Spatial clustering of TB-infected cattle herds prior to and following proactive badger removal.

Bovine tuberculosis (TB) is primarily a disease of cattle. In both Ireland and the UK, badgers (Meles meles) are an important wildlife reservoir of infection. This paper examined the hypothesis that TB is spatially correlated in cattle herds, established the range of correlation and the effect, if any, of proactive badger removal on this. We also re-analysed data from the Four Area Project in Ireland, a large-scale intervention study aimed at assessing the effect of proactive badger culling on bovine TB incidence in cattle herds, taking possible spatial correlation into account. We established that infected herds are spatially correlated (the scale of spatial correlation is presented), but at a scale that varies with time and in different areas. Spatial correlation persists following proactive badger removal.

Estimating the extent of spatial association of Mycobacterium bovis infection in badgers in Ireland.

Mycobacterium bovis infects the wildlife species badgers Meles meles who are linked with the spread of the associated disease tuberculosis (TB) in cattle. Control of livestock infections depends in part on the spatial and social structure of the wildlife host. Here we describe spatial association of M. bovis infection in a badger population using data from the first year of the Four Area Project in Ireland. Using second-order intensity functions, we show there is strong evidence of clustering of TB cases in each the four areas, i.e. a global tendency for infected cases to occur near other infected cases. Using estimated intensity functions, we identify locations where particular strains of TB cluster. Generalized linear geostatistical models are used to assess the practical range at which spatial correlation occurs and is found to exceed 6 in all areas. The study is of relevance concerning the scale of localized badger culling in the control of the disease in cattle.

The impact of badger removal on the control of tuberculosis in cattle herds in Ireland.

In Ireland, the herd prevalence of bovine tuberculosis has remained stable for several decades, and in common with several other countries, progress towards eradication has stalled. There is evidence in support of the potential role of infected badgers (Meles meles, a protected species) in bovine tuberculosis in Ireland and Britain. However, this evidence on its own has not been sufficient to prove disease causation. Field trials are likely to offer the best opportunity to define this role. Building on the earlier East Offaly project, our objectives were to assess the impact of badger removal on the control of tuberculosis in cattle herds in Ireland. The study was conducted from September 1997 to August 2002 in matched removal and reference areas (average area of 245.1km(2)) in four counties: Cork, Donegal, Kilkenny and Monaghan. Badger removal was intensive and proactive throughout the study period in the removal areas, but reactive (in response to severe tuberculosis outbreaks in cattle) in the reference areas. Removal intensity in the removal and reference areas during the first 2 years of the study averaged 0.57 and 0.07 badgers/km(2)/year, respectively. The outcome of interest was restriction of cattle herds due to confirmed tuberculosis, where tuberculous lesions were detected in one or more animals. Data were analysed using logistic regression (modelling the probability of a confirmed herd restriction) and survival analysis (modelling time to a confirmed herd restriction). During the study period, there was a significant difference between the removal and reference areas in all four counties in both the probability of and the time to a confirmed herd restriction due to tuberculosis. In the final year of the study, the odds of a confirmed herd restriction in the removal (as compared to the reference areas) were 0.25 in Cork, 0.04 in Donegal, 0.26 in Kilkenny and 0.43 in Monaghan. Further, the hazard ratios (removal over reference) ranged from 0.4 to 0.04 (a 60-96% decrease in the rate at which herds were becoming the subject of a confirmed restriction).

Interactions between HIV and hepatitis B virus in homosexual men: effects on the natural history of infection.

