The acceptability and cost of a home-based chlamydia retesting strategy: findings from the REACT randomised controlled trial.

BACKGROUND: Chlamydia retesting three months after treatment is recommended to detect reinfections, but retesting rates are typically low. The REACT (retest after Chlamydia trachomatis) randomised trial demonstrated that home-based retesting using postal home-collection kits and SMS reminders, resulted in substantial improvements in retesting rates in women, heterosexual men and men who have sex with men (MSM), with detection of more repeat positive tests compared with SMS reminder alone. In the context of this trial, the acceptability of the home-based strategy was evaluated and the costs of the two strategies were compared. METHODS: REACT participants (200 women, 200 heterosexual men, 200 MSM) were asked to complete an online survey that included home-testing acceptability and preferred methods of retesting. The demographics, sexual behaviour and acceptability of home collection were compared between those preferring home-testing versus clinic-based retesting or no preference, using a chi-square test. The costs to the health system of the clinic-based and home retesting strategies and the cost per infection for each were also compared. RESULTS: Overall 445/600 (74 %) participants completed the survey; 236/445 from the home-testing arm, and 141 of these (60 %) retested at home. The majority of home arm retesters were comfortable having the kit posted to their home (86 %); found it easy to follow the instructions and collect the specimens (96 %); were confident they had collected the specimens correctly (90 %); and reported no problems (70 %). Most (65 %) preferred home retesting, 21 % had no preference and 14 % preferred clinic retesting. Comparing those with a preference for home testing to those who didn't, there were significant differences in being comfortable having a kit sent to their home (p = 0.045); not having been diagnosed with chlamydia previously (p = 0.030); and living with friends (p = 0.034). The overall cost for the home retest pathway was $154 (AUD), compared to $169 for the clinic-based retesting pathway and the cost per repeat infection detected was $1409 vs $3133. CONCLUSIONS: Among individuals initially diagnosed with chlamydia in a sexual health clinic setting, home-based retesting was shown to be highly acceptable, preferred by most participants, and cost-efficient. However some clients preferred clinic-based testing, often due to confidentiality concerns in their home environment. Both options should be provided to maximise retesting rates. TRIAL REGISTRATION: The trial was registered with the Australia New Zealand Clinical Trials Registry on September 9, 2011: ACTRN12611000968976.

Is azithromycin adequate treatment for asymptomatic rectal chlamydia?

Rectal chlamydia is a common sexually transmissible infection (STI) in men who have sex with men (MSM) that is predominantly asymptomatic. The recommended treatment of azithromycin 1 g as a single oral dose has not been subject to randomized trials and so its efficacy is unknown. We conducted a retrospective case-note review of all MSM diagnosed at the Sydney Sexual Health Centre with asymptomatic rectal chlamydia in 2009. We identified 116 MSM who received azithromycin; 85 (73%) attended for the recommended re-test at varying times (median 78 days, range 21-372 days). Of the men who returned, 11 (13%) had a persistently positive result; we reviewed behavioural data to classify these men as probable re-infections (6/11) or possible treatment failures (5/11), suggesting an efficacy of 94%. Until a randomized controlled trial (RCT) is conducted, patients with rectal chlamydia should be encouraged to attend for a re-test at 6-12 weeks.

The behaviour and sexual health of young international travellers (backpackers) in Australia.

OBJECTIVES: To study the demographics, risk behaviours and morbidity of young long-term international travellers (backpackers) attending a sexual health service in Sydney, Australia. METHODS: Data on new patients were extracted from the Sydney Sexual Health Centre database for the period 1998 to 2006. The sexual risk behaviours and morbidity of the backpackers were compared with other patients of a similar age. RESULTS: The 5698 backpackers who attended the centre reported higher numbers of sexual partners (three or more partners in the past 3 months, 18% vs 12%, p<0.001) and a greater proportion drank alcohol at hazardous levels (22%) than the comparison group (9%, p<0.001). Rates of consistent (100%) condom use in the past 3 months were low in both backpackers (22%) and the comparison population (19%). Backpackers had higher rates of genital chlamydia infection (7% vs 5%, p<0.001) and reported higher rates of previous sexually transmitted infections (15% vs 10%, p<0.001). CONCLUSIONS: Backpackers should be a priority population for sexual health promotion and access to services.

Increasing role of herpes simplex virus type 1 in first-episode anogenital herpes in heterosexual women and younger men who have sex with men, 1992-2006.

