Existing small-animal models of tuberculosis (TB) rarely develop cavitary disease, limiting their value for assessing the biology and dynamics of this highly important feature of human disease. To develop a smaller primate model with pathology similar to that seen in humans, we experimentally infected the common marmoset (Callithrix jacchus) with diverse strains of Mycobacterium tuberculosis of various pathogenic potentials. These included recent isolates of the modern Beijing lineage, the Euro-American X lineage, and M. africanum. All three strains produced fulminant disease in this animal with a spectrum of progression rates and clinical sequelae that could be monitored in real time using 2-deoxy-2-[18F]fluoro-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). Lesion pathology at sacrifice revealed the entire spectrum of lesions observed in human TB patients. The three strains produced different rates of progression to disease, various extents of extrapulmonary dissemination, and various degrees of cavitation. The majority of live births in this species are twins, and comparison of results from siblings with different infecting strains allowed us to establish that the infection was highly reproducible and that the differential virulence of strains was not simply host variation. Quantitative assessment of disease burden by FDG-PET/CT provided an accurate reflection of the pathology findings at necropsy. These results suggest that the marmoset offers an attractive small-animal model of human disease that recapitulates both the complex pathology and spectrum of disease observed in humans infected with various M. tuberculosis strain clades.
Physiological investigations of snakes have established the importance of heart position and pulmonary structure in contexts of gravity effects on blood circulation. Here we investigate morphological correlates of cardiopulmonary physiology in contexts related to ecology, behavior and evolution. We analyze data for heart position and length of vascular lung in 154 species of snakes that exhibit a broad range of characteristic behaviors and habitat associations. We construct a composite phylogeny for these species, and we codify gravitational stress according to species habitat and behavior. We use conventional regression and phylogenetically independent contrasts to evaluate whether trait diversity is correlated with gravitational habitat related to evolutionary transitions within the composite tree topology. We demonstrate that snake species living in arboreal habitats, or which express strongly climbing behaviors, possess relatively short blood columns between the heart and the head, as well as relatively short vascular lungs, compared to terrestrial species. Aquatic species, which experience little or no gravity stress in water, show the reverse – significantly longer heart–head distance and longer vascular lungs. These phylogenetic differences complement the results of physiological studies and are reflected in multiple habitat transitions during the evolutionary histories of these snake lineages, providing strong evidence that heart–to–head distance and length of vascular lung are co–adaptive cardiopulmonary features of snakes.
heart; lung; circulation; phylogeny; hydrostatic pressure; aquatic; arboreal
Rose hips are popular in health promoting products as the fruits contain high content of bioactive compounds. The aim of this study was to investigate whether health benefits are attributable to ascorbic acid, phenols, or other rose-hip-derived compounds. Freeze-dried powder of rose hips was preextracted with metaphosphoric acid and the sample was then sequentially eluted on a C18 column. The degree of amelioration of oxidative damage was determined in an erythrocyte in vitro bioassay by comparing the effects of a reducing agent on erythrocytes alone or on erythrocytes pretreated with berry extracts. The maximum protection against oxidative stress, 59.4 ± 4.0% (mean ± standard deviation), was achieved when incubating the cells with the first eluted meta-phosphoric extract. Removal of ascorbic acid from this extract increased the protection against oxidative stress to 67.9 ± 1.9%. The protection from the 20% and 100% methanol extracts was 20.8 ± 8.2% and 5.0 ± 3.2%, respectively. Antioxidant uptake was confirmed by measurement of catechin by HPLC-ESI-MS in the 20% methanol extract. The fact that all sequentially eluted extracts studied contributed to protective effects on the erythrocytes indicates that rose hips contain a promising level of clinically relevant antioxidant protection.
Socioeconomic inequalities in survival were observed for many cancers in England during 1981–1999. The NHS Cancer Plan (2000) aimed to improve survival and reduce these inequalities. This study examines trends in the deprivation gap in cancer survival after implementation of the Plan.
Materials and method:
We examined relative survival among adults diagnosed with 1 of 21 common cancers in England during 1996–2006, followed up to 31 December 2007. Three periods were defined: 1996–2000 (before the Cancer Plan), 2001–2003 (initialisation) and 2004–2006 (implementation). We estimated the difference in survival between the most deprived and most affluent groups (deprivation gap) at 1 and 3 years after diagnosis, and the change in the deprivation gap both within and between these periods.
