Dental caries remains a significant public health problem, prevalence being linked to social and economic deprivation. Occlusal surfaces of first permanent molars are the most susceptible site in the developing permanent dentition. Cochrane reviews have shown pit and fissure sealants (PFS) and fluoride varnish (FV) to be effective over no intervention in preventing caries. However, the comparative cost and effectiveness of these treatments is uncertain. The primary aim of the trial described in this protocol is to compare the clinical effectiveness of PFS and FV in preventing dental caries in first permanent molars in 6-7 year-olds. Secondary aims include: establishing the costs and the relative cost-effectiveness of PFS and FV delivered in a community/school setting; examining the impact of PFS and FV on children and their parents/carers in terms of quality of life/treatment acceptability measures; and examining the implementation of treatment in a community setting.
The trial design comprises a randomised, assessor-blinded, two-arm, parallel group trial in 6–7 year old schoolchildren. Clinical procedures and assessments will be performed at 66 primary schools, in deprived areas in South Wales. Treatments will be delivered via a mobile dental clinic. In total, 920 children will be recruited (460 per trial arm). At baseline and annually for 36 months dental caries will be recorded using the International Caries Detection and Assessment System (ICDAS) by trained and calibrated dentists. PFS and FV will be applied by trained dental hygienists. The FV will be applied at baseline, 6, 12, 18, 24 and 30 months. The PFS will be applied at baseline and re-examined at 6, 12, 18, 24, and 30 months, and will be re-applied if the existing sealant has become detached/is insufficient. The economic analysis will estimate the costs of providing the PFS versus FV. The process evaluation will assess implementation and acceptability through acceptability scales, a schools questionnaire and interviews with children, parents, dentists, dental nurses and school staff. The primary outcome measure will be the proportion of children developing new caries on any one of up to four treated first permanent molars.
The objectives of this study have been identified by the National Institute for Health Research as one of importance to the National Health Service in the UK. The results of this trial will provide guidance on which of these technologies should be adopted for the prevention of dental decay in the most susceptible tooth-surface in the most at risk children.
ISRCTN ref: ISRCTN17029222 EudraCT: 2010-023476-23 UKCRN ref: 9273
Dental caries; Clinical trial; Pit and fissure sealants; Fluoride varnish; Preventive dentistry; Oral health
Blood alcohol levels (BAL) cycle up and down over a 7–8 day period when ethanol is fed continuously for one month in the intragastric tube feeding rat model (ITFRM) of alcoholic liver disease. The cycling phenomenon is due to an alternating increase and decrease in the metabolic rate. Recently, we found that S-adenosyl-methionine (SAMe) fed with alcohol prevented the BAL cycle.
Using the ITFRM we fed rats betaine (2 g/kg/day) with ethanol for 1 month and recorded the daily 24 h urine ethanol level (UAL) to measure the BAL cycle. UAL is equivalent to BAL because of the constant ethanol infusion. Liver histology, steatosis and BAL were measured terminally after 1 month of treatment. Microarray analysis was done on the mRNA extracted from the liver to determine the effects of betaine and alcohol on changes in gene expression.
Betaine fed with ethanol completely prevented the BAL cycle similar to SAMe. Betaine also significantly reduced the BAL compared to ethanol fed rats without betaine. This was also observed when SAMe was fed with ethanol. The mechanism involved in both cases is that SAMe is required for the conversion of epinephrine from norepinephrine by phenylethanolamine methyltransferase (PNMT). Epinephrine is 5 to 10 fold more potent than norepinephrine in increasing the metabolic rate. The increase in the metabolic rate generates NAD, permitting ADH to increase the oxidation of alcohol. NAD is the rate limiting factor in oxidation of alcohol by alcohol dehydrogenase (ADH). This explains how SAMe and betaine prevented the cycle. Microarray analysis showed that betaine feeding prevented the up regulation of a large number of genes including TLR2/4, Il-1b, Jax3, Sirt3, Fas, Ifngr1, Tgfgr2, Tnfrsf21, Lbp and Stat 3 which could explain how betaine prevented fatty liver.
Betaine feeding lowers the BAL and prevents the BAL cycle by increasing the metabolic rate. This increases the rate of ethanol elimination by generating NAD.