OBJECTIVES: Hepatitis B virus (HBV) and HIV infections share risk-factors; therefore coinfection is common. Interactions have been reported but controlled studies have been limited. Our objective was to study the effect of HIV infection on the natural history of chronic HBV infection and the reverse effect of the HBV carrier state on HIV infection. DESIGN: Prospective observational cohort study. SETTING: Open-access outpatient HIV/genitourinary medicine clinic at a Central London hospital. PATIENTS: Total of 152 untreated homosexual male HBV carriers and 212 HBV surface antigen-negative controls (41.4 and 70.3% HIV-seropositive, respectively). OUTCOME MEASURES: The rate of loss of serum HBV e antigen (HBeAg) and its reappearance in HIV-infected and HIV-uninfected HBV carriers; serum HBV DNA levels measured by dot-blot hybridization assay), HBV DNA polymerase activity and liver transaminase activities, the progression of HIV infection to symptomatic disease or AIDS in HIV-infected compared with HBV-HIV coinfected patients. RESULTS: In HIV-infected HBV carriers, serum HBV DNA polymerase activity was higher, alanine aminotransferase was lower and loss of serum HBeAg (mean follow-up, 2.8 years) occurred at a lower rate when compared with HIV-uninfected HBV carriers (estimated relative hazard, 0.39; 95% confidence interval, 0.161-0.942) Concomitant chronic HBV infection had no detectable effect on the rate of progression of HIV disease after correction for lead-time bias. CONCLUSION: This study strengthens the evidence for a significant effect of HIV infection on the natural history of chronic HBV infection, which by prolonging the period of infectivity could have an important impact on the epidemiology of HBV infection in regions, or patient groups, with high HIV seroprevalence. There was no evidence of an important effect of HBV carriage on HIV disease progression.

Effects of immunosuppressive therapy on the induction of skin tumors by ultraviolet irradiation in hairless mice.

The effects of therapy with four commonly used immunosuppressants--azathioprine, prednisolone, cyclophosphamide, and cyclosporine, on (UVI)-induced skin carcinogenesis were studied in the albino hairless (HRA/Skh-1) mouse. Following 30 weeks' exposure to UVI (290-400 nm) alone, 87% of mice developed skin tumors; the mean incidence of tumors at that time was 2.4 per mouse; and the tumors were predominantly papillomas (72%), with the remainder being carcinomas (25%) and keratoacanthomas (3%). Mice received immunosuppressive drug therapy beginning shortly after the start of UVI and continuing for up to 28 weeks. All drugs were given at immunosuppressive levels and dosages were comparable on a body weight basis to those used in clinical transplantation. Prednisolone had no effect on UVI-induced tumor development. Cyclosporine caused a moderate reduction in the latent period for tumor induction. Azathioprine and cyclophosphamide had strong promoting effects; the latent period for tumor induction was shortened and the tumor yield per mouse was increased (4.3 and 5.7 tumors per mouse, respectively, at 30 weeks after the start of UVI). Azathioprine, but not cyclophosphamide, also induced a larger proportion of carcinomas (43% and 15%, respectively). The results suggest that for kidney transplant recipients treated with the standard immunosuppressive drug regimen of azathioprine/prednisone, the increased susceptibility of the sun-exposed skin of these patients to squamous cell carcinoma is likely to be contributed to by specific promotion by the azathioprine therapy of the carcinogenic effects of sunlight.

Nonspecific immunological studies in kidney transplant recipients with and without skin cancer.

The immunocompetence of the following patient groups was compared using peripheral blood mononuclear cells in a variety of in vitro assays: controls (84); hemodialysis patients (32); kidney transplant recipients without cancer (172), and those with skin cancer (18). The in vitro functions assayed were blastogenic responsiveness to phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen, allogeneic lymphocytes, and two cocktails of bacterial, viral, and fungal antigens; cytotoxic functions assayed were spontaneous cell-mediated cytotoxicity (SCMC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Compared with control subjects, hemodialysis patients showed depressed responsiveness to one antigen cocktail only. Transplant patients with no cancer showed uniformly depressed responsiveness to PHA and allogeneic lymphocytes and reduced SCMC and ADCC activity up to 12 years after transplant; responsiveness in these patients to the two antigen cocktails, after initial depression, recovered by 3 years after transplant to exceed control values. The group of 18 transplant recipients with skin cancer, when compared with transplant recipients with no cancer at a comparable period after transplant, showed similar depression of SCMC and ADCC activity, but significantly greater depression of responsiveness to PHA (P less than 0.01), allogeneic lymphocytes (P less than 0.05), and the 2 antigen cocktails (P less than 0.05).