OBJECTIVES: Herpes simplex virus (HSV) type 1 is causing an increasing proportion of anogenital herpes; however, it is unclear which populations are affected. We describe the contribution of HSV-1 to first-episode anogenital herpes and its associations. METHODS: For all cases of first-episode anogenital herpes diagnosed at the Sydney Sexual Health Centre from 1992 to 2006, medical record review was used to confirm the type and anatomical site. Age, sex, HIV status and sexual behaviour data were extracted from the clinic database. RESULTS: Overall, among 1845 confirmed cases of first-episode anogenital herpes the proportion attributable to HSV-1 increased from 29% to 42% (odds ratio (OR) per 3-year band 1.19; 95% CI 1.11 to 1.27). When stratified by gender of sexual partners the proportion of first-episode anogenital herpes due to HSV-1 increased over time, but only achieved significance in heterosexual women (p<0.01). Among men who have sex with men (MSM), HSV-1 only increased for those less than 28 years of age, 17% in 1992-4 to 76% in 2004-6 (OR per 3-year band 1.58; 95% CI 1.14 to 2.19). The proportion attributable to HSV-1 was higher for anal than genital herpes and MSM were much more likely to have anal disease. CONCLUSIONS: The proportion of first-episode anogenital herpes due to HSV-1 significantly increased among younger MSM and heterosexual women over the 15-year period. In some clinical populations, such as young MSM and women or patients with anal disease, HSV-1 may now account for the majority of first-episode anogenital herpes.

Gonorrhoea screening in general practice: perceived barriers and strategies to improve screening rates.

OBJECTIVE: To investigate perceived barriers to gonorrhoea screening in general practice and suggest strategies to overcome them. DESIGN: Questionnaire-based survey. SETTING AND PARTICIPANTS: All 47 general practitioners (GPs) authorised to prescribe subsidised HIV drugs under the Pharmaceutical Benefits Scheme in inner, eastern and northern Sydney. MAIN OUTCOME MEASURES: Agreement on a five-point Likert scale with statements about attitudes and practices in relation to gonorrhoea screening of homosexually active men, and views on how testing rates could be increased. RESULTS: 32 GPs responded (68%). Perceived barriers to gonorrhoea testing included structural measures imposed by the Federal Government to limit pathology testing by GPs (the Medicare "three-test rule") (17 respondents agreed or strongly agreed), pressure from the Health Insurance Commission (HIC) to minimise pathology testing (15), concerns about confidentiality of notification procedures (8), clinical time pressure (8), and concerns about recriminations against HIV patients with gonorrhoea (6). Suggested measures to increase testing were education of gay men to request testing (25), relaxation of the three-test rule (25), easier tests (23), anonymous notification procedures, review of HIC policy on screening, and training about testing (21 each). CONCLUSIONS: Sydney GPs with high HIV caseloads perceived structural barriers to gonorrhoea testing and supported a range of achievable strategies to overcome these. As the sustained epidemic of gonorrhoea in Sydney may be directly promoting HIV transmission, these strategies should be considered urgently.

Design, synthesis, and proposed active site binding analysis of monocyclic 2-azetidinone inhibitors of prostate specific antigen.

A homology derived molecular model of prostate specific antigen (PSA) was created and refined. The active site region was investigated for specific interacting functionality and a binding model postulated for the novel 2-azetidinone acyl enzyme inhibitor 1 (IC(50) = 8.98 +/- 0.90 microM) which was used as a lead compound in this study. A single low energy conformation structure II (Figure 2) was adopted as most likely to represent binding after minimization and dynamics calculations. Systematic analysis of the binding importance of all three side chains appended to the 2-azetidinone was conducted by the synthesis of several analogues. A proposed salt bridge to Lys-145 with 4 (IC(50) = 5.84 +/- 0.92 microM) gave improved inhibition, but generally the binding of the N-1 side chain in a specific secondary aromatic binding site did not tolerate much structural alteration. A hydrophobic interaction of the C-4 side chain afforded inhibitor 6 (IC(50) = 1.43 +/- 0.19 microM), and polar functionality could also be added in a proposed interaction with Gln-166 in 5 (IC(50) = 1.34 +/- 0.05 microM). Reversal of the C-4 ester connectivity furnished inhibitors 7 (IC(50) = 1.59 +/- 0.15 microM), 11 (IC(50) = 3.08 +/- 0.41 microM), and 13 (IC(50) = 2.19 +/- 0.36 microM) which were perceived to bind to PSA by a rotation of 180 degrees relative to the C-4 ester of normal connectivity. Incorporation of hydroxyl functionality into the C-3 side chain provided 16 (IC(50) = 348 +/- 50 nM) with the greatest increase in PSA inhibition by a single modification. Multiple copy simultaneous search (MCSS) analysis of the PSA active site further supported our model and suggested that 18 would bind strongly. Asymmetric synthesis yielded 18 (IC(50) = 226 +/- 10 nM) as the most potent inhibitor of PSA reported to date. It is concluded that our design approach has been successful in developing PSA inhibitors and could also be applied to the inhibition of other enzymes, especially in the absence of crystallographic information.