S-adenosylmethionine (SAMe); Betaine; Blood Alcohol Cycle (BAL); Microarray Analysis; NAD
Although several studies have described an association between Alzheimer disease (AD) and genetic variation of mitochondrial DNA (mtDNA), each has implicated different mtDNA variants, so the role of mtDNA in the etiology of AD remains uncertain.
We tested 138 mtDNA variants for association with AD in a powerful sample of 4,133 AD case patients and 1,602 matched controls from 3 Caucasian populations. Of the total population, 3,250 case patients and 1,221 elderly controls met the quality control criteria and were included in the analysis.
In the largest study to date, we failed to replicate the published findings. Meta-analysis of the available data showed no evidence of an association with AD.
The current evidence linking common mtDNA variations with AD is not compelling.
Testing for mutations in the KRAS oncogene for patients with metastatic colorectal cancer (mCRC) is generally performed using DNA from formalin-fixed paraffin-embedded tumor tissue; however, access to specimens can be limited and analysis challenging. This study assessed the identification of KRAS mutations in circulating free DNA (cfDNA) using a commercially available KRAS polymerase chain reaction (PCR) kit. Matched plasma, serum and tumor samples were available from 71 patients with mCRC who had received prior therapy but whose disease progressed following therapy. Yields of cfDNA from plasma and serum samples were comparable. Analyses were successful in 70/71 plasma-extracted samples (specificity: 97%, sensitivity: 31%) and 67/71 serum- extracted samples (specificity: 100%, sensitivity: 25%). This study demonstrates that KRAS mutations can be detected in cfDNA using a commercially available KRAS PCR kit, confirming cfDNA as a potential alternative source of tumor DNA in a diagnostic setting if access to archival tumor specimens is limited.
KRAS; mutation; cfDNA; colorectal cancer
An increasing number of studies are demonstrating an association between childhood abuse and psychosis. However, the majority of these rely on retrospective self-reports in adulthood that may be unduly influenced by current psychopathology. We therefore set out to explore the reliability and comparability of first-presentation psychosis patients’ reports of childhood abuse. Psychosis case subjects were drawn from the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (ÆSOP) epidemiological study and completed the Childhood Experience of Care and Abuse Questionnaire to elicit abusive experiences that occurred prior to 16 years of age. High levels of concurrent validity were demonstrated with the Parental Bonding Instrument (antipathy: rs = 0.350–0.737, P < .001; neglect: rs = 0.688–0.715, P < .001), and good convergent validity was shown with clinical case notes (sexual abuse: κ = 0.526, P < .001; physical abuse: κ = 0.394, P < .001). Psychosis patients’ reports were also reasonably stable over a 7-year period (sexual abuse: κ = 0.590, P < .01; physical abuse: κ = 0.634, P < .001; antipathy: κ = 0.492, P < .01; neglect: κ = 0.432, P < .05). Additionally, their reports of childhood abuse were not associated with current severity of psychotic symptoms (sexual abuse: U = 1768.5, P = .998; physical abuse: U = 2167.5, P = .815; antipathy: U = 2216.5, P = .988; neglect: U = 1906.0, P = .835) or depressed mood (sexual abuse: χ2 = 0.634, P = .277; physical abuse: χ2 = 0.159, P = .419; antipathy: χ2 = 0.868, P = .229; neglect: χ2 = 0.639, P = .274). These findings provide justification for the use in future studies of retrospective reports of childhood abuse obtained from individuals with psychotic disorders.
psychotic disorders; child abuse; trauma; schizophrenia; psychometrics
Childhood adversity has been associated with onset of psychosis in adulthood but these studies have used only general definitions of this environmental risk indicator. Therefore, we sought to explore the prevalence of more specific adverse childhood experiences amongst those with and without psychotic disorders using detailed assessments in a large epidemiological case-control sample (ÆSOP).
Data were collected on 182 first-presentation psychosis cases and 246 geographically-matched controls in two UK centres. Information relating to the timing and frequency of exposure to different types of childhood adversity (neglect, antipathy, physical and sexual abuse, local authority care, disrupted living arrangements and lack of supportive figure) was obtained using the Childhood Experience of Care and Abuse Questionnaire.
