Arterial Stiffness in a Cohort of Young People Living With Perinatal HIV and HIV Negative Young People in England.

Background: Antiretroviral therapy (ART) has increased life expectancy and consequently the risk of cardiovascular disease (CVD) in adults living with HIV. We investigated the levels and predictors of arterial stiffness in young people (YP) living with perinatal HIV (PHIV) and HIV negative YP in the Adolescents and Adults Living with Perinatal HIV (AALPHI) study. Methods: AALPHI was a prospective study evaluating the impact of HIV infection and exposure to ART on YP living with PHIV (aged 13-21 years) who had known their HIV status for at least 6 months, and HIV negative YP (aged 13-23 years) who either had a sibling, friend or parent living with HIV. Participants were enrolled from HIV clinics and community services in England. Two hundred and thirteen PHIV and 65 HIV negative YP (42% siblings of PHIV) had pulse wave velocity (PWV) measurements taken (Vicorder software) from the supra-sternal notch to the middle of the thigh cuff, at their second interview in the study between 2015 and 2017. Average PWV was calculated from the three closest readings (≥3 and ≤ 12 m/s) within 0.6 m/s of each other. Linear regression examined predictors of higher (worse) PWV, including age, sex, HIV status and height as a priori, ethnicity, born outside UK/Ireland, alcohol/nicotine/drug use, weight, waist-to-hip-ratio, mean arterial pressure (MAP), caffeine 2 h before PWV and nicotine on day of PWV. A separate PHIV model included CD4, viral load, years taking ART and ART regimen. Findings: One hundred and twenty eight (60%) PHIV and 45 (69%) HIV negative YP were female (p = 0.18), with median (IQR) age 18 (16, 20) and 18 (16, 21) years (p = 0.48) respectively. Most PHIV were taking a combination of three ART drugs from two classes. There was a trend toward higher (worse) mean PWV in the PHIV group than the HIV negative group [unvariable analysis 6.15 (SD 0.83) m/s vs. 5.93 (0.70) m/s, respectively, unadjusted p = 0.058], which was statistically significant in the multivariable analysis [adjusted p (ap) = 0.020]. In multivariable analysis being male (ap = 0.002), older age (ap < 0.001), higher MAP (ap < 0.001) and nicotine use on day of measurement (ap = 0.001) were also predictors of higher PWV. The predictors were the same in the PHIV model. Interpretation: By late adolescence PHIV had worse PWV in comparison to HIV negative peers, and traditional risk factors for CVD (higher arterial pressure, being male and older age) were associated with higher PWV values. Regular detailed monitoring of cardiovascular risk factors should become standard of care for every young person with PHIV worldwide.

Mortality and AIDS-defining events among young people following transition from paediatric to adult HIV care in the UK.

OBJECTIVES: To investigate risk of AIDS and mortality after transition from paediatric to adult care in a UK cohort of young people with perinatally acquired HIV. METHODS: Records of people aged ≥ 13 years on 31 December 2015 in the UK paediatric HIV cohort (Collaborative HIV Paediatric Study) were linked to those of adults in the UK Collaborative HIV Cohort (CHIC) cohort. We calculated time from transition to a new AIDS event/death, with follow-up censored at the last visit or 31 December 2015, whichever was the earliest. Cumulative incidence of and risk factors for AIDS/mortality were assessed using Kaplan-Meier and Cox regression. RESULTS: At the final paediatric visit, the 474 participants [51% female, 80% black, 60% born outside the UK, median (interquartile range) age at antiretroviral therapy (ART) initiation = 9 (5-13) years] had a median age of 18 (17-19) years and CD4 count of 471 (280-663) cell/µL; 89% were prescribed ART and 60% overall had a viral load ≤ 400 copies/mL. Over median follow-up in adult care of 3 (2-6) years, 35 (8%) experienced a new AIDS event (n = 25) or death (n = 14) (incidence = 1.8/100 person-years). In multivariable analyses, lower CD4 count at the last paediatric visit [adjusted hazard ratio = 0.8 (95% confidence interval: 0.7-1.0)/100 cells/µL increment] and AIDS diagnosis in paediatric care [2.7 (1.4-5.5)] were associated with a new AIDS event/mortality in adult care. CONCLUSIONS: Young people with perinatally acquired HIV transitioning to adult care with markers of disease progression in paediatric care experienced poorer outcomes in adult care. Increased investment in multidisciplinary specialized services is required to support this population at high risk of morbidity and mortality.