Simple bi- and tricyclic inhibitors of human steroid 5alpha-reductase.

A number of tricyclic thiolactams, bicyclic lactams, and bicyclic thiolactams have been prepared and evaluated in vitro as inhibitors of types 1 and 2 steroid 5alpha-reductase. The tricycles with an 8-chloro substituent in the C-ring are nM (IC50) inhibitors of type 1 steroid 5alpha-reductase (SR). In all the cases studied, lactams are more potent than the corresponding thiolactams. Activity against type 2 SR is greatly enhanced by a styryl (or azo) substituent on the aryl ring of the tri- and bicycles and also a related tricyclic aryl acid.

Increased AKT activity contributes to prostate cancer progression by dramatically accelerating prostate tumor growth and diminishing p27Kip1 expression.

The PTEN tumor suppressor gene is frequently inactivated in human prostate cancers, particularly in more advanced cancers, suggesting that the AKT/protein kinase B (PKB) kinase, which is negatively regulated by PTEN, may be involved in human prostate cancer progression. We now show that AKT activation and activity are markedly increased in androgen-independent, prostate-specific antigen-positive prostate cancer cells (LNAI cells) established from xenograft tumors of the androgen-dependent LNCaP cell line. These LNAI cells show increased expression of integrin-linked kinase, which is putatively responsible for AKT activation/Ser-473 phosphorylation, as well as for increased phosphorylation of the AKT target protein, BAD. Furthermore, expression of the p27(Kip1) cell cycle regulator was diminished in LNAI cells, consistent with the notion that AKT directly inhibits AFX/Forkhead-mediated transcription of p27(Kip1). To assess directly the impact of increased AKT activity on prostate cancer progression, an activated hAKT1 mutant was overexpressed in LNCaP cells, resulting in a 6-fold increase in xenograft tumor growth. Like LNAI cells, these transfectants showed dramatically reduced p27(Kip1) expression. Together, these data implicate increased AKT activity in prostate tumor progression and androgen independence and suggest that diminished p27(Kip1) expression, which has been repeatedly associated with prostate cancer progression, may be a consequence of increased AKT activity.

Kinetic analysis of LY320236: competitive inhibitor of type I and non-competitive inhibitor of type II human steroid 5alpha-reductase.

Type I and type II steroid 5alpha-reductases (5alpha-R) catalyze the conversion of testosterone (T) to dihydrotestosterone (DHT). LY320236 is a benzoquinolinone (BQ) that inhibits 5alpha-R activity in human scalp skin (Ki(typeI)=28.7+/-1.87 nM) and prostatic homogenates (Ki(typeII)=10.6+/-4.5 nM). Lineweaver-Burk, Dixon, and non-linear analysis methods were used to evaluate the kinetics of 5alpha-R inhibition by LY320236. Non-linear modeling of experimental data evaluated V(max) in the presence or absence of LY320236. Experimental data modeled to the following equation 1v=+ fixing the In0c value equal to 1.0 or 0 are consistent with non-competitive or competitive inhibition, respectively. LY320236 is a competitive inhibitor of type I 5alpha-R (In0c=0, Ki=3.39+/-0.38, RMSE = 1.300) and a non-competitive inhibitor of type II 5alpha-R (In0c=1, Ki=29. 7+/-3.4, RMSE = 0.0592). These data are in agreement with linear transformation of the data using Lineweaver-Burk and Dixon analyses. These enzyme kinetic data support the contention that the BQ LY320236 is a potent dual inhibitor with differing modes of activity against the two known human 5alpha-reductase isozymes. LY320236 represents a class of non-steroidal 5alpha-R inhibitors with potential therapeutic utility in treating a variety of androgen dependent disorders.

Growth regulation of prostatic stromal cells by prostate-specific antigen.

BACKGROUND: Prostate-specific antigen (PSA) is a serine protease that can cleave insulin-like growth factor-binding protein-3 (IGFBP3), thereby decreasing its affinity for insulin-like growth factor-I (IGF-I). Dissociation of the IGF-I-IGFBP3 complex renders IGF-I available to bind to its receptor and stimulates cellular proliferation. We evaluated the potential for PSA to modulate the effects of IGF-I and IGFBP3 on the proliferation of human benign prostatic hyperplasia (BPH)-derived fibromuscular stromal cells in primary cultures. METHODS: We cultured BPH-derived stromal cells for 48 hours in serum-free RPMI-1640 medium supplemented with 0.2% bovine serum albumin and studied the effects of IGF-I, IGFBP3, PSA, and ZnCl(2) at varying concentrations. Differences in cell growth between control and treated cultures were evaluated by use of Dunnett's test. Concentration-related trends were evaluated by linear regression of log-transformed concentrations of test reagents on BPH-derived stromal cell number responses. Statistical tests were two-sided. RESULTS: We observed a concentration-dependent proliferative response of BPH-derived stromal cells to IGF-I. IGFBP3 inhibited this response in a concentration-dependent fashion. IGFBP3 alone had no effect on stromal cell proliferation. When stromal cells were incubated with PSA alone or with PSA, IGF-I, and IGFBP3, an increase in stromal cell numbers that was dependent on PSA concentration was evident in both instances. Zinc, an endogenous inhibitor of PSA enzymatic activity, was able to attenuate the stimulatory effect of PSA at intraprostatic physiologic concentrations. CONCLUSIONS: These results are consistent with the idea that PSA can modulate in vitro interactions between IGF-I and IGFBP3 and suggest that PSA may play a role in the regulation of human prostatic fibromuscular cell growth.