Psychosis cases were three times more likely to report severe physical abuse from mother that commenced prior to 12 years of age, even after adjustment for other significant forms of adversity and demographic confounders. A non-significant trend was also evident for greater prevalence of reported severe maternal antipathy amongst those with psychosis. Associations with maternal neglect and childhood sexual abuse disappeared after adjusting for maternal physical abuse and antipathy. Paternal maltreatment and other forms of adversity were not associated with psychosis nor was there evidence of a dose-response effect.
These findings suggest that only specific adverse childhood experiences are associated with psychotic disorders and only in a minority of cases. If replicated, this greater precision will ensure that research into the mechanisms underlying the pathway from childhood adversity to psychosis is more fruitful.
child abuse; psychotic disorders; childhood trauma; aetiology; psychosis
The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.
A conformationally-biased, agonist of human C5a65–74 (EP67) was assessed for its adjuvant activities in vitro and in vivo. EP67 induced the release of the inflammatory (Th1) type cytokines from C5a receptor (CD88)-bearing antigen presenting cells (APC). Serum from mice immunized with EP67-ovalbumin (OVA) contained high OVA-specific antibody (Ab) titers [IgG1, IgG2a (IGg2c), IgG2b]. Mice receiving OVA alone produced only IgG1 Abs, indicating the ability of EP67 to induce a Th1-like antibody (A)b class switch. Spleen cell cultures from wild type mice but not CD88−/− mice showed an enhanced OVA-specific proliferative response in vitro. These results indicate the ability of EP67 to drive a Th1-mediated immune response and its potential use as a unique adjuvant
Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes.
We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset.
We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD.
Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.
Using magnetic resonance images we analyzed the relationship between urethral sphincter anatomy, urethral function and pelvic floor function.
Materials and Methods
A total of 103 women with stress incontinence and 108 asymptomatic continent controls underwent urethral profilometry, urethral axis measurement with a cotton swab, vaginal closure force measurement with an instrumented speculum and magnetic resonance imaging. Striated urogenital sphincter length was determined and its thickness was measured in the proximal sphincter, where its circular shape enables estimation of striated urogenital sphincter area. A length-area index was calculated as a proxy for volume.
The striated urogenital sphincter in women with stress incontinence was 12.5% smaller than that in asymptomatic continent women (mean ± SD length-area index 766.4 ± 294.3 vs 876.2 ± 407.3 mm3, p = 0.04). The groups did not differ significantly in striated urogenital sphincter length (13.2 ± 3.4 vs 13.7 ±3.9 mm, p = 0.40), thickness (2.83 ± 0.8 vs 3.11± 1.4 mm, p = 0.09) or area (59.1 ± 18.4 vs 62.9 ± 24.7 mm2, p = 0.24). Striated urogenital sphincter length and area, and the length-area index were associated during voluntary pelvic muscle contraction with more urethral axis elevation and increased vaginal closure force augmentation.
A smaller striated urogenital sphincter is associated with stress incontinence and poorer pelvic floor muscle function.
urethra; urinary incontinence, stress; magnetic resonance imaging; female; muscle, striated
We undertook a two-stage genome-wide association study of Alzheimer's disease involving over 16,000 individuals. In stage 1 (3,941 cases and 7,848 controls), we replicated the established association with the APOE locus (most significant SNP: rs2075650, p= 1.8×10−157) and observed genome-wide significant association with SNPs at two novel loci: rs11136000 in the CLU or APOJ gene (p= 1.4×10−9) and rs3851179, a SNP 5′ to the PICALM gene (p= 1.9×10−8). Both novel associations were supported in stage 2 (2,023 cases and 2,340 controls), producing compelling evidence for association with AD in the combined dataset (rs11136000: p= 8.5×10−10, odds ratio= 0.86; rs3851179: p= 1.3×10−9, odds ratio= 0.86). We also observed more variants associated at p< 1×10−5 than expected by chance (p=7.5×10−6), including polymorphisms at the BIN1, DAB1 and CR1 loci.
