Translesion DNA synthesis across double-base lesions derived from cross-links of an antitumor trinuclear platinum compound: primer extension, conformational and thermodynamic studies.

Polynuclear platinum complexes represent a unique structural class of DNA-binding agents of biological significance. They contain at least two platinum coordinating units bridged by a linker, which means that the formation of double-base lesions (cross-links) in DNA is possible. Here, we show that the lead compound, bifunctional [{trans-PtCl(NH3)2}2µ-trans-Pt(NH3)2{H2N(CH2)6NH2}2]4+ (Triplatin or BBR3464), forms in DNA specific double-base lesions which affect the biophysical and biochemical properties of DNA in a way fundamentally different compared to the analogous double-base lesions formed by two adducts of monofunctional chlorodiethylenetriamineplatinum(ii) chloride (dienPt). We find concomitantly that translesion DNA synthesis by the model A-family polymerase, the exonuclease deficient Klenow fragment, across the double-base lesions derived from the intrastrand CLs of Triplatin was markedly less extensive than that across the two analogous monofunctional adducts of dienPt. Collectively, these data provide convincing support for the hypothesis that the central noncovalent tetraamine platinum linker of Triplatin, capable of hydrogen-bonding and electrostatic interactions with DNA and bridging the two platinum adducts, represents an important factor responsible for the markedly lowered tolerance of DNA double-base adducts of Triplatin by DNA polymerases.

Enhancement of the physicochemical properties of [Pt(dien)(nucleobase)]2+ for HIVNCp7 targeting.

Physicochemical properties of coordination compounds can be exploited for molecular recognition of biomolecules. The inherent π-π stacking properties of [Pt(chelate)(N-donor)]2+ ([PtN4]) complexes were modulated by systematic variation of the chelate (diethylenetriamine and substituted derivatives) and N-donor (nucleobase or nucleoside) in the formally substitution-inert PtN4 coordination sphere. Approaches to target the HIV nucleocapsid protein HIVNCp7 are summarized building on (i) assessment of stacking interactions with simple tryptophan or tryptophan derivatives to (ii) the tryptophan-containing C-terminal zinc finger and (iii) to the full two-zinc finger peptide and its interactions with RNA and DNA. The xanthosine nucleoside was identified as having significantly enhanced stacking capability over guanosine. Correlation of the LUMO energies of the modified nucleobases with the DFT π-stacking energies shows that frontier orbital energies of the individual monomers can be used as a first estimate of the π-stacking strength to Trp. Cellular accumulation studies showed no significant correlation with lipophilicity of the compounds, but all compounds had very low cytotoxicity suggesting the potential for antiviral selectivity. The conceptual similarities between nucleobase alkylation and platination validates the design of formally substitution-inert coordination complexes as weak Lewis acid electrophiles for selective peptide targeting.

Canada Communicable Disease Report 2016 readership survey.

BACKGROUND: The Canada Communicable Disease Report (CCDR) is a peer reviewed scientific journal published since 1975. In 2011, a readership survey was conducted to inform a revitalization process. In late 2016, this survey was repeated to assess progress. OBJECTIVE: To provide information about the results of the CCDR 2016 readership survey, which identified CCDR's readership and their needs, obtained feedback on the journal's revitalization and sought suggestions for further improvement. METHODS: An online readership survey was conducted from September 7 to 28, 2016. Invitations were sent via email to CCDR subscribers. The survey was based on the 2011 version and checked for face-validity. Analysis included descriptive statistics and a qualitative assessment of comments for themes. RESULTS: A total of 549 people responded to the survey (12% participation rate). The majority of respondents worked in public health (61%), clinical care (23%), academia (16%) and laboratory medicine (9%). Approximately 45% of respondents had received CCDR for less than four years, which is consistent with the fact that the number of subscribers more than doubled over this time. Over 90% of respondents reported they read the articles in CCDR (always 15%, often 43%, sometimes 35%). When asked about their primary source of infectious disease information in Canada, CCDR was the number one response, identified by 72% of respondents. When asked "What do you like best about CCDR?" typical comments were that it provided Canadian content, was well written, evidence-based, interesting and relevant. The number one suggestion for improvement was that CCDR should be listed with PubMed. CONCLUSION: The survey results suggest that CCDR has been successfully revitalized and is meeting its readership's needs for a scientific journal on infectious disease with Canadian content, high quality and relevance. Consistent with suggestions for improvement, CCDR will be joining the PubMed database over the next year.

