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.

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.

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.

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.

MHC-restricted recognition of immunogenic T cell epitopes of pertussis toxin reveals determinants in man distinct from the ADP-ribosylase active site.

The S1 subunit of Pertussis toxin (PT) is responsible for the reactogenicity and in part the immunogenicity of Bordetella pertussis vaccine. The critical residues associated with the immunomodulatory effects of PT were located around Glu140 in the S1 subunit. In man, T cell responses to PT are directed at S1 peptides distinct from Glu140. Two such epitopes, p64-75 and p151-161, are immunogenic in a panel of individuals covering a wide range of HLA genotypes. The response to PT peptides is HLA class II restricted. The response to p64-75 is blocked by an anti-HLA-DQ mAb, while that to p151-161 is blocked by an anti-HLA-DR mAb. These findings may allow for the development of a B. pertussis vaccine free from reactogenicity.

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.

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.

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.

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.

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.

Mechanisms by which thionin induces susceptibility of S49 cell membranes to extracellular phospholipase A2.

Whereas cells normally resist attack by PLA2, they become susceptible under certain pathological conditions. To ascertain the regulatory mechanisms that induce cellular susceptibility to PLA2, the effect of thionin on S49 cells was examined in the presence of PLA2. Thionin alone was unable to evoke hydrolysis of the lipid bilayer. Likewise, the addition of PLA2 alone caused production of only a minimal amount of free fatty acid. However, thionin and PLA2 together resulted in significant hydrolysis of the cell membrane. Thionin caused perturbation of the bilayer structure as suggested by the changes in the emission spectra of laurdan and the permeability of the membrane to propidium iodide. These changes correlated quantitatively with the susceptibility of the lipid bilayer to PLA2. Furthermore, thionin induced a modest increase in intracellular Ca2+. The source of this Ca2+ was the extracellular fluid since EDTA in the extracellular medium inhibited the Ca2+ influx. Moreover, cobalt chloride, a universal Ca2+ channel blocker, prevented the rise in intracellular Ca2+, the uptake of propidium iodide, and the susceptibility to PLA2 induced by thionin. In contrast, the changes in the laurdan emission caused by the thionin were not affected by the cobalt. Furthermore, incubation of the cells with the calcium ionophore A23187 also caused the cells to become susceptible to PLA2. We hypothesize that thionin causes S49 cell membranes to become susceptible to PLA2 by a Ca2+-dependent perturbation of the bilayer structure.

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.

HIV prevalence and risk behaviour among female injecting drug users in London, 1990 to 1996.

OBJECTIVE: To describe trends in HIV prevalence among female injecting drug users (IDU) in London between 1990 and 1996. DESIGN: HIV prevalence and risk behaviour were measured yearly between 1990 and 1993, and in 1996, in point prevalence HIV surveys of IDU recruited from both drug-treatment and community-based settings within Greater London. Sample sizes were 173 in 1990, 111 in 1991, 128 in 1992, 146 in 1993 and 200 in 1996. METHODS: Each survey used structured questionnaires and common sampling and interview strategies. Oral fluid specimens were collected for testing for antibodies to HIV (anti-HIV). Multiple logistic regression was used to assess the trend in HIV prevalence. RESULTS: The percentage of female IDU testing positive for antibodies to HIV showed a marked decline over the study period, from 15.0% in 1990 to 1.0% in 1996 (P < 0.001). This trend was independent of all other variables examined. Each year, higher HIV prevalences were found among IDU recruited from community settings compared with treatment agencies. CONCLUSIONS: These results concur with those of IDU recruited from treatment sites, although the yearly estimates in this study are higher. London benefits from low prevalence of HIV infection among IDU, coupled with behaviour change facilitated by early intervention. Continued surveillance of injectors recruited from both community and treatment settings is necessary in order properly to assess HIV prevalence among IDU.

Dopamine inhibits calcium flux in the 7315a prolactin-secreting pituitary tumour.

