The current batch potency test for Leptospira interrogans serovar Canicola vaccines requires the use of a large number of hamsters and has severe effects (i.e., hepatic and renal failure resulting in death); while this vaccine is effective, a safer, cheaper, more ethical replacement is desired. The aim of this study was to analyze vaccine proteomes and identify target molecules common to all L. interrogans serovar Canicola vaccines which could be used to design an in vitro potency test. Initial analysis of L. interrogans serovar Canicola vaccines (A to E) from different manufacturers, using the Limulus amebocyte lysate assay and silver-stained sodium dodecyl sulfate polyacrylamide gels, indicated that lipopolysaccharide was not present in all vaccines, preventing it from being a suitable target molecule. The protein contents of vaccines A to E were therefore determined by two-dimensional liquid chromatography mass spectrometry ([2D-LC/MS] 221 ± 31, 9 ± 8, 34 ± 4, 21 ± 5, and 34 ± 17 proteins [mean ± 1 standard deviation] found, respectively). The outer membrane protein LipL32 was established to be common to all and to be present at a significantly higher (P ≤ 0.05) relative spectral abundance in a batch of vaccine which passed the in vivo potency test than in one which had failed. Further analysis using multiple reaction monitoring revealed that the concentration of the N terminus of LipL32 was significantly lower (P ≤ 0.01) in failed batches (n = 2) of vaccine than in passed batches (n = 2); the concentration of the C terminus between the two batches was approximately the same. An in vitro Leptospira vaccine potency test, based on N-terminal amino acid quantification of LipL32, was subsequently developed.

Aim

Several studies have indicated that genes in the human leucocyte antigen (HLA) region additional to the HLA class II DRB1-DQB1 contribute to type 1 diabetes (T1D) susceptibility. The aim of this study was to assess if markers in the class III Major Histocompatibility Complex (MHC) region are associated with T1D after accounting for linkage disequilibrium (LD) with DRB1-DQB1.

Methods

We investigated 356 single nucleotide polymorphisms (SNPs) in the class III region covering 1.1 megabases in two subsets of data: 289 Human Biological Data Interchange (HBDI) Caucasian families and 597 additional Caucasian families collected by the Type 1 Diabetes Genetics Consortium (T1DGC). Analysis conditioning on DRB1-DQB1 was performed using the overall conditional genotype method.

Results

Thirteen SNPs replicated in both subsets of the data and showed evidence of an additional effect on disease risk. Although some of the SNPs are in tight LD with each other, at least six of the associations were not because of LD with other class III markers. The strongest association within class III markers was with rs2395106 that maps 5′ to the NOTCH4 gene, which has also been implicated in susceptibility to rheumatoid arthritis. The second association was with rs707915 mapping to the MSH5 gene, in a block of six markers significantly associated with T1D after adjusting for LD with DR-DQ. In total, six-independent associations within class III were observed although results were not adjusted for LD with class I.

Conclusions

Our data confirm that the class III region is involved in T1D susceptibility and suggest that more than one gene in the region is involved.

Aim

Type 1 diabetes (T1D) is a complex trait for which variation in the classical human leucocyte antigen (HLA) loci within the Major Histocompatibility Complex (MHC) significantly influences disease risk. To date, HLA class II DR-DQ genes confer the strongest known genetic effect in T1D. HLA loci may also influence T1D through additional inherited or non-inherited effects. Evidence for the role of increased maternal–offspring HLA compatibility, and both parent-of-origin (POO) and non-inherited maternal HLA (NIMA) effects in autoimmune disease has been previously established. The current study tested hypotheses that classical HLA loci influence T1D through these mechanisms, in addition to genetic transmission of particular risk alleles.

Methods

The Type 1 Diabetes Genetics Consortium (T1DGC) cohort was of European descent and consisted of 2271 affected sib-pair families (total n = 11 023 individuals). Class I genes HLA-A, Cw and B, and class II genes HLA-DRB1, DQA1, DQB1, DPA1 and DPB1 were studied. The pedigree disequilibrium test was used to examine transmission of HLA alleles to individuals with T1D. Conditional logistic regression was used to model compatibility relationships between mother–offspring and father–offspring for all HLA loci. POO and NIMA effects were investigated by comparing frequencies of maternal and paternal transmitted and non-transmitted HLA alleles for each locus. Analyses were also stratified by gender of T1D-affected offspring.