An avian femur from the Late Cretaceous of Vega Island, Antarctic Peninsula: removing the record of cursorial landbirds from the Mesozoic of Antarctica.

In 2006, a partial avian femur (South Dakota School of Mines and Technology (SDSM) 78247) from the Upper Cretaceous (Maastrichtian) Sandwich Bluff Member of the López de Bertodano Formation of Sandwich Bluff on Vega Island of the northern Antarctic Peninsula was briefly reported as that of a cariamiform-a clade that includes extant and volant South American species and many extinct flightless and cursorial species. Although other authors have since rejected this taxonomic assignment, SDSM 78247 had never been the subject of a detailed description, hindering a definitive assessment of its affinities. Here we provide the first comprehensive description, illustration, and comparative study of this specimen. Comparison of characters that may be assessed in this femur with those of avian taxa scored in published character matrices refutes the inclusion of SDSM 78247 within Cariamiformes, instead supporting its assignment to a new, as-yet unnamed large-bodied species within the genus Vegavis, and therefore its referral to a clade of semiaquatic anseriforms. Important character states diagnostic of Vegavis + Polarornis include strong craniocaudal bowing of the femoral shaft, the presence of a distinct fossa just proximal to the fibular trochlea, and the broad and flat shape of the patellar sulcus. Referral to Vegavis is based on the presence of a distinctive proximocaudal fossa and distolateral scar. This genus was previously known only from Vegavis iaai, a smaller-bodied taxon from the same locality and stratigraphic unit. Our reassignment of SDSM 78247 to Vegavis sp. removes the record of cariamiform landbirds from the Antarctic Cretaceous.

Emergence of nasal chondrosarcoma in a dog with nasal polyposis.

Whilst the malignant transformation of nasal polyps or secondary development of nasal neoplasia after chronic inflammation is likely to be relatively rare, this potential complication should be considered, and the clinician should be vigilant for evidence of malignant transformation.

A hypothesis for the existence of two types of tuberculosis, reflecting two distinct types of immune failure to control the pathogen, based upon prevalence of mycobacterium-specific IgG subclasses.

Most people infected by Mycobacterium tuberculosis, about 90%, contain the pathogen and are healthy. Most investigators have concluded that pathogen-specific Th1 cells contribute to protection. Pulmonary tuberculosis, the most prevalent form of disease, is associated with destructive granulomas, the formation of which also appears to involve Th1 cells. In what sense then do the two Th1 components of the response, in healthy infected individuals and patients, differ? An insight into this question might provide clues for attaining effective vaccination and better treatment. We approached this question by examining the relative prevalence of different IgG isotypes among anti-mycobacterium-specific antibodies in patients and healthy infected individuals as a surrogate marker for the Th1/Th2 phenotype of the response. Our observations lead us to agree that healthy infected individuals generate a predominant Th1 response. Our observations also lead us to propose that many patients make a similar kind of response as healthy infected individuals, but that this response is too weak to contain the infection. We refer to such individuals as having type I tuberculosis. Other patients appear to have a greater and detrimental Th2 component to their immune response than that of healthy infected individuals. We refer to these individuals as having type II tuberculosis. This proposal that there are two types of tuberculosis, reflecting two distinct types of failure by the immune system, will, if correct, be pertinent to vaccine design, treatment of tuberculosis and in making further progress in our understanding the genetics of susceptibility to M. tuberculosis.

Higher rates of triple-class virological failure in perinatally HIV-infected teenagers compared with heterosexually infected young adults in Europe.