Changes in mitochondrial stability during the progression of the Barrett's esophagus disease sequence.

BACKGROUND: Barrett's esophagus follows the classic step-wise progression of metaplasia-dysplasia-adenocarcinoma. While Barrett's esophagus is a leading known risk factor for esophageal adenocarcinoma, the pathogenesis of this disease sequence is poorly understood. Mitochondria are highly susceptible to mutations due to high levels of reactive oxygen species (ROS) coupled with low levels of DNA repair. The timing and levels of mitochondria instability and dysfunction across the Barrett's disease progression is under studied. METHODS: Using an in-vitro model representing the Barrett's esophagus disease sequence of normal squamous epithelium (HET1A), metaplasia (QH), dysplasia (Go), and esophageal adenocarcinoma (OE33), random mitochondrial mutations, deletions and surrogate markers of mitochondrial function were assessed. In-vivo and ex-vivo tissues were also assessed for instability profiles. RESULTS: Barrett's metaplastic cells demonstrated increased levels of ROS (p < 0.005) and increased levels of random mitochondrial mutations (p < 0.05) compared with all other stages of the Barrett's disease sequence in-vitro. Using patient in-vivo samples, Barrett's metaplasia tissue demonstrated significantly increased levels of random mitochondrial deletions (p = 0.043) compared with esophageal adenocarcinoma tissue, along with increased expression of cytoglobin (CYGB) (p < 0.05), a gene linked to oxidative stress, compared with all other points across the disease sequence. Using ex-vivo Barrett's metaplastic and matched normal patient tissue explants, higher levels of cytochrome c (p = 0.003), SMAC/Diablo (p = 0.008) and four inflammatory cytokines (all p values <0.05) were secreted from Barrett's metaplastic tissue compared with matched normal squamous epithelium. CONCLUSIONS: We have demonstrated that increased mitochondrial instability and markers of cellular and mitochondrial stress are early events in the Barrett's disease sequence.

Effects of coordination mode of 2-mercaptothiazoline on reactivity of Au(I) compounds with thiols and sulfur-containing proteins.

Gold(I) based drugs are interesting for their potential medical use. The relatively facile ligand substitution in linear gold(I) compounds makes the identification of active species complicated. Ligands such as PR3 and CN- are likely to be carrier ligands due to their strong trans-directing properties and will dictate the nature of substitution reactions. The 2-mercaptothiazoline (mtz) ligand is an N,S-heterocyclic compound which presents an exocyclic thiol sulfur as well as a heterocyclic nitrogen. The coordination of mtz to transition metals can be modulated by the trans ligand and complexes with metal bound through the nitrogen and/or the exocyclic sulfur are known. Therefore, the complexes [NCAu(N-mtz)] (N-coordinated) and [(Ph3P)Au(S-mtz)] (S-coordinated) were investigated to compare the influence of CN- and PR3 as well as the coordination mode of the mtz ligand on reactivity with thiols and sulfur-containing proteins. As a further comparison the compound [(Ph3P)AuCN] was also studied. Human serum albumin, egg white lysozyme and, principally, the C-terminal zinc finger (ZF2) of the nucleocapsid NCp7protein of HIV-1 were studied. Results from zinc finger studies show that the coordination structure can determine the reactivity toward biomolecules. Due to ligand scrambling, the complex [NCAu(N-mtz)] forms very reactive species in solution generating [NCyAux-biomolecule] adducts, where x,y≤3. The observation by mass spectrometry of [(CN)Au]-ZF confirms the ability of Au(I) compounds to form [(Ligand)Au] adducts on zinc fingers, in contrast to Au(III), where all ligands are lost upon reaction with the zinc finger. On the other hand, [(Ph3P)Au(S-mtz)] also generates the [(Ph3P)2Au]+ species due to ligand scrambling, that showed lower reactivity, probably due to steric hindrance. For this complex [(Ph3P)Au-biomolecule] and [Au-biomolecule] adducts are dominant. The results corroborate the hypothesis of modulation through coordination as the reactivity clearly depends on not only the ligand, but also the coordination mode.

