEL was 60% less at 10 degrees C than at 25 degrees C. We conclude that the reduced hydrolysis of ATP by GroEL is a major but perhaps not the only factor responsible for the diminished chaperonin activity at 10 degrees C. GroEL may function primarily at higher temperatures in which the ability of GroEL to hydrolyze ATP is not compromised.

Adenosine Triphosphate↗
PubMed2000

Serum haptoglobin: an objective indicator of experimentally-induced Salmonella infection in calves.

Experimental models of Salmonella -induced gastroenteritis have previously relied on crude subjective clinical markers of infection to assess disease severity. The aim of this study was to investigate the possibility that changes in serum levels of the acute phase protein, haptoglobin, may be used as an objective, quantitative measurement of infection. Eight 3- to 4-week-old animals were challenged with a mixture of three Salmonella serotypes containing 6 x 10(10)bacteria and compared with five animals given a placebo preparation. Animals were monitored and characteristic clinical symptoms of infection; diarrhoeal scores, morbidity scores and rectal temperature, were recorded. Serum samples, from both animal groups, taken prior to challenge and again on days 1, 3, and 5 post-challenge, were analysed for haptoglobin levels using a direct serum binding assay. Prior to challenge, all 13 animals had normal levels of haptoglobin in their serum. By day 3 post-challenge six of eight animals challenged with Salmonella had abnormal serum haptoglobin levels (median level = 212 microg ml(-1)), while haptoglobin levels remained normal in placebo-challenged animals (median level = 0 microg ml(-1)). The change in haptoglobin levels during the 5-day observation period was statistically significant in the Salmonella -challenged animals (P = 0.0003, H = 16.477). Serum haptoglobin levels showed a statistical correlation with clinical measures of disease severity; diarrhoeal scores (P = 0.0015, H =8. 988), morbidity scores (P = 0.0004, H = 15.711) and rectal temperature (P = 0.0001, Z = 4.304). Thus, serum haptoglobin levels closely reflect the clinical symptoms of infection and are therefore a useful marker of infection severity in salmonellosis in calves.

Animals↗
PubMed1999

Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. Chiron HSV Vaccine Study Group.

CONTEXT: In the last 3 decades, herpes simplex virus type 2 (HSV-2) infection seroprevalence and neonatal herpes have increased substantially. An effective vaccine for the prevention of genital herpes could help control this epidemic. OBJECTIVE: To evaluate the efficacy of a vaccine for prevention of HSV-2 infection. DESIGN: Two randomized, double-blind, placebo-controlled multicenter trials of a recombinant subunit vaccine containing 30 microg each of 2 major HSV-2 surface glycoproteins (gB2 and gD2) against which neutralizing antibodies are directed, administered at months 0, 1, and 6. Control subjects were given a citrate buffer vehicle. Participants were followed up for 1 year after the third immunization. SETTING AND PARTICIPANTS: We enrolled 2393 persons from December 10, 1993, to April 4, 1995, who were HSV-2 and human immunodeficiency virus seronegative. One trial with 18 centers enrolled 531 HSV-2-seronegative partners of HSV-2-infected persons; the other, with 22 centers, enrolled 1862 persons attending sexually transmitted disease clinics. A total of 2268 (94.8%) met inclusion criteria and were included in the analysis with 1135 randomized to placebo and 2012 to vaccine. MAIN OUTCOME MEASURE: Time to acquisition of HSV-2 infection, defined by seroconversion or isolation of HSV-2 in culture during the study period by randomization group. RESULTS: Time-to-event curves indicated a 50% lower acquisition rate among vaccine vs placebo recipients during the initial 5 months of the trial; however, overall vaccine efficacy was 9% (95% confidence interval, -29% to 36%). Acquisition rates of HSV-2 were 4.6 and 4.2 per 100 patient-years in the placebo and vaccine recipients, respectively (P =.58). Follow-up of vaccine recipients acquiring HSV-2 infection showed vaccination had no significant influence on duration of clinical first genital HSV-2 episodes (vaccine, median of 7.1 days; placebo, 6.5 days; P>.10) or subsequent frequency of reactivation (median monthly recurrence rate with vaccine, 0.2; with placebo, 0.3; P>.10). The vaccine induced high levels of HSV-2-specific neutralizing antibodies in vaccinated persons who did and did not develop genital herpes. CONCLUSIONS: Efficient and sustained protection from sexual acquisition of HSV-2 infection will require more than high titers of specific neutralizing antibodies. Protection against sexually transmitted viruses involving exposure over a prolonged period will require a higher degree of vaccine efficacy than that achieved in this study.

Adolescent↗
PubMed1999

Association of major histocompatibility complex determinants with the development of symptomatic and asymptomatic genital herpes simplex virus type 2 infections.

The clinical spectrum of herpes simplex virus (HSV) infections, ranging from asymptomatic to frequently distressing outbreaks, suggests that there may be immunologic determinants of disease severity that are associated with human leukocyte antigen (HLA) expression. A controlled, prospective study identified several major histocompatibility complex (MHC) class I and II antigens whose frequencies are associated with HSV-2 infection or with frequent symptomatic genital recurrences. Previous studies were hampered by the inability to serologically identify patients with asymptomatic HSV-2 infection. Clinical evaluation and Western blot assay were used to identify 3 subject cohorts: 1 with no prior HSV infections, 1 with HSV-2 antibodies but no recognized symptoms, and 1 with HSV-2 antibodies and frequent genital recurrences. Statistical comparisons of HLA frequencies among these cohorts showed associations of HLA-B27 and -Cw2 with symptomatic disease. Also, HLA-Cw4 was significantly associated with HSV-2 infection. These associations indicate that immunologic factors linked to the MHC influence the risk of HSV-2 infection and disease expression.