OBJECTIVES: The aim of the study was to determine the time to, and risk factors for, triple-class virological failure (TCVF) across age groups for children and adolescents with perinatally acquired HIV infection and older adolescents and adults with heterosexually acquired HIV infection. METHODS: We analysed individual patient data from cohorts in the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). A total of 5972 participants starting antiretroviral therapy (ART) from 1998, aged < 20 years at the start of ART for those with perinatal infection and 15-29 years for those with heterosexual infection, with ART containing at least two nucleoside reverse transcriptase inhibitors (NRTIs) and a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (bPI), were followed from ART initiation until the most recent viral load (VL) measurement. Virological failure of a drug was defined as VL > 500 HIV-1 RNA copies/mL despite ≥ 4 months of use. TCVF was defined as cumulative failure of two NRTIs, an NNRTI and a bPI. RESULTS: The median number of weeks between diagnosis and the start of ART was higher in participants with perinatal HIV infection compared with participants with heterosexually acquired HIV infection overall [17 (interquartile range (IQR) 4-111) vs. 8 (IQR 2-38) weeks, respectively], and highest in perinatally infected participants aged 10-14 years [49 (IQR 9-267) weeks]. The cumulative proportion with TCVF 5 years after starting ART was 9.6% [95% confidence interval (CI) 7.0-12.3%] in participants with perinatally acquired infection and 4.7% (95% CI 3.9-5.5%) in participants with heterosexually acquired infection, and highest in perinatally infected participants aged 10-14 years when starting ART (27.7%; 95% CI 13.2-42.1%). Across all participants, significant predictors of TCVF were those with perinatal HIV aged 10-14 years, African origin, pre-ART AIDS, NNRTI-based initial regimens, higher pre-ART viral load and lower pre-ART CD4. CONCLUSIONS: The results suggest a beneficial effect of starting ART before adolescence, and starting young people on boosted PIs, to maximize treatment response during this transitional stage of development.

Tuberculosis in HIV-infected children in Europe, Thailand and Brazil: Paediatric TB-HIV EuroCoord study

SETTING: Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil. OBJECTIVE: To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children. DESIGN: Observational study of TB diagnosed in HIV-infected children in 2011-2013. RESULTS: Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0-11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti-tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes. CONCLUSION: Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention

Tuberculosis in HIV-infected children in Europe, Thailand and Brazil: paediatric TB-HIV EuroCoord study.

SETTING: Centres participating in the Paediatric European Network for Treatment of AIDS (PENTA), including Thailand and Brazil. OBJECTIVE: To describe the incidence, presentation, treatment and treatment outcomes of tuberculosis (TB) in human immunodeficiency virus (HIV) infected children. DESIGN: Observational study of TB diagnosed in HIV-infected children in 2011-2013. RESULTS: Of 4265 children aged <16 years, 127 (3%) were diagnosed with TB: 6 (5%) in Western Europe, 80 (63%) in Eastern Europe, 27 (21%) in Thailand and 14 (11%) in Brazil, with estimated TB incidence rates of respectively 239, 982, 1633 and 2551 per 100 000 person-years (py). The majority (94%) had acquired HIV perinatally. The median age at TB diagnosis was 6.8 years (interquartile range 3.0-11.5). Over half (52%) had advanced/severe World Health Organization stage immunodeficiency; 67 (53%) were not on antiretroviral therapy (ART) at TB diagnosis. Preventive anti-tuberculosis treatment was given to 23% (n = 23) of 102 children diagnosed with HIV before TB. Eleven children had unfavourable TB outcomes: 4 died, 5 did not complete treatment, 1 had recurrent TB and 1 had an unknown outcome. In univariable analysis, previous diagnosis of acquired immune-deficiency syndrome, not being virologically suppressed on ART at TB diagnosis and region (Brazil) were significantly associated with unfavourable TB outcomes. CONCLUSION: Most TB cases were from countries with high TB prevalence. The majority (91%) had favourable outcomes. Universal ART and TB prophylaxis may reduce missed opportunities for TB prevention.

Interleukin 6 increases the in vitro expression of key proteins associated with steroidogenesis in the bovine adrenal zona fasciculata.