This study investigated five confirmed rheumatoid arthritis (RA) susceptibility genes/loci (HLA-DRB1, PTPN22, STAT4, OLIG3/TNFAIP3 and TRAF1/C5) for association with susceptibility and severity in an inception cohort.
The magnitude of association for each genotype was assessed in 1,046 RA subjects from the Yorkshire Early RA cohort and in 5,968 healthy UK controls. Additional exploratory subanalyses were undertaken in subgroups defined by autoantibody status (rheumatoid factor and anti-cyclic citrullinated peptide) or disease severity (baseline articular erosions, Health Assessment Questionnaire (HAQ) score and swollen joint count (SJC)).
In the total RA inception cohort, the HLA-DRB1 shared epitope (per-allele odds ratio (OR) = 2.1, trend P < 0.0001), PTPN22 (per-allele OR = 1.5, trend P < 0.0001), OLIG3/TNFAIP3 locus (per-allele OR = 1.2, trend P = 0.009) and TRAF1/C5 locus (per-allele OR = 1.1, trend P = 0.04) were associated with RA. The magnitude of association for these loci was increased in those patients who were autoantibody-positive. PTPN22 was associated with autoantibody-negative RA (per-allele OR = 1.3, trend P = 0.04). There was no evidence of association between these five genetic loci and baseline erosions or SJC in the total RA cohort, after adjustment for symptom duration. TRAF1/C5 was significantly associated with baseline HAQ, however, following adjustment for symptom duration (P trend = 0.03).
These findings support the mounting evidence that different genetic loci are associated with autoantibody-positive and autoantibody-negative RA, possibly suggesting that many of the genes identified to date are associated with autoantibody production. Additional studies with a specific focus on autoantibody-negative RA will be needed to identify the genes predisposing to this RA subgroup. The TRAF1/C5 locus in particular warrants further investigation in RA as a potential disease severity locus.
Family involvement in help-seeking is associated with a shorter duration of untreated psychoses [DUP], but it is unknown whether neighbourhood-level factors are also important.
DUP was estimated for all cases of first-episode psychoses identified over 2 years in 33 Southeast London neighbourhoods (n=329). DUP was positively skewed and transformed to the natural logarithm scale. We fitted various hierarchical models, adopting different assumptions with regard to spatial variability of DUP, to assess whether there was evidence of neighbourhood heterogeneity in DUP, having accounted for a priori individual-level confounders.
Neighbourhood-level variation in DUP was negligible compared to overall variability. A non-hierarchical model with age, sex and ethnicity covariates, but without area-level random effects, provided the best fit to the data.
Neighbourhood factors do not appear to be associated with DUP, suggesting its predictors lie at individual and family levels. Our results inform mental healthcare planning, suggesting that in one urbanised area of Southeast London, where you live does not affect duration of untreated psychosis.
Neighbourhood; DUP; Spatial epidemiology; Psychosis; Geography
Treatment of head louse infection is primarily through topical insecticides. However, there is growing evidence of resistance. A representative population sample was tested using biochemical and molecular methods; it was shown that, in Wales, treatments containing pyrethroids are likely to be less effective in controlling head louse infection than those containing organophosphates.
head lice; surveillance; insecticide resistance
Cbln1 and the orphan glutamate receptor GluRδ2 are pre- and postsynaptic components, respectively, of a novel transneuronal signaling pathway regulating synapse structure and function. We show here that Cbln1 is secreted from cerebellar granule cells in complex with a related protein, Cbln3. However, cbln1- and cbln3-null mice have different phenotypes and cbln1 cbln3 double-null mice have deficits identical to those of cbln1 knockout mice. The basis for these discordant phenotypes is that Cbln1 and Cbln3 reciprocally regulate each other's degradation and secretion such that cbln1-null mice lack both Cbln1 and Cbln3, whereas cbln3-null mice lack Cbln3 but have an approximately sixfold increase in Cbln1. Unlike Cbln1, Cbln3 cannot form homomeric complexes and is secreted only when bound to Cbln1. Structural modeling and mutation analysis reveal that, by constituting a steric clash that is masked upon binding Cbln1 in a “hide-and-run” mechanism of endoplasmic reticulum retention, a single arginine confers the unique properties of Cbln3.