A urinary profile study of dietary phytoestrogens. The identification and mode of metabolism of new isoflavonoids.

The metabolic fate of the dietary isoflavones daidzein and genistein was investigated in human volunteers challenged with soya. Urinary diphenols, isolated by partition chromatography on Sephadex LH-20, were characterized and identified by profile capillary gas chromatography (GC) and electron ionization mass spectrometry (GC-EIMS) analysis of the trimethylsilyl ether (TMS) derivatives. Novel isoflavonic phytoestrogens found in the urine of volunteers were those of tetrahydrodaidzein, dihydrogenistein, 6'-hydroxy-O-demethylangolesin and 2-dehydro-O-demethylangolensin. Other known diphenols identified were those of equal, dehydrodaidzein, O-demethylangolensin, daidzein, genistein, glycitein, and the lignan enterolactone. Two other urinary isomers with a fragmentation pattern closely resembling that of the persilylated TMS ethers of cis/trans-isomers of tetrahydrodaidzein, were characterized based on the elucidation of fragments associated with the loss of a non-phenolic-OTMS functional group in ring-C. These are fragments presented in the persilylated mass spectra of isoflavan-4-ols and isoflav-3-ene-4-ols, demonstrated here by a combination of simple and tandem mass spectrometry study of the deuterated persilylated TMS ethers of dihydrodaidzein. In a similar study we also present the data on the structural identification and fragment elucidation of the keto/enol tautomers of the TMS ether derivatives of the dihydro derivatives of daidzein and genistein, observed in the urine of volunteers and considered probable products of the derivatization process. Finally, the GC and GC-MS data of two unknown isoflavonoids and that of a lignan-like compound are presented together with those of dihydrodaidzein, dihydrogenistein, tetrahydrodaidzein and 2-dehydro-O-demethylangolensin. The latter four were obtained here as products of small scale chemical synthesis in a preliminary study on the tentative identification of urinary isoflavonoids in human volunteers challenged with soya.

Metabolites of dietary (soya) isoflavones in human urine.

This study was undertaken to better understand the metabolic fate of dietary isoflavones in humans. Twelve volunteers were challenged with soya flour and urinary diphenol levels were then determined by gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). The presence of previously described urinary diphenols was confirmed, i.e. the isoflavones, daidzein and genistein; the isoflavonoid metabolites, equol, dihydrodaidzein (Int-O-D), O-desmethyl-angolensin (O-Dma); the lignan, enterolactone. Diphenols detected for the first time were the isoflavone, glycitein and five novel isoflavonoid metabolites which are tentatively identified as 6'-hydroxy-O-desmethylangolensin (6' OH-O-Dma), dihydrogenistein (Int-O-G), dehydro-O-desmethylangolensin (dehydro-O-Dma) and two isomers of tetrahydrodaidzein. Urinary excretion rates of the three isoflavones (daidzein, genistein, glycitein) over a 3-day period following soya challenge showed moderate variation (4x, 6x and 12x, respectively) between the 12 individuals suggesting some individual variabilities in ability to deconjugate and to absorb dietary isoflavones. However, urinary excretion rates of each of three major isoflavonoid metabolites (equol, O-Dma, 6' OH-O-Dma) showed more marked variation (922x, 17x, 15x, respectively); while some of this variability may reflect varying individual ability to ferment dietary isoflavones per se, an inverse relationship was found between urinary levels of equol and both O-Dma and 6' OH-O-Dma suggesting individual variability in the preferred metabolic pathways of dietary isoflavones.

Effects of oral retinoid (vitamin A and etretinate) therapy on photocarcinogenesis in hairless mice.