In this study, the in vitro effects of interleukin 6 (IL-6) on the messenger RNAs (mRNAs) and proteins for key steroidogenic factors in the bovine adrenal zona fasciculata (ZF) were determined. Bovine adrenal glands were obtained from an abattoir, and the ZF was isolated. Strips of ZF were then exposed to different concentration of murine IL-6 and/or adrenocorticotropic hormone (ACTH) for various intervals, the protein and mRNA extracted, and the mRNA and protein expression determined by real-time polymerase chain reaction and Western blots. Exposure (1 h) to IL-6 increased in a concentration-dependent manner (10-pg IL-6/mL, P < 0.05 vs control; 100-pg IL-6/mL, P < 0.01 vs control) the relative expression of the mRNAs and proteins for steroidogenic acute regulatory protein (StAR), cholesterol side-chain cleavage enzyme (P450scc), 3ß hydroxysteroid dehydrogenase type 2 (3ß HSD), 17α-hydroxylase/17,20-lyase/17,20-desmolase (P450 17OH), steroid 21-hydroxylase (P450 21OH), steroid 11-ß-hydroxylase type 1 (P450 11ßOH), and steroidogenic factor 1 (SF-1), a nuclear factor that increases StAR and steroidogenic enzymes (SEs) expression. Similarly, IL-6 (10 pg/mL) increased the relative expression of proteins and mRNAs for StAR, P450scc, 3ß HSD, P450 17OH, P450 21 OH, P450 11ßOH, and SF-1 in a time-dependent manner (30 min, P < 0.05 vs control; 60, 120, and 240 min, P < 0.01 vs control). In contrast, IL-6 decreased in a concentration-dependent (P < 0.01 vs control for 1, 10, and 100 pg IL-6/mL) and time-dependent (P < 0.05 vs control for 30, 60,120, and 240 min of 10 pg IL-6/mL) manner the relative expression of the mRNA and protein for adrenal hypoplasia congenita-like protein (DAX-1), a nuclear factor that decreases expression of StAR and SEs. Incubation (1 h) of ZF with 100-nM ACTH increased (P < 0.05 vs control) the relative expression of StAR, P450scc, 3ß HSD, P450 17OH, P450 21OH, P450 11ßOH, and SF-1 and decreased (P < 0.01 vs control) the relative expression of DAX-1. Murine IL-6 (10 pg/mL) augmented (P < 0.05 vs ACTH) both the stimulatory and inhibitory effects of ACTH. Bovine IL-6 (100 pg/mL, 1-h incubation) also increased (P < 0.01 vs control) the relative expression of the proteins for StAR, P450scc, and SF-1 and decreased (P < 0.01 vs control) the relative expression of DAX-1. In summary, IL-6 increased ZF expression of StAR and 5 SEs, which may be mediated in part by decreasing DAX-1 expression and increasing SF-1 expression.

Interleukin-6 inhibits adrenal androgen release from bovine adrenal zona reticularis cells by inhibiting the expression of steroidogenic proteins.

Interleukin-6 (IL-6) is secreted by adrenocortical cells and modifies cortisol secretion. In this study, the effects of IL-6 on adrenal androgen release were investigated. The zona reticularis (ZR) was generally isolated from bovine adrenal glands by dissection. In select experiments, the intact adrenal cortex (ie, all 3 adrenocortical zones) was dissected from the adrenal glands. For androgen release experiments, ZR and intact adrenocortical cubes were dispersed into isolated cells, the cells cultured and exposed to IL-6 and/or adrenocorticotropic hormone (ACTH), and androgen release determined by radioimmunoassay. Basal and ACTH-stimulated androgen release from the ZR was inhibited by IL-6 in a concentration-dependent (10-1000 pg/mL) and time-dependent (4-24 h) manner (P < 0.01 by 1-way analysis of variance and the Bonferroni test). In contrast, IL-6 increased basal and ACTH-stimulated androgen release from mixed adrenocortical cells (P < 0.01). The mechanism of IL-6 inhibition of androgen release was investigated by exposing ZR strips to IL-6 and measuring the expression of the messenger RNA (mRNA) and protein of steroidogenic factors. Basal and ACTH-stimulated expression of the mRNA and protein for steroidogenic acute regulatory protein, cholesterol side chain cleavage enzyme, 3-ß-hydroxysteroid dehydrogenase type 2, steroid 17-α-hydroxylase/17,20 lyase/17,20 desmolase, and the nuclear factor steroidogenic factor 1 (SF-1), that stimulates steroidogenesis, were decreased by IL-6 (P < 0.01). In contrast IL-6 increased the mRNA and protein for dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1), a nuclear factor that inhibits steroidogenesis (P < 0.01). In summary, IL-6 decreased androgen release and the expression of steroidogenic factors in the ZR, and this decrease may be mediated in part through increasing DAX-1 and decreasing SF-1.

Mortality in perinatally HIV-infected young people in England following transition to adult care: an HIV Young Persons Network (HYPNet) audit.