Multi-platinum anti-cancer agents. Substitution-inert compounds for tumor selectivity and new targets.

This tutorial review summarizes chemical, biophysical and cellular biological properties of formally substitution-inert "non-covalent" polynuclear platinum complexes (PPCs). We demonstrate how modulation of the pharmacological factors affecting platinum compound cytotoxicity such as cellular accumulation, reactivity toward extracellular and intracellular sulfur-ligand nucleophiles and consequences of DNA binding is achieved to afford a profile of biological activity distinct from that of covalently-binding agents. The DNA binding of substitution-inert complexes is achieved by molecular recognition through minor groove spanning and backbone tracking of the phosphate clamp. In this situation, the square-planar tetra-am(m)ine Pt(ii) coordination units hydrogen bond to phosphate oxygen OP atoms to form bidentate N-O-N motifs. The modular nature of the polynuclear compounds results in high-affinity binding to DNA and very efficient nuclear condensation. These combined effects distinguish the phosphate clamp as a third mode of ligand-DNA binding, discrete from intercalation and minor-groove binding. The cellular consequences mirror those of the biophysical studies and a significant portion of nuclear DNA is compacted, a unique effect different from mitosis, senescence or apoptosis. Substitution-inert PPCs display cytotoxicity similar to cisplatin in a wide range of cell lines, and sensitivity is indifferent to p53 status. Cellular accumulation is mediated through binding to heparan sulfate proteoglycans (HSPG) allowing for possibilities of tumor selectivity as well as disruption of HSPG function, opening new targets for platinum antitumor agents. The combined properties show that covalently-binding chemotypes are not the unique arbiters of cytotoxicity and antitumor activity and meaningful antitumor profiles can be achieved even in the absence of Pt-DNA bond formation. These dual properties make the substitution-inert compounds a unique class of inherently dual-action anti-cancer agents.

Solution studies on DNA interactions of substitution-inert platinum complexes mediated via the phosphate clamp.

The phosphate clamp is a distinct mode of ligand-DNA binding where the molecular recognition is manifested through ("non-covalent") hydrogen-bonding from am(m)ines of polynuclear platinum complexes to the phosphate oxygens on the oligonucleotide backbone. This third mode of DNA binding is unique to the "classical" DNA intercalators and minor groove binding agents and even the closely related covalently binding mononuclear and polynuclear drugs. 2D (1)H NMR studies on the Dickerson-Drew dodecamer (DDD, d(CGCGAATTCGCG)2) showed significant A-T contacts mainly on nucleotides A6, T7 and T8 implying a selective bridging from C9G10 in the 3' direction to C9G10 of the opposite strand. {(1)H, (15)N} HSQC NMR spectroscopy using the fully (15)N-labelled compound [{trans-Pt(NH2)3(H2N(CH2)6NH3}2µ-(H2N(CH2)6NH2)2(Pt(NH3)2](8+) (TriplatinNC) showed at pH 6 significant chemical shifts and (1)J((195)Pt-(15)N) coupling constants for the free drug and DDD-TriplatinNC at pH 7 indicative of formation of the phosphate clamp. (31)P NMR results are also reported for the hexamer d(CGTACG)2 showing changes in (31)P NMR chemical shifts indicative of changes around the phosphorus center. The studies confirm the DNA binding modes by substitution-inert (non-covalent) polynuclear platinum complexes and help in further establishing the chemotype as a new class of potential anti-tumour agents in their own right with a distinct profile of biological activity.

A Barrett's esophagus registry of over 1000 patients from a specialist center highlights greater risk of progression than population-based registries and high risk of low grade dysplasia.