Cells of the 7315a prolactin-secreting tumour express biochemically normal cell-surface receptors for dopamine. However, dopamine inhibits prolactin release from these cells only when the basal rate of prolactin release is augmented by increasing the intracellular and/or extracellular calcium concentration of the tumour cells. This suggests that dopaminergic modulation of calcium ion flux could have a central physiological role in these neoplastic cells. In 7315a cells we examined the ability of dopamine to regulate 45Ca2+ influx and fractional 45Ca2+ efflux under conditions of enhanced calcium flux using the calcium channel activator, maitotoxin. It was observed that unidirectional calcium influx stimulated by maitotoxin was significantly inhibited by dopamine. Maitotoxin stimulated fractional efflux and prolactin release from the tumour cells and dopamine simultaneously inhibited both processes by a haloperidol-reversible mechanism. Therefore, in 7315a cells dopamine receptor activation is coupled to inhibition of calcium flux as at least one component in the regulation of prolactin release. These cells may provide further opportunity to study intracellular signalling mechanisms that are modulated by dopamine receptor activity.

Impaired calcium mobilisation in the 7315a prolactin-secreting pituitary tumour.

The 7315a tumour secretes prolactin, but is refractory to enhancement of prolactin release by thyrotrophin-releasing hormone (TRH). In order to investigate further this refractoriness of the 7315a tumour cell, we compared cells from the tumour and from the normal pituitary with regard to TRH-enhanced fractional 45Ca2+ efflux and inositol phosphate production. TRH caused a large efflux of calcium from normal pituitary cells, but only mildly enhanced calcium efflux from the tumour cells. In contrast, TRH enhanced total inositol phosphate generation in both groups of cells to a similar degree. We therefore conclude that prolactin release from 7315a tumour cells is refractory to TRH due, at least in part, to impaired mobilisation of intracellular calcium by inositol phosphates.

Regulation of the intracellular calcium concentration in MMQ pituitary cells by dopamine and protein kinase C.

The MMQ pituitary cell line, which expresses a membranal dopamine receptor, was used to examine the individual contributions of dopamine and protein kinase C (PKC) to control of the intracellular calcium concentration. The calcium concentrations, monitored with the fluorescent dye Indo-1, increased in response to elevated K+, BAY K8644, and maitotoxin, implicating the presence of voltage-dependent calcium channels. Dopamine had no detectable independent effect, but significantly inhibited the rise in intracellular calcium mediated by activation of voltage-dependent calcium channels; this dopaminergic action was prevented by haloperidol. Acute pharmacological activation of PKC for 60 s inhibited the stimulatory effects of these calcium channel activators, and this acute inhibitory action was abolished by prior depletion of PKC. In contrast, however, PKC depletion did not alter the calcium response to BAY K8644 or maitotoxin. Thus, MMQ cells appear to have voltage-dependent calcium channels which, at rest, are either at low density or in a closed state. The rise in intracellular calcium resulting from stimulation of the channels is under inhibitory control by an apparent D-2 dopamine receptor. When pharmacologically activated, phorbol diester-sensitive PKC limits the rise in the cellular calcium level associated with calcium uptake. In the absence of pharmacological activation, however, this enzyme system does not appear to play a role in the cellular calcium response to BAY K8644 or maitotoxin.

Trophic effects of somatostatin on calcium flux: dynamic analysis and correlation with pituitary hormone release.

Somatostatin (SRIF) modulates many aspects of normal physiology, appears useful as a potent antineoplastic agent, and may influence the development of degenerative brain disorders such as Alzheimer's disease. Regulation of cellular calcium flux by SRIF may contribute greatly to many of these interactions, yet remains controversial. SRIF rapidly causes a sustained inhibition of fractional calcium efflux from prelabeled dispersed rat pituitary cells (IC50, approximately 40 pM) and evokes a large rebound increase in efflux after the infusion, each coinciding temporally with expected physiological effects on GH release. These data support a particular role for SRIF-regulated calcium flux in the normal pulsatile pattern of GH secretion and a more general role in the varied biological actions of the peptide.