OBJECTIVES: Mortality in young people with perinatally acquired HIV infection (PHIV) following transfer to adult care has not been characterized in the UK. We conducted a multicentre audit to establish the number of deaths and associated factors. METHODS: Fourteen adult clinics caring for infected young people reported deaths to 30 September 2011 on a proforma. Deaths were matched to the Collaborative HIV Paediatric Study, a clinical database of HIV-infected children in the UK/Ireland, to describe clinical characteristics in paediatric care of those who died post-transition. RESULTS: Eleven deaths were reported from 14 clinics which cared for 248 adults with PHIV. For the 11 deaths, the median age at transfer to adult care was 17 years (range 15-21 years), and at death was 21 years (range 17-24 years). Causes of death were suicide (two patients), advanced HIV disease (seven patients) and bronchiectasis (one patient), with one cause missing. At death, the median CD4 count was 27 cells/µL (range 0-630 cells/µL); five patients were on antiretroviral therapy (ART) but only two had a viral load < 50 HIV-1 RNA copies/mL. Nine had poor adherence when in paediatric care, continuing into adult care despite multidisciplinary support. Eight had ART resistance, although all had potentially suppressive regimens available. Nine had mental health diagnoses. CONCLUSIONS: Our findings highlight the complex medical and psychosocial issues faced by some adults with PHIV, with nine of the 11 deaths in our study being associated with poor adherence and advanced HIV disease. Novel adherence interventions and mental health support are required for this vulnerable cohort.

Vertically acquired HIV diagnosed in adolescence and early adulthood in the United Kingdom and Ireland: findings from national surveillance.

OBJECTIVE: The aim of the study was to describe the characteristics of young people with vertically acquired HIV diagnosed aged > or =13 years. METHODS: A retrospective review of HIV diagnoses reported to well-established national paediatric and adult HIV surveillance systems in the United Kingdom/Ireland was conducted. RESULTS: Forty-two young people with vertically acquired HIV diagnosed aged > or =13 years were identified; 23 (55%) were female, 40 (95%) were black African and 36 (86%) were born in sub-Saharan Africa. The median age at HIV diagnosis was 14 years (range, 13-20 years). Half of the patients presented with symptoms; the remainder were screened for HIV following diagnosis of a relative. The median CD4 count at diagnosis was 210 cells/microL (range, 0-689 cells/microL), 12 patients (29%) were diagnosed with AIDS at HIV diagnosis or subsequently, and 34 (81%) started combination antiretroviral therapy (ART), most (31 of 34) within a year of diagnosis. CONCLUSION: A small number of young people with vertically acquired HIV survive childhood without ART and are diagnosed at age > or =13 years in the United Kingdom/Ireland. Half of the patients were asymptomatic, highlighting the importance of considering HIV testing for all offspring of HIV-infected women, regardless of age or symptoms. Increased awareness among clinicians and parents is required to reduce delayed presentation with advanced disease and to avoid onward transmission as these young people become sexually active.

Use of superabsorbent polymer gels for surface decontamination of Bacillus anthracis spores.

AIMS: This study evaluated the inactivation of Bacillus anthracis Vollum spores dried on a nonporous surface using a superabsorbent polymer (SAP) gel containing commercially available liquid decontaminants. METHODS AND RESULTS: The first phase determining the availability of the liquid decontaminant within the SAP showed that the SAP gel containing pH-adjusted sodium hypochlorite (NaOCl) inhibited B. anthracis growth while the water control SAP gel had no affect on growth. For testing surface decontamination, B. anthracis spores were dried onto steel coupons painted with chemical agent resistant coating and exposed to SAP containing either pH-adjusted NaOCl, chlorine dioxide (ClO(2)) or hydrogen peroxide/peracetic acid (H(2)O(2)/PA) for 5 and 30 min. At contact times of both 5 and 30 min, all of the SAP gels containing pH-adjusted NaOCl, ClO(2) or H(2)O(2)/PA inactivated B. anthracis spores at levels ranging from 2.2 to > or =7.6 log reductions. CONCLUSIONS: Incorporation of three commercially available decontaminant technologies into a SAP gel promotes inactivation of B. anthracis spores without observable physical damage to the test surface. SIGNIFICANCE AND IMPACT OF THE STUDY: This work provides preliminary data for the feasibility of using SAP in inactivating B. anthracis spores on a nonporous surface, supporting the potential use of SAP in surface decontamination.

Hepatitis B vaccine uptake among injecting drug users in England 1998 to 2004: is the prison vaccination programme driving recent improvements?