Adult↗
PubMed1996

The ATPase activity of chaperonin GroEL is highly stimulated at elevated temperatures.

The chaperonin GroEL is a heat-shock protein that stabilizes folding intermediates by forming binary complexes. The release of bound polypeptides as active proteins requires ATP hydrolysis by GroEL. The ability of GroEL to support the folding of urea-unfolded rhodanese and to hydrolyze ATP was investigated at high temperatures. We found that the chaperonin-mediated folding of rhodanese and the ATPase activity of GroEL are temperature dependent. The GroEL ATPase activity, however, increases very strongly over the range of temperatures that is physiologically relevant for Escherichia coli growth. Further, GroES partially suppresses the GroEL ATPase activity in the same temperature range.

Adenosine Triphosphatases↗
PubMed1989

Vascular permeability factor, an endothelial cell mitogen related to PDGF.

Vascular permeability factor (VPF) is a 40-kilodalton disulfide-linked dimeric glycoprotein that is active in increasing blood vessel permeability, endothelial cell growth, and angiogenesis. These properties suggest that the expression of VPF by tumor cells could contribute to the increased neovascularization and vessel permeability that are associated with tumor vasculature. The cDNA sequence of VPF from human U937 cells was shown to code for a 189-amino acid polypeptide that is similar in structure to the B chain of platelet-derived growth factor (PDGF-B) and other PDGF-B-related proteins. The overall identity with PDGF-B is 18%. However, all eight of the cysteines in PDGF-B were found to be conserved in human VPF, an indication that the folding of the two proteins is probably similar. Clusters of basic amino acids in the COOH-terminal halves of human VPF and PDGF-B are also prevalent. Thus, VPF appears to be related to the PDGF/v-sis family of proteins.

Amino Acid Sequence↗
PubMed1989

N-glycosylation and in vitro enzymatic activity of human recombinant tissue plasminogen activator expressed in Chinese hamster ovary cells and a murine cell line.

To probe the effects of N-glycosylation on the fibrin-dependent plasminogenolytic activity of tissue-type plasminogen activator (t-PA), we have expressed a human recombinant t-PA (rt-PA) gene in Chinese hamster ovary (CHO) cells and in a murine C127 cell line. The resulting rt-PA glycoproteins were isolated and their associated N-linked oligosaccharide structures determined by using a combination of high-resolution Bio-Gel P-4 gel filtration chromatography, sequential exoglycosidase digestion, and methylation analysis. The results show that CHO rt-PA is N-glycosylated differently from murine C127 derived rt-PA. Further, both rt-PA's are N-glycosylated differently from t-PA derived from a human colon fibroblast and the Bowes melanoma cell line (Parekh et al., 1989), confirming that N-glycosylation of the human t-PA polypeptide is cell-type-specific. Both CHO and murine rt-PA were fractionated on lysine-Sepharose chromatography. The N-glycosylation of the major forms was analyzed and their fibrin-dependent plasminogenolytic activity determined by using an indirect amidolytic assay with Glu-plasminogen and a chromogenic plasmin substrate. The results suggest that the various forms of rt-PA differ from one another with respect to the kinetics of their fibrin-dependent activation of plasminogen. Together, these data support the notion (Wittwer et al., 1989) that N-glycosylation influences the fibrin-dependent catalytic activity of t-PA and that t-PA when expressed in different cell lines may consist of kinetically and structurally distinct glycoforms.

Animals↗
PubMed1988

A related moderately repetitive DNA family in the nematodes Ascaris lumbricoides and Panagrellus silusiae.

Digestion of genomic DNA from the nematodes Panagrellus silusiae and Ascaris lumbricoides with restriction endonuclease BamH1 releases a 0.7 kilobase (kb) fragment. The 0.7 kb fragment from both nematodes was cloned onto E. coli plasmid pUC19. Using representative clones as DNA hybridization probes, it was found that (i) the BamH1 fragments cross-hybridize; (ii) a ladder-effect with multiples of 0.7 kb was evident in both species after hybridization to genomic DNA and (iii) the genomic copy number of BamH1 elements is 150 and 195 for P. silusiae and A. lumbricoides respectively. DNA sequence analysis of the inserts, AL700-1 and PS700-1, revealed nucleotide blocks with over 85% similarity. No open reading frames are present in either DNA fragment. Neither fragment hybridizes to genomic DNA from Caenorhabditis elegans. Northern blot hybridization indicated that the 0.7 kb element is transcribed into poly(A)(-)-RNA in P. silusiae; but, is not transcribed in adult Ascaris muscle. Thus, P. silusiae and A. lumbricoides share a homologous, tandemly arrayed, moderately repetitive DNA family.

Animals↗
PubMed1985

Neurologic signs in senescence.

We examined 2,029 volunteers 50 to 93 years of age in a cross-sectional study of nine bedside neurologic tests to determine the frequency of "abnormal" responses in uncomplicated aging (senescence). Rates of abnormal responses remained constant until age 70 years, after which they increased significantly. The number of abnormal signs per subject also increased, especially over 70 years of age. These results provide normative data against which these signs may be compared when applied as a clinical screening battery for diffuse cerebral dysfunction.

Aged↗