Results

Strong associations were observed for all classical HLA loci except for DPA1, as expected. Compatibility differences between mother–offspring and father–offspring were not observed for any HLA loci. Furthermore, POO and NIMA HLA effects influencing T1D were not present.

Conclusions

Maternal–offspring HLA compatibility, POO and NIMA effects for eight classical HLA loci were investigated. Results suggest that these HLA-related effects are unlikely to play a major role in the development of T1D.

Methods: Data on deaths from international terrorism (US State Department database) were collated (1994–2003) and compared to the road injury deaths (year 2000 and 2001 data) from the OECD International Road Transport Accident Database.

Results: In the 29 OECD countries for which comparable data were available, the annual average death rate from road injury was approximately 390 times that from international terrorism. The ratio of annual road to international terrorism deaths (averaged over 10 years) was lowest for the United States at 142 times. In 2001, road crash deaths in the US were equal to those from a September 11 attack every 26 days.

Conclusions: There is a large difference in the magnitude of these two causes of deaths from injury. Policy makers need to be aware of this when allocating resources to preventing these two avoidable causes of mortality.

Objective:

To evaluate the long-term effectiveness and tolerability of adalimumab in the treatment of psoriatic arthritis (PsA).

Methods:

Patients with PsA who completed a 24-week, double-blind study of adalimumab versus placebo were eligible to enroll in an open-label extension study and receive adalimumab 40 mg subcutaneously every other week for up to an additional 120 weeks. At the time of this analysis, available efficacy evaluations throughout 2 years of treatment (n  =  245) included American College of Rheumatology (ACR) 20%, 50% and 70% improvement scores, measures of joint disease and skin disease, disability and quality of life; modified total Sharp scores (mTSS) were available for 2.75 years of treatment for patients who received adalimumab in the 24-week study.

Results:

After 24 weeks of double-blind treatment, the mean change in mTSS was −0.2 for the adalimumab group (N  =  144) and 1.0 for the placebo group (N  =  152; p<0.001), and outcomes for all individual ACR component variables were significantly improved in adalimumab compared with placebo-treated patients. Compared with 24-week responses, inhibition of radiographic progression and improvements in joint disease were maintained in most patients during long-term, open-label adalimumab treatment. Also, improvements in skin disease were maintained, with >20% of patients achieving the strict criterion of psoriasis area and severity index 100. The nature and frequency of adverse events during long-term adalimumab treatment were consistent with the safety profile during short-term treatment.

Conclusions:

The clinical and radiographic efficacy of adalimumab demonstrated during short-term treatment was sustained during long-term treatment. Adalimumab has a favourable risk–benefit profile in patients with PsA.

Trial registration number:

NCT00195689.

Objective: To estimate the loss of life expectancy attributable to tobacco taxation (via financial hardship and flow-on health effect) in New Zealand.

Design: Data were used on the gradients in life expectancy and smoking by neighbourhood socioeconomic deprivation and survey data on tobacco expenditure. Three estimates were modelled of the percentage of the crude association of neighbourhood deprivation with life expectancy that might be mediated via financial hardship: 100%, 50%, and 25% (best estimate). From this information the impact of tobacco taxation on life expectancy was estimated.

Main results: For the total population, the estimated loss of life expectancy due to tobacco tax ranged from 0.005 years to 0.027 years. For people living in the most deprived 30% of neighbourhoods, the range was 0.009 to 0.044 years (that is, 3 to 16 days of lost life expectancy). For the total population the loss of life expectancy attributable to tobacco tax ranged from 119 to 460 times less than that attributable to deprivation. The loss of life expectancy attributable to tobacco tax was 42 to 257 times less than that attributable to smoking.

Conclusions: The estimated harm to life expectancy from tobacco taxation (via financial hardship) is orders of magnitude smaller than the harm from smoking. Although the analyses involve a number of simplistic assumptions, this conclusion is likely to be robust. Policy makers should be reassured that tobacco taxation is likely to be achieving far more benefit than harm in the general population and in socioeconomically deprived populations.

Methods: A compact disc produced by the National Portrait Gallery in London, UK, was systematically searched for artworks produced in the years 1950 to 1999. A "smoking portrayal" in an artwork was defined as having a cigarette, cigar or pipe in the mouth or hand of a named individual.