In 1999, the Department of Health allocated additional funding to Health Authorities in England to expand hepatitis B immunization among injecting drug users (IDUs), with the aim of increasing coverage by 20%. In 2001, a vaccination programme for prison inmates in England was also instigated. Between 1998 and 2004 current IDUs participated in a series of annual unlinked anonymous surveys that recorded vaccine uptake (n = 11 383). The proportion self-reporting vaccine uptake rose significantly from 27% in 1998 to 59% in 2004 [adjusted odds ratio: 3.7 (95% CI 3.2-4.3); increase in uptake of 25% per annum (95% CI 22-27%)]. A second survey, which recruited 852 current IDUs from community settings in 2003/04, found that prisons were the most common source (38%) of vaccine doses, followed by drug services (28%) and general practitioners (17%), with only 14% receiving doses through needle exchanges. These data suggest that the 20% target of improving vaccination coverage has been met, with the prison vaccination programme likely to have made a substantive contribution in recent years. However, prevalence of antibodies to the hepatitis B core antigen was stable (21%) and is currently similar among the vaccinated and unvaccinated. Consideration needs to be given to improving community vaccination provision for IDUs, targeting recent initiates, and determining when surveillance data should indicate reductions in infection so that the effectiveness of the targeted strategy can be assessed.

Twenty years of selective hepatitis B vaccination: is hepatitis B declining among injecting drug users in England and Wales?

Injection drug use is a common route of infection for the hepatitis B virus (HBV) in the UK. The aim of this study was to establish the prevalence and force of infection for HBV among injecting drug users (IDUs) recruited from multiple community and drug agency settings in England and Wales between 1990 and 2004. Cross-sectional studies of IDUs in and out of contact with drug agencies were conducted throughout the 15-year period. Oral fluid samples were tested for antibodies to the hepatitis B core antigen (anti-HBc). Logistic regression was used to investigate associations between risk factors and anti-HBc positivity and force of infection models were explored. In total, 2527 injectors were recruited from community settings, and 29 386 from drug agencies. Anti-HBc prevalence was 31% (95% CI 30.7-31.8%). It declined in the early 1990s from around 50% in 1992 to 25% in 1999, after which it increased slightly. It was also higher in those who had injected for longer, older IDUs, those recruited in London and North West England, and those reporting having a previous voluntary confidential HIV test. The force of infection models suggested that the incidence of infection increased in 1999-2004 compared with 1993-1998, and was higher in new injectors compared with those injecting for > or =1 year. In conclusion, findings suggest ongoing HBV transmission in recent years despite an overall decline in prevalence in the early and mid-1990s, and highlight the importance of targeting vaccination programmes at new IDUs who have high incidence rates of infection.

Modelling the impact on Hepatitis C transmission of reducing syringe sharing: London case study.

BACKGROUND: Hepatitis C virus (HCV) prevalence and incidence among injecting drug users (IDUs) has increased in London and rest of UK. To inform public health action, mathematical modelling is used to explore the possible impact of strategies to decrease syringe sharing. METHODS: A mathematical model was developed to simulate HCV transmission amongst IDUs in London. Because of parameter uncertainty, numerical search algorithms were used to obtain different model fits to HCV seroprevalence data from London for 2002-03. These simulations were used to explore the likely impact of HCV prevention activities that reduce syringe sharing amongst all IDUs, IDUs that have injected for greater than one year, or IDUs with lower or higher frequencies of syringe sharing. RESULTS: Key differences between model fits centred on how they simulated the high HCV incidence amongst new injectors, either through assuming increased HCV infectivity during acute infection, a large sub-group of high frequency syringe sharers, or increased sharing among new IDUs. Despite parameter uncertainty, the model projections suggest that modest reductions in syringe sharing frequency (<25%) will reduce the HCV seroprevalence in newly initiated IDUs (injecting less than four years) but much larger and sustained reductions (>50%) are required to reduce the HCV seroprevalence in long-term IDUs (injecting more than 8 years). Critically the model also suggested that large reductions in HCV seroprevalence will be achieved only if interventions target all IDUs and reach IDUs within 12 months of injecting. DISCUSSION: Public health interventions must reduce syringe sharing amongst all IDUs, including newly initiated IDUs, and be sustained for many years to reduce HCV infection. More accurate data on key behavioural (sharing frequency) and biological (percentage of infected IDUs that clear infection) parameters is required to improve model projections.

Prevalence of, and risk factors for, hepatitis C virus infection among recent initiates to injecting in London and Glasgow: cross sectional analysis.