Synthesis and 5 alpha-reductase inhibitory activity of 8-substituted benzo[f]quinolinones derived from palladium mediated coupling reactions.

Benzoquinolinones have been shown to be potent, selective inhibitors of the Type I 5 alpha-reductase enzyme, which is responsible for the production of dihydrotestosterone from testosterone localized in the scalp. In an effort to identify compounds that demonstrate inhibition of both 5 alpha-reductase isozymes, we have employed 8-bromobenzoquinolinone as an advanced intermediate for participation in a variety of palladium mediated carbon-carbon bond forming reactions. By varying the 8-substituent it is possible to alter the selectivity profile of the series.

Responses of LNCaP prostatic adenocarcinoma cell cultures to LY300502, a benzoquinolinone human type I 5alpha-reductase inhibitor.

We evaluate the metabolic inhibitory, antiproliferative, and antisecretory effects of LY300502, a benzoquinolinone human-specific type I-selective steroid 5alpha-reductase inhibitor in LNCaP human prostatic adenocarcinoma cell cultures. Reductive metabolism of [3H-T] in the LNCaP cells was inhibited in a concentration-dependent manner by LY300502 (IC50 approximately 5.77 nM). The proliferative responses of LNCaP cells to LY300502 were examined in the presence of 0.1 NM testosterone (T), a concentration that stimulates maximal LNCaP cell numbers 40% above control levels. LY300502 significantly anatagonized T-induced stimulation of LNCaP cellular proliferation at concentrations greater that 10 nM (P<0.05), and at 1,000 nMcompletely blocked the mitogenic effects of T on LNCaP cells. In the absence of androgen, LY300502 had no effect on LNCaP cellular proliferation. In the presence of 100 nM T, an androgen concentration that maximally stimulates in vitro PSA production, LY300502 significantly antagonized T-induced PSA secretion at a concentration equal to or greater than 30 nM (P<0.05). These studies provide the basis for additional investigations into the pathophysiologic significance of type I 5alpha-reductase to prostatic cancer and the potential utility of selective inhibitors as therapeutic agents.

Alterations in K(+)-evoked release of 3H-norepinephrine and contractile responses in urethral and bladder tissues induced by norepinephrine reuptake inhibition.

The effects of norepinephrine (NE) reuptake inhibition on NE release and contractile responses in lower urinary tract tissues were evaluated using tomoxetine, a selective NE reuptake inhibitor, and imipramine, a nonselective reuptake inhibitor. Although both compounds significantly increased K(+)-evoked release of NE from urethral fragments obtained from rabbits, tomoxetine was at least 10X more potent than imipramine. Tomoxetine significantly enhanced the effects of NE to contract rabbit urethral fragments and to relax carbachol contracted rabbit bladder smooth muscle. Imipramine suppressed the effects of NE on urethral tissue and was less potent than tomoxetine in enhancing bladder responses to NE. These presynaptic and postsynaptic effects of NE reuptake inhibition in lower urinary tract tissues may contribute to the efficacy of imipramine in treating incontinence and represent a new clinical utility for selective and more potent reuptake inhibitors, such as tomoxetine.

Endoluminal radio-frequency electrocautery for permanent ureteral occlusion in swine.

An animal experiment was undertaken to assess the feasibility of using radio-frequency current-mediated thermal injury of the ureter to produce ureteral occlusion by means of an endoluminal approach. Through open pyelotomies, balloon angioplasty catheters coated with gold bipolar electrodes were introduced into the ureters. Doses (at 650 kHz) were delivered for specific energy totals in 13 of 15 ureters in eight pigs. Two ureters served as controls (balloon inflation without current application). In six experimental animals not killed immediately after the procedure, postoperative ureteral manometric studies and nephrostography were performed and nephrostomy drainage was maintained until death (1-8 weeks). Treatment with 200-400 J produced safe, reliable occlusion by 4 weeks. At histopathologic study at 4 and 8 weeks, necrotic muscularis propria had been replaced by fibrous tissue. Cardiac rhythm was not affected during treatment.