Oral retinoid therapy has been considered for the prevention of skin carcinogenesis in humans, although animal studies have failed to provide any evidence of a protective effect of these drugs in the one-step photocarcinogenic system. In this study, oral therapy with vitamin A or a synthetic analogue, etretinate, was tested for ability to protect hairless mice (Skh-hr1) from the development of skin tumours following exposure to broad-band light (280-700 nm) for 25 weeks. Retinoids were given by gavage 3 times weekly either at low dosage (2000 IU vitamin A or 4 mg etretinate per kg body weight) or high dosage (10,000 IU vitamin A or 20 mg etretinate per kg body weight). None of the retinoid therapies compared to control mice (gavage vehicle only) modified skin tumour production in terms of time to onset of tumours, total tumour yield, or the types of tumours produced.

Models for estimating the change-point in gas exchange data.

In subjects undertaking an incremental exercise test to exhaustion, the onset of metabolic acidosis can be detected by an increased rate of carbon dioxide output (VCO2) relative to the rate of increase of oxygen uptake (VO2). To locate the change-point (the gas exchange threshold) in such subjects, a two-line regression model relating these two quantities has been used, where the location of the change-point is unknown. We argue that statistical models where the change-point is set on time (rather than VO2) are more appropriate. This is because VO2 is not monotone in time. We use novel statistical methodology of hidden Markov models to demonstrate the existence of the change-point. We use time series models, to estimate the position of the change-point. In these models distributions other than the multivariate normal are considered. For some subjects, the variance of VCO2 increases with time because of increasing ventilation and this is also modelled. The results are illustrated using gas exchange data on three healthy subjects who performed a 20 W min(-1) workrate ramp test.

Has there been a turning point in the numbers of AIDS and HIV antibody positive cases in Ireland?

BACKGROUND: Major developments in the prevention and treatment of human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) have taken place in recent years. Changes in the size of the HIV and AIDS epidemic need to be monitored to assess these developments and plan future services. AIMS: To describe temporal trends in the incidence of HIV and AIDS in Ireland, describing separately the major risk groups, and to explore possible associations between these trends with developments in care. METHODS: The annual numbers of HIV and AIDS in Ireland were analysed to determine whether there has been a turning point in incidence. RESULTS: For AIDS, there has been an overall decrease in numbers since 1993, with both homosexual and intravenous drug users (IDU) risk groups exhibiting a decrease. For HIV antibody positive individuals, overall numbers have remained constant. However, there has been an upward trend in the heterosexual risk group and a downward trend in the IDU risk group. Thus both AIDS and HIV numbers exhibit turning points. CONCLUSIONS: Declines in HIV and AIDS incidence in the homosexual and IDU risk groups are indirectly attributable to health safety and treatment programmes. The increase in HIV antibody positive cases among heterosexuals may reflect a relapse in safe sex behaviour.

Current prospects for renal transplantation in veterinary practice.

In dogs, the surgical techniques and other technical considerations for the transplantation of most tissues and organs in the body are well established. The last remaining obstacle to uniformly safe and successful organ transplantation is the immune response to foreign tissue antigen and our present inability to completely suppress this response in a specific and safe manner. Immunosuppressive techniques currently available are largely non-specific and unfortunately cause many potentially fatal side effects. As a result graft recipients must be constantly monitored so that enough immunosuppressive treatment is given to prevent rejection but not so much that the recipient develops life threatening complications. The enormous cost and the services necessary to provide this attention in view of the relatively poor survival rates of tissue and organ grafts in dogs will continue to prevent organ transplantation becoming a reality in veterinary practice. Hopefully future advances in tissue-typing and the induction of specific immunological adaption in dogs by ensuring consistently safe and successful transplantation will ead to minimal postoperative attention.

Hepatitis C virus: evidence for sexual transmission.