Barrett's esophagus (BE) arising from chronic gastro-oesophageal reflux (GERD) is the main pathologic precursor of esophageal adenocarcinoma (EAC). The risk of progression to high-grade dysplasia (HGD) and EAC is unclear, and recent population studies from Denmark and Northern Ireland suggest that this has been overestimated in the past. No data exist from the Republic of Ireland. A detailed clinical, endoscopic, and pathologic database was established in one center as a proposed pilot for a national registry, and initial and follow-up data were abstracted by a data manager. One thousand ninety-three patients were registered, 60 patients with HGD were excluded, leaving 1033, with a median age of 59 and 2 : 1 male to female ratio, and 3599 person-years of follow-up. The overall incidence of HGD/EAC was 1.33% per year overall, 0.85% if the first year is excluded. Within the first year after index endoscopy, 18 cases of HGD or EAC were identified, and 30 following the first year. Low-grade dysplasia (LGD) on index endoscopy was associated with an incidence of progression of 6.5% per year, and 3.1% when tertiary referrals were excluded. These data provide important demographic and clinical information on the population of Irish patients with BE, with incidence rates of progression higher than recently published population-based registry series, perhaps relating to sampling and pathological assessment. Low-grade dysplasia on initial biopsy is a significant proxy marker of risk of progression.

Outcomes in gastric and junctional cancer using neoadjuvant and adjuvant chemotherapy (epirubicin, oxaliplatin, and capecitabine) and radical surgery.

BACKGROUND: The MAGIC/UK Medical Research Council (MRC) trial set the standard of care for treatment of resectable gastric and junctional adenocarcinoma, demonstrating that perioperative chemotherapy with epirubicin, cisplatin and 5-fluorouracil (ECF) confers a survival benefit over surgery alone. The randomized ECF for advanced and locally advanced esophagogastric cancer (REAL-2) trial showed that, in the metastatic setting, the EOX regimen (epirubicin, oxaliplatin and capecitabine) is as effective as ECF, with a favourable toxicity profile. METHODS: Consecutive patients with resectable gastric or junctional adenocarcinoma treated with perioperative EOX, between 2007 and 2012, were retrospectively analysed. RESULTS: Fifty-nine patients (12 female, 47 male), commenced EOX therapy; 47 underwent surgery. A good pathological response was seen in 34%, (16/47). Disease recurrence occurred in 19 patients (19/47, 40%). Median overall survival was 22 months, with 4-year survival of 47%. Chemotoxicities were consistent with those previously reported for this regimen. CONCLUSION: This study in a high-volume centre demonstrates that EOX in resectable gastric and junctional adenocarcinoma is associated with a reasonable safety profile, and efficacy consistent with that reported for ECF.

Value of CT-PET after neoadjuvant chemoradiation in the prediction of histological tumour regression, nodal status and survival in oesophageal adenocarcinoma.

BACKGROUND: The role of CT-PET after neoadjuvant chemoradiation (nCRT) for prediction of pathological response and oncological outcome in oesophageal and junctional adenocarcinoma (OAC) is unclear. The relationship between complete metabolic response (cMR), pathological complete response (pCR) and nodal status has not been clarified. METHODS: Patients with locally advanced OAC selected to receive nCRT and surgery with curative intent, on the basis of staging that included CT-PET positivity, were included. Repeat scanning (PET2) with an identical protocol was performed 2-4 weeks after completion of nCRT (cisplatin and 5-fluorouracil plus 44 Gy radiation). Changes in [(18) F]fluorodeoxyglucose uptake, considered as either a maximum standardized uptake value (SUVmax) or a relative reduction (%ΔSUVmax), and PET-predicted nodal status following nCRT were compared with histopathological response, histological node positivity and survival. RESULTS: One hundred consecutive patients with PET-positive OAC were studied. Following nCRT, PET2 identified M1 disease in 2·0 per cent of patients. There were no significant associations between PET2 SUVmax or %ΔSUVmax with respect to primary tumour stage (ypT) (P = 0.216 and P = 0·975 respectively), tumour regression grade (P = 0·109 and P = 0·232), pCR (P = 0·633 and P = 0·870) or complete resection (R0) (P = 0·440 and P = 0·235). The sensitivity of PET2 for ypN was 10 per cent. %ΔSUVmax was not associated with disease-free or overall survival (P = 0·162 and P = 0·154 respectively). Of 46 patients with a cMR on PET2, 37 (80 per cent) had histological evidence of residual tumour in the resected specimen, and cMR was not associated with overall survival benefit (P = 0·478). CONCLUSION: CT-PET following nCRT for OAC has poor prognostic and discriminatory value for clinical application.

Differential expression of mitochondrial energy metabolism profiles across the metaplasia-dysplasia-adenocarcinoma disease sequence in Barrett's oesophagus.

