Antitumour potential of BPT: a dual inhibitor of cdk4 and tubulin polymerization.

The marine natural product fascaplysin (1) is a potent Cdk4 (cyclin-dependent kinase 4)-specific inhibitor, but is toxic to all cell types possibly because of its DNA-intercalating properties. Through the design and synthesis of numerous fascaplysin analogues, we intended to identify inhibitors of cancer cell growth with good therapeutic window with respect to normal cells. Among various non-planar tryptoline analogues prepared, N-(biphenyl-2-yl) tryptoline (BPT, 6) was identified as a potent inhibitor of cancer cell growth and free from DNA-binding properties owing to its non-planar structure. This compound was tested in over 60 protein kinase assays. It displayed inhibition of Cdk4-cyclin D1 enzyme in vitro far more potently than many other kinases including Cdk family members. Although it blocks growth of cancer cells deficient in the mitotic-spindle checkpoint at the G0/G1 phase of the cell cycle, the block occurs primarily at the G2/M phase. BPT inhibits tubulin polymerization in vitro and acts as an enhancer of tubulin depolymerization of paclitaxel-stabilized tubulin in live cells. Western blot analyses indicated that, in p53-positive cells, BPT upregulates the expression of p53, p21 and p27 proteins, whereas it downregulates the expression of cyclin B1 and Cdk1. BPT selectively kills SV40-transformed mouse embryonic hepatic cells and human fibroblasts rather than untransformed cells. BPT inhibited the growth of several human cancer cells with an IC50<1 µM. The pharmacokinetic study in BALB/c mice indicated good plasma exposure after intravenous administration. It was found to be efficacious at 1/10th the maximum-tolerated dose (1000 mg/kg) against human tumours derived from HCT-116 (colon) and NCI-H460 (lung) cells in SCID (severe-combined immunodeficient) mice models. BPT is a relatively better anticancer agent than fascaplysin with an unusual ability to block two overlapping yet crucial phases of the cell cycle, mitosis and G0/G1. Its ability to effectively halt tumour growth in human tumour-bearing mice would suggest that BPT has the potential to be a candidate for further clinical development.

Increased rainfall is associated with increased risk for legionellosis.

Legionnaires' disease (LD) is caused by Legionella species, most of which live in water. The Mid-Atlantic region experienced a sharp rise in LD in 2003 coinciding with a period of record-breaking rainfall. To investigate a possible relationship, we analysed the association between monthly legionellosis incidence and monthly rainfall totals from January 1990 to December 2003 in five Mid-Atlantic states. Using negative binomial model a 1-cm increase in rainfall was associated with a 2.6% (RR 1.026, 95% CI 1.012-1.040) increase in legionellosis incidence. The average monthly rainfall from May to September 1990-2002 was 10.4 cm compared to 15.7 cm from May to September 2003. This change in rainfall corresponds to an increased risk for legionellosis of approximately 14.6% (RR 1.146, 95% CI 1.067-1.231). Legionellosis incidence increased during periods of increased rainfall; identification of mechanisms that increase exposure and transmission of Legionella during rainfall might lead to opportunities for prevention.

Geographic epidemiology of gonorrhoea and chlamydia on a large military installation: application of a GIS system.

OBJECTIVES: The geographic epidemiology of infectious diseases can help in identifying point source outbreaks, elucidating dispersion patterns, and giving direction to control strategies. We sought to establish a geographic information system (GIS) infectious disease surveillance system at a large US military post (Fort Bragg, North Carolina) using STDs as the initial outcome for the model. METHODS: Addresses of incident cases were plotted onto digitised base maps of Fort Bragg (for on-post addresses) and surrounding Cumberland County, NC (for off-post addresses) using MAPINFO Version 5. We defined 26 geographic sectors on the installation. Active duty soldiers attending the post preventive medicine clinic were enrolled between July 1998 and June 1999. RESULTS: Gonorrhoea (GC) was diagnosed in 210/2854 (7.4%) and chlamydia (CT) in 445/2860 (15.6%). African-American male soldiers were at higher risk for GC (OR = 4.6 (95% CL 3.0 to 7.2)) and chlamydia (OR = 2.0 (1.4 to 2.7)). For women, there were no ethnic differences in gonorrhoea prevalence, but chlamydia was higher in African-Americans (OR = 2.0 (1.4-2.7)). Rank and housing type were associated with gonorrhoea and chlamydia in men, but were not significant factors in women. For gonorrhoea, two geographic sectors had prevalences between 14.0%-16.5%, three between 10.3%-13.9%, three between 7.1%-10.2%, and five between 3.0%-7.1%. The geographic distribution demonstrated a core-like pattern where the highest sectors were contiguous and were sectors containing barracks housing lower enlisted grade personnel. In contrast, chlamydia prevalence was narrowly distributed. CONCLUSION: GIS based disease surveillance was easily and rapidly implemented in this setting and should be useful in developing preventive interventions.