The action of insulin in the central nervous system produces sympathetic nervous system activation (also called sympathoactivation), although the neuronal intracellular mechanisms that mediate this are unclear. We hypothesized that PI3K and MAPK, the major pathways involved in insulin receptor signaling, mediate sympathetic nerve responses to insulin. Intracerebroventricular administration of insulin in rat increased multifiber sympathetic nerve activity to the hindlimb, brown adipose tissue (BAT), adrenal gland, and kidney. Ex vivo biochemical studies of mediobasal hypothalamic tissue revealed that insulin stimulated the association of insulin receptor substrate–1 with the p85α subunit of PI3K and also tyrosine phosphorylation of p42 and p44 subunits of MAPK in the hypothalamus. In order to determine whether PI3K and/or MAPK were involved in insulin-mediated sympathoactivation, we tested the effect of specific inhibitors of PI3K (LY294002 and wortmannin) and MAPK (PD98059 and U0126) on regional sympathetic responses to insulin. Interestingly, regional sympathoactivation to insulin was differentially affected by blockade of PI3K and MAPK. Inhibition of PI3K specifically blocked insulin-induced sympathoactivation to the hindlimb, while inhibition of MAPK specifically blocked insulin-induced sympathoactivation to BAT. Sympathoactivation to corticotrophin-releasing factor, however, was not affected by inhibition of PI3K and MAPK. These data demonstrate that PI3K and MAPK are specific and regionally selective mediators of the action of insulin on the sympathetic nervous system.
The pathogenesis of human immunodeficiency virus (HIV) associated spondyloarthropathy (SpA) is poorly understood. In this case report a patient is described with severe HIV associated reactive arthritis, who on magnetic resonance imaging and sonographic imaging of inflamed knees had extensive polyenthesitis and adjacent osteitis. The arthritis deteriorated despite conventional antirheumatic treatment, but improved dramatically after highly active antiretroviral treatment, which was accompanied by a significant rise in CD4 T lymphocyte counts. The implications of the localisation of pathology and effect of treatment for pathogenic models of SpA and rheumatoid arthritis in the setting of HIV infection are discussed.
OBJECTIVES: To study longitudinal biological monitoring data on urinary and blood cadmium collected in a small cohort of nine workers who had been brazing for several years with solders containing cadmium. METHODS: Cadmium was measured by neutron activation analysis in livers and kidneys, and estimates of renal function were carried out in 1983 and 1995. During the intervening period exposure to cadmium was dramatically reduced by local exhaust ventilation control and substitution of the solder containing cadmium. RESULTS: From urinary protein measurements there was evidence within the group of increasing renal tubular damage over the 12 year period, even though exposure to cadmium was dramatically reduced over this period and almost eliminated by 1995. There was no evidence from serum creatinine of decreasing glomerular filtration rate, and the renal tubular handling of calcium, phosphate, or urate had not worsened significantly. Blood and urinary cadmium concentrations reduced significantly over the 12 year period but were still substantial in 1995. Blood cadmium concentrations tended to reflect cadmium body burden in 1995 when exposure had been low for several years, and decreased most significantly during 1983-90. By contrast urinary cadmium concentrations only decreased significantly from about 1990 onwards. Urinary cadmium was not significantly correlated with liver or kidney cadmium concentration in either 1983 or 1995. This may be due to the level of tubular dysfunction in the cohort. Calculated cumulative excretion of cadmium over the 12 year period was substantially greater than the loss of cadmium measured in livers and kidneys and the derived loss in body burden. Reasons for this are discussed. It is possible that in cohorts, where renal damage is apparent, urinary concentrations reflect a substantial component of current exposure rather than stored body losses. CONCLUSIONS: The data reinforce the concept that blood cadmium concentrations may not always reflect recent exposure, but may reflect body burden derived from historical exposure depending on the degree of current exposure; and that the decline in urinary and blood cadmium measurements after removal from, or reduction in, exposure will be slow and depend on the historical body burden.