Contemporary clinical management of Barrett's oesophagus has highlighted the lack of accurate predictive markers of disease progression to oesophageal cancer. This study aims to examine alterations in mitochondrial energy metabolism profiles across the entire disease progression sequence in Barrett's oesophagus. An in-vitro model was used to screen 84 genes associated with mitochondrial energy metabolism. Three energy metabolism genes (ATP12A, COX4I2, COX8C) were significantly altered across the in-vitro Barrett's disease sequence. In-vivo validations across the Barrett's sequence demonstrated differential expression of these genes. Tissue microarrays demonstrated significant alterations in both epithelial and stromal oxidative phosphorylation (ATP5B and Hsp60) and glycolytic (PKM2 and GAPDH) protein markers across the in-vivo Barrett's sequence. Levels of ATP5B in sequential follow up surveillance biopsy material segregated Barrett's non progressors and progressors to HGD and cancer. Utilising the Seahorse XF24 flux analyser, in-vitro Barrett's and adenocarcinoma cells exhibited altered levels of various oxidative parameters. We show for the first time that mitochondrial energy metabolism is differentially altered across the metaplasia-dysplasia-adenocarcinoma sequence and that oxidative phosphorylation profiles have predictive value in segregating Barrett's non progressors and progressors to adenocarcinoma.

Lack of independent significance of a close (<1 mm) circumferential resection margin involvement in esophageal and junctional cancer.

BACKGROUND: For rectal cancer, an involved circumferential resection margin (CRM), defined as tumor cells within 1 mm of the CRM, is of established prognostic significance. This definition for the esophagus, however, is controversial, with the UK Royal College of Pathologists (RCP) recommending the 1 mm definition, while the College of American Pathologists (CAP) advises that only tumor cells at the cut margin (0 mm) define an incomplete (R1) resection. The aim of this study was to compare the clinical significance of both definitions in patients with pT3 tumors. METHODS: CAP- and RCP-defined CRM status in patients treated by surgery only or by multimodal therapy was recorded prospectively in a comprehensive database from May 2003 to May 2011. Kaplan-Meier survival curves were generated, and factors affecting survival were assessed by univariate and multivariate analysis. RESULTS: A total of 157 of 340 patients had pT3 esophageal tumors, with RCP-positive CRM in 60 %, and 18 % by CAP. There were no significant differences between RCP-positive CRM and negative margins for node-positive disease, local recurrence, and survival. CAP-positive CRM was associated with positive nodes (P = 0.036) and poorer survival (P = 0.023). Multivariate analysis revealed nodal invasion to be the only independent prognostic variable (P = 0.004). CONCLUSIONS: A CRM margin of <1 mm is common in pT3 esophageal tumors, a finding consistent with other reports. The <1 mm definition was not associated with node positivity, local recurrence, or survival, in contrast to actual involvement at the margin, suggesting lack of independent prognostic significance of the RCP definition and possible superiority of the CAP criteria for prospective registration of CRM.

Evolving changes in the management of early oesophageal adenocarcinoma in a tertiary centre.

OBJECTIVES: Series from high volume oesophageal centres highlight an increasing prevalence of early malignant (EM) lesions. The advent of endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) offer alternatives to traditional surgery. The evolution of this pattern of care in a high volume centre is analysed. METHODS: Data were collected from a prospectively maintained database. 96 patients were treated with an EM lesion from 2000 to 2011. Surgery was the standard approach during the initial period (2000-2006). In 2007, with the introduction of EMR±RFA to our Centre, a rising trend toward definitive endoscopic treatment was seen. This study details the selection of cases into treatment groups and their outcomes. RESULTS: From 2000 to 2006, 23 patients were treated with EM lesions, 96% by surgery. Seventy-three were treated from 2007 to 2011, 55% surgically and 45% by EMR±RFA. In the entire experience, there was one death from surgery and morbidity was higher in the surgery group compared with EMR±RFA (p<0.001). Three surgical patients (4.8%) relapsed with HGD or cancer, and one patient with T1N1 disease died of disease recurrence. At a median of 13 months, EMR±RFA offered 100% disease control, 72% had no endoscopic or histological evidence of Barrett's oesophagus and one patient represented with low grade dysplasia. CONCLUSIONS: This study highlights the changing pattern of care in the management of early oesophageal cancer. EMR±RFA appears an acceptable alternative to surgery in carefully selected cases. However, long-term outcome analysis using these methods is required and close interdisciplinary collaboration of specialists in gastroenterology, surgery, pathology and radiology is mandatory to achieve optimum outcomes.