Application of a geographic information system to the tracking and control of an outbreak of shigellosis.

A personal computer-based commercial geographic information system (GIS) was applied to an outbreak of Shigella sonnei infection at Fort Bragg, North Carolina. We used a database consisting of demographic, temporal, and home-address information for all recognized cases of S. sonnei that occurred among health care beneficiaries from 23 May 1997 through 14 August 1997. We imported this database into the GIS, which contained a digitized basemap of the local community. Through simultaneous examination of temporal and spatial distribution of the 59 identified cases of S. sonnei, a focus of infection in a single housing area was identified. Targeted education among residents of the neighborhood in which there was intense transmission was associated with prompt extinction of the epidemic. A GIS offers an efficient and practical way to directly visualize the dynamics of transmission of infectious diseases in the setting of a community outbreak.

Correlates of human immunodeficiency virus infection risk behavior in male attendees of a clinic for sexually transmitted disease.

Human immunodeficiency virus (HIV) infection risk behavior was evaluated in a cross-sectional survey of 400 male active-duty US Army personnel who presented at a sexually transmitted disease (STD) clinic with symptoms of acute urethritis. High-risk partners were common, and nearly one-quarter of the sample had previously had STDs. Logistic regression models examined correlates of HIV exposure risk, of inconsistent condom use, and of having partners with increased risk of HIV infection. Frequent partner turnover, sex "binging," negative attitudes toward condom use, and engaging in sex during military leaves were important correlates of risk. Individuals with HIV infection risk behavior generally were cognizant of their risk for HIV infection. Implications for intervention are discussed.

Reducing risk of sexually transmitted disease (STD) and human immunodeficiency virus infection in a military STD clinic: evaluation of a randomized preventive intervention trial.

Three single-session preventive interventions for reducing sexually transmitted disease (STD) and human immunodeficiency virus infection risk behaviors were evaluated with a sample of 400 men who attended a large military STD clinic. A quasi-experimental, pre-evaluation/postevaluation design was used, comparing standard clinic care alone versus standard care combined with 1 of 3 experimental interventions: health-risk appraisal, interactive video, and targeted situational behaviors. Questionnaire data were collected at baseline and during follow-up visits at 2 weeks and 2 months. Findings indicated that the health-risk appraisal and interactive video increased adherence with clinic recommendations to abstain from sex (chi(2)3199=19.67; P<.001) and increased readiness to change "risky" partner-selection behavior (chi(2)2194=6.42; P<.04). Follow-up data suggested that STD-related risk behavior was particularly resistant to change but that the single-session intervention had some impact, which could be viewed as a "priming" effect that enhances multisession interventions.

Features of urethritis in a cohort of male soldiers.

Of 400 cases of urethritis in male soldiers enrolled in a behavioral intervention project, the etiology of 69% was defined at study enrollment, as well as the etiology of 72% of 25 repeated episodes involving 21 men during the first 78 days of active follow-up (5% of the cohort). Chlamydia trachomatis (36%), Neisseria gonorrhoeae (34%), and Ureaplasma urealyticum (19%) were the most common causes of infection identified at enrollment and during subsequent visits (44%, 28%, and 12%, respectively). By univariate analysis, patients with repeated infection ("repeaters") were significantly more likely to report a history of sexually transmitted disease (STD; relative risk [RR], 3) and sex with sex workers (RR, 4) than were nonrepeaters. By multivariate analysis, only STD history was significant (RR, 2.8). Characteristics of repeaters in this cohort suggest that specific patterns may be used to establish screening "profiles" of potential repeaters, by which such individuals might be targeted for aggressive intervention at the time of the initial diagnosis.