Between September 1995 and August 1998, the incidence and diversity of the main human rotavirus genotypes (G1, G2, G3, and G4 and P, P, P, and P) among Irish children were determined by using established and adapted reverse transcriptase PCR-based genotyping methods. From a total of 193 rotavirus-positive specimens collected from nine hospitals we successfully identified the P type in 182 (94%) of the samples and the G type in 165 (85.5%) of the samples. Only four samples could not be assigned a G or P type. Two P types existed in Ireland, P (78%) and P (16%), and their relative incidence varied over the 3 years of this study. No P or P types were detected. G1 was the most predominant G type (55%), and the incidences of G2, G3, and G4 isolates were 15.5, 1, and 11%, respectively. Three percent of the samples tested had a mixed G type. A P and G type was assigned to 158 (81.8%) of samples. Of the typeable samples, G1 P was the most prevalent (65%), whereas G2 P (17%), G3 P (1%), G4 P (12%), and mixed types (all G1/ G4 P) (4%) were detected less frequently. In the third year a significant genotypic shift from G1 P to G2 P and G4 P was observed. During the study, we noticed that the inclusion of random primers during cDNA synthesis greatly increased the specificity of the PCR typing assays. No correlation was seen between the contributing hospitals and a specific genotype. In conclusion, the coverage of infection given by the recently licensed tetravalent vaccine would be significantly high in Ireland, although future monitoring of genotypic changes among Irish isolates should be encouraged.
STUDY OBJECTIVES--To recruit a representative sample of farmworkers, accurately quantify the range and extent of their animal exposures, and measure the associated risks of illness. DESIGN--Inception cohort. SETTING--The study was undertaken among farmworkers living in five local authority areas in the catchment of Hereford and Preston Public Health Laboratories, England. PARTICIPANTS--A quota sample of 404 people on 255 agricultural holdings took part. The holdings were selected at random from the Ministry of Agriculture, Fisheries and Food register. Altogether 58% of eligible subjects approached agreed to participate. MEASUREMENTS AND MAIN RESULTS--The sample had the same sex distribution as the 1991 census for those giving their occupation as agriculture. The mean age was significantly (p < 0.01) higher (44.6 years v 42.2 years) than that of those giving their occupation as agriculture, forestry or fishing in the census, although the modal range (45-59 years) was the same. At enrollment interviews, subjects individually reported contact with up to nine animal species (mode 4) out of 26 reported in all. Based on the numbers contacted and the frequency and intimacy of contact, scores on a ranked ordinal scale from 0-5 were constructed for each species and frequencies for each score were plotted. Subjects also reported past operations and serious illness. A history of pneumonia was significantly (p < 0.05) associated with a pigeon loft on the farm (relative risk (RR) 7.3) and attending farrowing pigs (RR 6.6), and one of leptospirosis with a rat problem on the farm (RR 28.1). Cattle contact was associated with a significantly lower likelihood (protective) of glandular fever (RR 0.19) and rheumatic or scarlet fever (RR 0.12). These effects were significantly related to rankings of the extent of exposure. CONCLUSIONS--It is possible to recruit a representative sample of farmworkers and measure their animal exposures in great detail. Among these exposures, associations with plausible risk factors for pneumonia and leptospirosis and apparently protective factors for glandular fever, scarlet fever, and rheumatic fever have been demonstrated, which further show a relationship between the extent of exposure and response. These findings can be tested further by examining the relationship of exposures to serological evidence of illness or by further prospective follow up of this and similarly well characterised cohorts, or both.
The genomic DNA of Helicobacter pylori was studied by electrophoretic analysis of restriction endonuclease fragments. Twenty seven isolates from eight patients in the United Kingdom, obtained before and after treatment with nitrofurantoin, and two reference strains from Australia and Peru were investigated. Digestion of DNA with HaeIII, which gave the clearest band pattern of the 20 enzymes tested, showed that each set of isolates from a single patient had a unique band pattern. The DNA signature band patterns of strains from different patients were less than or equal to 62% similar (average 43%); similarities of patterns from the same patient were generally greater than or equal to 86%. Some minor but reproducible polymorphisms (less than or equal to five bands) in the signature region were detected in most consecutive isolates. Plasmid DNA was detected in isolates from five patients, but major pattern differences were attributed to genomic variation. It is concluded that the HaeIII DNA digest signature fingerprints provide a reproducible and sensitive method of discriminating between isolates of H pylori.