Laparoscopic adrenalectomy: Single centre experience.

BACKGROUND: Laparoscopic adrenalectomy is an attractive alternative to the traditional open approach in the surgical excision of an adrenal gland. It has replaced open adrenalectomy in our institution and we review our experience to date. METHODS: All cases of laparoscopic adrenalectomies in our hospital over eight years (from 2001 to May 2009) were retrospectively reviewed. Patient demographics, diagnosis, length of hospital stay, histology and all operative and post-operative details were evaluated. RESULTS: Fifty-five laparoscopic adrenalectomies (LA) were performed on 51 patients over eight years. The mean age was 48 years (Range 16-86 years) with the male: female ratio 1:2. Twenty-three cases had a right adrenalectomy, 24 had a left adrenalectomy and the remaining four patients had bilateral adrenalectomies. 91% were successfully completed laparoscopically with five converted to an open approach. Adenomas (functional and non functional) were the leading indication for LA, followed by phaeochromocytomas. Other indications for LA included Cushing's disease, adrenal malignancies and rarer pathologies. There was one mortality from necrotising pancreatitis following a left adrenalectomy for severe Cushing's disease, with subsequent death 10 days later. CONCLUSION: Laparoscopic adrenalectomy is effective for the treatment of adrenal tumours, fulfilling the criteria for the ideal minimally invasive procedure. It has replaced the traditional open approach in our centre and is a safe and effective alternative. However, in the case of severe Cushing's disease, laparoscopic adrenalectomy has the potential for significant adverse outcomes and mortality.

The financial imperative of physicians to control demand of laboratory testing.

It is an integral component of doctor's duty of care to understand the significant impact laboratory testing has on the expense an ultimate quality of healthcare patients receive, yet the costs of these tests are poorly perceived. Utilising semi-structured interviews and questionnaires, we assessed surgeon's perceived costs of two commonly encountered clinical scenarios requiring out of hours laboratory testing. Of the 35 participants only 23.3% (n = 7) accurately estimated the overall cost. The most expensive test was "Type and Screen" at Euro 83, with 77.3% (n = 17) underestimating the cost. Non-consultant hospital doctors qualified for 3 years were more likely to underestimate on-call costs (p = 0.042). It is of utmost importance to improve the knowledge of all surgeons of the financial implications of investigations. Through education we can potentially reduce un-warranted costs and fulfill our duty of care in the most cost efficient manner.

European guideline for the management of donovanosis, 2010.

Donovanosis is a rare sexually transmitted infection now mainly seen in sporadic cases in Papua New Guinea, South Africa, India, Brazil and Australia. The causative organism is Calymmatobacterium granulomatis though a proposal has been put forward that the organism be reclassified as Klebsiella granulomatis comb. nov. The incubation period is approximately 50 days with genital papules developing into ulcers that increase in size. Four types of lesions are described - ulcerogranulomatous, hypertrophic, necrotic and sclerotic. The diagnosis is usually confirmed by microscopic identification of characteristic Donovan bodies on stained tissue smears. More recently, polymerase chain reaction (PCR) methods have been developed. The recommended treatment is azithromycin 1 g weekly until complete healing is achieved.

Pyogenic liver abscesses: diminished role for operative treatment.