Results: Out of 1063 artworks included in the analysis, 53 portrayed smoking by identifiable individuals (5.0%). The rate of portrayal was highest in the 1950s (10%) and 1960s (11%) and then declined sharply thereafter (p value for trend < 0.00001). Smoking virtually disappeared from portraiture in the 1990s (at 0.6%). The median age of the smokers portrayed was significantly higher in the 1970 to 1999 period when compared to the 1950 to 1969 period.

Conclusions: The decline of smoking in this collection of portraiture is consistent with the decline in smoking in the UK over these decades, but contrasts with trends for increasing smoking portrayal described elsewhere for film and television.

Objective: To examine the role of tobacco use in creating financial hardship for New Zealand (NZ) low income households with children.

Data: The 1996 NZ census (smoking prevalence by household types), Statistics NZ (household spending surveys 1988-98), and NZ Customs (tobacco released from bond 1988-98).

Main outcome measures: Proportion of children in households with smokers and ≤$NZ15 000 gross income per adult. Proportion of spending on tobacco of second lowest equivalised household disposable income decile and of solo parent households.

Results: In ≤$NZ15 000 gross income per adult households with both children and smokers, there were over 90 000 children, or 11% of the total population aged less than 15 years. Enabling second lowest income decile households with smokers to be smoker-free would on average allow an estimated 14% of the non-housing budgets of those households to be reallocated.

Conclusions: The children in low income households with smokers need to be protected from the financial hardship caused by tobacco use. This protection could take the form of more comprehensive government support for such households and stronger tobacco control programmes. A reliance on tobacco price policy alone to deter smokers is likely to have mixed outcomes—for example, increased hardship among some of these households. The challenge for tobacco control is to move from a sole focus on "doing good" towards incorporating the principle of "doing no harm".

OBJECTIVE--To determine if there is evidence for genetic anticipation in rheumatoid arthritis (RA) by analysing the possibility that parental disease status and age at proband conception influence the age of onset and disease severity of the proband. METHOD--RA outpatients were identified and data were also taken from Newcastle multicase RA pedigrees. Comparisons of age of onset and parental age at proband conception were made for pedigrees grouped according to the disease status of the parents. Correlation coefficients and linear regression models were calculated for the age of RA onset in the probands. Measures of disease severity were compared in RA mother-proband pairs. RESULTS--The results were similar in both the outpatient (n = 153) and multicase pedigree (n = 15) samples. Significant results were confined to pedigrees in which the mother had RA (20 of the outpatient probands and seven of the multicase group). Probands in these sibships had a younger age of RA onset than their affected mothers (38.3 years (95% confidence interval (CI) 33.8 to 42.8) versus 53.7 (47.3 to 60.0) (p = 0.002) in the outpatient sample; 32.4 years (25.3 to 39.6) versus 43.4 years (29.0 to 57.9) (p = 0.1) in the multicase pedigrees). In the maternal RA group, both the maternal and paternal age at proband conception showed significant negative correlations (r = -0.65, p = 0.002 and r = -0.60, p = 0.005, respectively in the outpatient sample) and linear regression coefficients with age of proband disease onset. In seven affected mother-proband pairs, the probands had a tendency to more severe disease, despite shorter disease duration and younger age. CONCLUSIONS--This preliminary analysis has suggested that within pedigrees in which the mother has RA, the features of genetic anticipation and observations consistent with premutation models may prevail.

When the CMA General Council meets in Cape Breton, NS, Aug. 18-21, physicians will have an opportunity to visit the largest reconstructed colonial town in North America, which is only 40 km from the meeting site in Sydney. This article looks at the medical treatment available at the historic Fortress of Louisbourg in 1744, when it was France's Atlantic coast bastion.

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Dideoxy nucleotide sequencing of a portion of the 1D gene of SAT-type foot-and-mouth disease viruses (FMDV) was used to derive phylogenetic relationships between viruses recovered from the oesophageo-pharyngeal secretions of buffalo in the Kruger National Park as well as several other wildlife areas in southern Africa. The three serotypes differed from one another by more than 40% while intratypic variation did not exceed 29%. Within each type, isolates from particular countries were more closely related to one another than to isolates from other countries lending credence to previous observations that FMDV evolve independently in different regions of the subcontinent.