Our aim was to compare the prevalence of antibody to hepatitis C virus (anti-HCV) among recently initiated injecting drug users (IDUs) in London and Glasgow, and to identify risk factors which could explain differences in prevalence between the cities. Complementary studies of community recruited IDUs who had initiated injection drug use since 1996 were conducted during 2001-2002. Data on HCV risk behaviours were gathered using structured questionnaires with identical core questions and respondents were asked to provide an oral fluid specimen which was tested anonymously for anti-HCV but was linked to the questionnaire. Sensitivities of the anti-HCV assays for oral fluid were 92-96%. Prevalence of anti-HCV was 35% (122/354) in London and 57% (207/366) in Glasgow (P < 0.001). Multifactorially, factors significantly associated with raised odds of anti-HCV positivity were increasing length of injecting career, daily injection, polydrug use, having had a needlestick injury, and having served a prison sentence. In addition lower odds of anti-HCV positivity were associated with non-injection use of crack cocaine and recruitment from drug agencies. After adjustment for these factors, the increased odds of anti-HCV associated with being a Glasgow IDU were diminished but remained significant. HCV continues to be transmitted among the IDU population of both cities at high rates despite the availability of syringe exchange and methadone maintenance. Effectiveness of harm reduction interventions may be compromised by inadequate coverage and failure to reduce sufficiently the frequency of sharing different types of injecting equipment, as well as the high background prevalence of HCV, and its high infectivity. Comprehensive action is urgently required to reduce the incidence of HCV among injectors.

Formation of transient non-protein calcium pores by lysophospholipids in S49 Lymphoma cells.

Palmitoyl-lysophosphatidylcholine promotes a transient calcium influx in lymphoma cells. Previously, it was observed that this influx was accompanied by a temporary increase in propidium iodide permeability that appeared linked to calcium entry. Those studies demonstrated that cobalt or nickel could block the response to lysophosphatidylcholine and raised the question of whether the calcium conductance involved specific channels. This communication describes a series of experiments to address that issue. The time dependence and structural specificity of the responses to lysophosphatidylcholine reinforced the hypothesis of a specific channel or transporter. Nevertheless, observations using patch clamp or calcium channel blockers suggested that this "channel" does not involve proteins. Alternative protein-mediated mechanisms such as indirect involvement of the sodium-calcium exchanger and the sodium-potassium ATPase were also excluded. Experiments with extracellular and intracellular calcium chelators suggested a common route of entry for calcium and propidium iodide. More directly, the ability of lysophosphatidylcholine to produce cobalt-sensitive permeability to propidium iodide was reproduced in protein-free artificial membranes. Finally, the transient nature of the calcium time course was rationalized quantitatively by the kinetics of lysophosphatidylcholine metabolism. These results suggest that physiological concentrations of lysophosphatidylcholine can directly produce membrane pores that mimic some of the properties of specific protein channels.

Structure-activity studies on high affinity NOP-active hexapeptides.

Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G-protein coupled receptor ORL1 (NOP), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiologic functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited number of high-affinity ligands to NOP, and particularly the lack of availability of useful specific antagonists. Herein, we describe the pharmacologic activity of a series of modified amino acid containing modifications of the hexapeptide Ac-RYYRWR-NH2, with high affinity for NOP. These compounds were tested for binding affinity using [3H]N/OFQ binding to human NOP in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS-binding in CHO cell membranes. These studies suggest that each Arg of the hexapeptide is required to maintain high-binding affinity. The peptide maintains high affinity if the Tyr2 or Tyr3 are modified, but at least one of these residues must maintain its hydroxyl group or there is a large decrease in intrinsic activity of the peptide.

N-terminal modifications leading to peptide ORL1 partial agonists and antagonists.

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G protein-coupled receptor (opioid receptor like 1, ORL1), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiological functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited high affinity ligands to ORL1, and particularly the lack of availability of useful specific antagonists. Herein we describe the pharmacological activity of a series of N-terminally modified hexapeptides with high affinity for ORL1. These compounds were tested for binding affinity using [3H]N/OFQ binding to human ORL1 in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS binding in CHO cell membranes. The N-terminal modifications have produced compounds that maintained very high receptor affinity, but led to significant changes in intrinsic activity. One compound, pentanoyl-RYYRWR-NH2, with barely measurable agonist activity was tested in vivo. It was found to possess modest analgesic activity, but it was unable to block the morphine modulatory activity of N/OFQ.