DNA binding alkaloids from Prosopis alba.

The known beta-phenethylamine ( 1) and the new alkaloid 2-beta-methyl-3-beta-hydroxy-6-beta-piperidinedodecanol ( 2) were isolated from the aerial parts of PROSOPIS ALBA. Both compounds showed DNA binding effects of 27 and 50%, respectively, at 0.50 mg/ml.

Human immunodeficiency virus (HIV) education and HIV risk behavior: a survey of rapid deployment troops.

A paper-and-pencil questionnaire was administered to 1,377 U.S. Army troops from rapid deployment units at Fort Bragg, North Carolina. This yielded 1,368 surveys available for analysis. The primary goal of the survey was to evaluate this group's experience with the Army human immunodeficiency virus (HIV) education program and to determine their level of HIV risk behaviors as related to participation in the Army's HIV education program. Seventy-seven percent of the respondents (1,052 of 1,368) reported receiving some HIV education from the Army. Of those, 55% (578 of 1,052) reported receiving 1 hour of education within the past year. Soldiers of Asian, Native American, and "other" race/ethnicity, and to a lesser extent, Hispanic background, were more likely to report receiving no HIV education compared with whites and African Americans. Self-reported receipt of HIV education did not strongly differentiate individuals in their partner selection or in key sexual risk behaviors in which they engaged.

Early syphilis in an active duty military population and the surrounding civilian community, 1985-1993.

Syphilis among active duty soldiers at Fort Bragg, North Carolina, and the nonmilitary population of Cumberland County was examined during a 9-year period encompassing the most recent nationwide syphilis epidemic. A total of 762 cases of primary and secondary syphilis were recorded between 1985 and 1993, 27% of which occurred in soldiers. The epidemic struck both military and civilian populations simultaneously; epidemic curves in the two populations were parallel, peaking in 1990-1991, with highest annual incidences of 122.6/ 100,000 (military) and 48.0/100,000 (civilian). Individual risk factor data were not available for analysis, but a relationship was observed between primary and secondary syphilis diagnoses in both populations and cocaine arrests in Cumberland County. Our findings provide epidemiological support for a high degree of interplay between the military and the surrounding civilian communities that has significant implications for control of sexually transmitted diseases. Enhanced collaboration between military and civilian public health authorities is essential to the control of syphilis and other sexually transmitted diseases.

Altered hepatic clearance and killing of Candida albicans in the isolated perfused mouse liver model.

The adherence of Candida albicans was studied in situ by using the perfused mouse liver model. After exhaustive washing, 10(6) C. albicans were infused into mouse livers. At the time of recovery, 62 +/- 5% (mean +/- standard error of the mean) of the infused C. albicans were recovered from the liver and 14 +/- 3% were recovered from the effluent for a total recovery of 76 +/- 4%. This indicates that 86 +/- 3% of the original inoculum was trapped by the liver and that 24 +/- 4% was killed within the liver. Chemical pretreatment of C. albicans with 8 M urea, 12 mM dithiothreitol, 2% beta-mercaptoethanol, 1% sodium dodecyl sulfate, 10% Triton X-100, or 3 M potassium chloride or enzyme pretreatment with alpha-mannosidase, alpha-chymotrypsin, subtilisin, beta-N-acetyl-glucosaminidase, pronase, trypsin, papain, or lipase did not alter adherence of C. albicans to hepatic tissue. By contrast, pepsin pretreatment significantly decreased hepatic trapping. Simultaneous perfusion with either 100 mg of C. albicans glycoprotein per liter or 100 mg of C. albicans mannan per liter also decreased trapping. Furthermore, both substances eluted previously trapped C. albicans from hepatic tissue. Chemical pretreatment with 8 M urea, 12 mM dithiothreitol, or 3 M KCI or enzymatic pretreatment with alpha-mannosidase, subtilisin, alpha-chymotrypsin, or papain increased killing of C. albicans three- to fivefold within hepatic tissue. The data suggest that mannose-containing structures on the surface of C. albicans, for example. mannans or glucomannoproteins, mediate adherence of C. albicans within the liver. Indirectly, chemical and enzymatic pretreatment renders C. albicans more susceptible to hepatic killing.