OBJECTIVE: To determined the prevalence of hepatitis C virus infection and associated risk factors in patients attending a genitourinary medicine clinic, as evidence for sexual transmission. DESIGN: Seroprevalence estimated by reactivity in an enzyme immunoassay for antibodies to C100 protein with supplementary testing with a recombinant immunoblot assay and an assay for hepatitis C virus RNA. SETTING: Outpatient genitourinary medicine clinic in central London. PATIENTS: The panel of 1046 serum samples was from 1074 consecutive patients attending the clinic during November and December 1987 and having blood taken for routine testing for syphilis. Before samples were anonymised demographic and risk factor information was extracted from the clinic notes. Samples had already been tested for antibody to HIV-I and antibody to hepatitis B core antigen. MAIN RESULTS: Significantly more homosexual subjects than heterosexual subjects were positive for hepatitis C antibody determined by enzyme immunoassay alone (19/275 (6.9%) v 8/771 (1.0%), odds ratio 7.14, p less than 0.0001) and also when reactive serum samples were also tested by recombinant immunoblot assay (6/270) (2.2%) v 3/770 (0.4%), odds ratio 5.88, p less than 0.02). There were also significant associations in patients positive for hepatitis C antibody with positivity for antibodies to HIV and to hepatitis B core antigen, lifetime number of sexually transmitted diseases (homosexual men only), and age (all groups combined). Most patients whose serum samples contained specific antibodies to hepatitis C virus were viraemic. CONCLUSIONS: The study provides strong evidence for the sexual transmission of hepatitis C virus. Assays derived from other gene products are desirable to investigate the specificity and sensitivity of the enzyme immunoassay for C100 antibody as a marker of hepatitis C virus infection.

Bovine tuberculosis and udder health in Irish dairy herds.

The association between bovine tuberculosis (TB) infection status based on results from the single intradermal comparative tuberculin test (SICTT) and milk production has been described in dairy cows in TB-infected herds in Ireland. The biological basis was uncertain, but could be related to increased TB susceptibility among lower producing dairy cows. In this study, the relationship between somatic cell count (as an objective measure of udder health) and SICTT reactivity (as a proxy for TB infection status) was investigated. Somatic cell counts of TB infected cows, both during and prior to the lactation of diagnosis of TB infection, were examined and compared to non-infected cows. All Irish dairy herds restricted from trading between June 2004 and May 2005 as a result of two or more TB reactors (test positive) to the SICTT were considered for study. Data were collected on 4340 cows from 419 herds. Previous lactation data for the cows were taken into consideration and all lactations on a cow were analysed together with the years of lactations. There was an inherent hierarchical structure in the data, with lactations nested within cows and cows within herds and so a linear mixed model with two random effects was used to describe the data. Milk production (305-day milk yield) was also included in the model as a fixed effect. The results of the study showed that for all lactations and years under investigation, somatic cell counts for SICTT reactor cows when compared to the non-reactor cows were not significantly different. In this study population, TB infection status was not associated with udder health.

Bovine tuberculosis and milk production in infected dairy herds in Ireland.

This study describes the relationship between bovine tuberculosis (TB) and milk yield in TB-infected dairy herds in Ireland. The study had two objectives: to determine whether cows detected as TB reactors (and thus subject to immediate slaughter) were likely to be the higher milk-producing cows, and to determine whether subclinical TB infection was associated with reduced milk production at or around the time of disclosure (detection). All Irish dairy herds restricted from trading between the 1(st) June 2004 and the 31(st) May 2005 as a result of two or more TB reactors by the Single Intradermal Comparative Tuberculin Test (SICTT) were considered for study. The data consisted of 419 herds. Data were collected on all TB reactors and a random sample of 5 non-reactor cows in these herds: a data set of 4340 cows (2342 TB reactors and 1998 non-reactors). Previous milk data for the cows were taken into consideration and thus all lactations on a cow were analysed together with the years of lactations. There was an inherent hierarchical structure in the data, with lactations nested within cows and cows within herds and thus a linear mixed model with two random effects was used to describe the data. The results of this study showed that for all lactations and years under investigation, milk yield was significantly lower for TB reactor cows, with differences ranging from 120kg (2003, lactation 3) to 573kg (2001, lactation 1), when compared to the non-reactor cows.