BACKGROUND: Pyogenic liver abscess is a rare but potentially serious condition. It has traditionally been treated by open drainage; however interventional radiology is now becoming the standard of care. METHODS: All cases of liver abscesses admitted to a tertiary hospital over thirteen years (1995-2007) were retrospectively reviewed. Patient demographics, length of hospital stay, predisposing factors as well as cultured organisms were evaluated. Imaging techniques as well as patient management were also recorded. RESULTS: There were 66 hospital admissions of 61 patients with liver abscesses, 0.032% (66/205,079) of the total hospital admissions for the time period. Mean age was 61 years (range 26-90 years), male (36/61) 59%: female (25/61) 41%. Average hospital stay was 23 days (Range 1-84 days) and there were no deaths. 39 of 61 patients (64%) had a single abscess (90% right lobe). 20 of 61 patients (33%) had undergone a recent intra-abdominal procedure. Escherichia coli (10/61) and Enterococci (8/61) were the most frequent organisms isolated. Radiological intervention was performed in 50 of 61 (82%, 51% ultrasound and 31% CT guided). 9 of 61 (15%) were managed conservatively, while one case was managed surgically and another with endoscopic sphincterotomy and stent placement. CONCLUSIONS: Pyogenic liver abscesses are uncommon, and while associated with significant morbidity and prolonged hospital stay, mortality is now rare. Radiological intervention and anti-microbial therapy are the mainstay of treatment, and operative intervention is now rarely required.

Foreskin length in uncircumcised men is associated with subpreputial wetness.

This study was performed to identify possible factors associated with penile wetness, defined as the observation of a diffuse homogenous film of moisture on the surface of the glans and coronal sulcus, in men attending a sexually transmitted infection clinic. Genital examination was undertaken in 422 uncircumcised men and any degree of subpreputial wetness observed was recorded. The degree of visibility of the urinary meatus on direct inspection was also assessed. Subjects were asked whether they retracted the foreskin while urinating and how long since they had last passed urine. Penile wetness was observed in 13.0% of the men and was more common in those whose foreskin covered the urinary meatus on direct inspection (17.4% vs. 4.9%) and those with balanitis (33.3%). On multivariate analysis, penile wetness was independently associated with balanitis, non-specific urethritis/chlamydia, reporting sex with another man and having a visible urinary meatus on direct inspection. Penile wetness was not associated with retracting the foreskin while passing urine or duration since last passed urine. Men with a foreskin covering the urinary meatus on direct observation should be advised about the benefits of good genital hygiene if penile wetness was observed.

Population-level effect of HSV-2 therapy on the incidence of HIV in sub-Saharan Africa.

BACKGROUND: Herpes simplex virus type 2 (HSV-2) infection increases acquisition and transmission of HIV, but the results of trials measuring the impact of HSV-2 therapy on HIV genital shedding and HIV acquisition are mixed, and the potential impact of HSV-2 therapy on the incidence of HIV at the population level is unknown. METHODS: The effects of episodic and suppressive HSV-2 therapy were simulated using the individual-level model STDSIM fitted to data from Cotonou, Benin (relatively low HIV prevalence) and Kisumu, Kenya (high HIV prevalence). Clinician- and patient-initiated episodic therapy, started when symptomatic, were assumed to reduce ulcer duration. Suppressive therapy, given regardless of symptoms, was also assumed to reduce ulcer frequency and HSV-2 infectiousness. RESULTS: Clinician-initiated episodic therapy in the general population had almost no effect on the incidence of HIV. The impact of patient-initiated therapy was higher because of earlier treatment initiation, but still low (<5%) unless symptom recognition and treatment-seeking behaviour were very high. Suppressive therapy given to female sex workers (FSW) in Kisumu had little effect on population HIV incidence. In Cotonou, suppressive therapy in FSW with high coverage and long duration reduced population HIV incidence by >20% in the long term. Impact was increased in both cities by also treating a proportion of their clients. Long-term suppressive therapy with high coverage in the general population could reduce HIV incidence by more than 30%. CONCLUSIONS: These results show that HSV-2 therapy could potentially have a population-level impact on the incidence of HIV, especially in more concentrated epidemics. However, a substantial impact requires high coverage and long duration therapy, or very high symptom recognition and treatment-seeking behaviour.

Zinc metalloproteins as medicinal targets.

Zinc bioinorganic chemistry has emphasized the role of the metal ion on the structure and function of the protein. There is, more recently, an increasing appreciation of the role of zinc proteins in a variety of human diseases. This critical review, aimed at both bioinorganic and medicinal chemists, shows how apparently widely-diverging diseases share the common mechanistic approaches of targeting the essential function of the metal ion to inhibit activity. Protein structure and function is briefly summarized in the context of its clinical relevance. The status of current and potential inhibitors is discussed along with the prospects for future developments (162 references).