Survival improved for most cancers, but inequalities in survival were still wide for many cancers in 2006. Only the deprivation gap in 1-year survival narrowed slightly over time. A majority of the socioeconomic disparities in survival occurred soon after a cancer diagnosis, regardless of the cancer prognosis.
The recently observed reduction in the deprivation gap was minor and limited to 1-year survival, suggesting that, so far, the Cancer Plan has little effect on those inequalities. Our findings highlight that earlier diagnosis and rapid access to optimal treatment should be ensured for all socioeconomic groups.
relative survival; deprivation; socioeconomic inequalities; health policy
Cancer mortality has been examined among ethnic South Asian migrants in England and Wales, but not by generation of migration.
Using South Asian mortality records, identified by a name-recognition algorithm, and census information, age-standardised rates among South Asians, and South Asian vs non-South Asian rate ratios, were calculated.
Results and conclusions:
All-cancer rates in ethnic South Asians were half of those in non-South Asians in first-generation (all-cancer-standardised mortality ratio (SMR) in males 0.51 and in females 0.56) and subsequent-generation South Asians (SMR in males 0.43 and in females 0.36). The higher mortality in first-generation South Asians for liver (both sexes), oral cavity and gallbladder cancer (females), particularly marked among Bangladeshis, was reduced in subsequent generations.
cancer mortality; migrants: England and Wales; Asian continental ancestry group; health transition
To characterise the phenotype of the putative dendritic cells strongly expressing Jak3 and STAT4, which have been previously identified in the synovial tissue of patients with active rheumatoid arthritis (RA).
Synovial biopsy specimens were obtained at arthroscopy from 30 patients with active RA (42 synovial biopsies). Immunohistological analysis was performed using monoclonal antibodies to detect dendritic cell subsets, including activation markers and cytokines relevant to dendritic cell function. Co‐localisation of cell surface markers and cytokines was assessed primarily using sequential sections, with results confirmed by dual immunohistochemistry and immunofluorescence with confocal microscopy.
The dendritic cells identified in RA synovial tissue that strongly express Jak3 also strongly express STAT4 and STAT 6 and are correlated with the presence of serum rheumatoid factor. These cells are not confined to a single dendritic cell subset, with cells having phenotypes consistent with both myeloid‐ and plasmacytoid‐type dendritic cells. The activation status of these dendritic cells suggests that they are maturing or mature dendritic cells. These dendritic cells produce IL12 as well as interferon α and γ.
The close correlation of these dendritic cells with the presence of serum rheumatoid factor, a prognostic factor for worse disease outcome, and the strong expression by these cells of components of the Jak/STAT transcription factor pathway suggest a potential therapeutic target for the treatment of RA.
rheumatoid arthritis; myeloid dendritic cells; plasmacytoid dendritic cells; IL12; interferon alpha; interferon gamma
There is strong evidence that colorectal cancer survival differs between socioeconomic groups. We analysed data on 2481 patients diagnosed during 1989–1997 and recruited to a randomised controlled clinical trial (AXIS, ISRCTN32414363) of chemotherapy and radiotherapy for colorectal cancer. Crude and relative survival at 1 and 5 years was estimated in five categories of socioeconomic deprivation. Multiple imputation was used to account for missing data on tumour stage. A multivariable fractional polynomial model was fitted to estimate the excess hazard of death in each deprivation category, adjusting for the confounding effects of age, stage, cancer site (colon, rectum) and sex, using generalised linear models. Relative survival in the trial patients was higher than in the general population of England and Wales. The socioeconomic gradient in survival was much smaller than that seen for colorectal cancer patients in the general population, both at 1 year −3.2% (95% CI −7.3 to 1.0%, P=0.14) and at 5 years −1.7% (95% CI −8.3 to 4.9%, P=0.61). Given equal treatment, colorectal cancer survival in England and Wales does not appear to depend on socioeconomic status, suggesting that the socioeconomic gradient in survival in the general population could well be due to health-care system factors.
colorectal cancer; rectum cancer; cancer survival; deprivation; cancer registries
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis (IA).
To examine the effect of successful disease‐modifying antirheumatic drug (DMARD) treatment on the expression of Jak‐STAT in a cohort of patients with active rheumatoid arthritis.
Synovial tissue biopsy specimens from 16 patients with active rheumatoid arthritis, taken before and after initiation of DMARD treatment, were examined for the presence of janus kinase (Jak)3, signal transducer and activator of transcription (STAT)1, STAT4 and STAT6 expression using immunohistochemistry.
Successful treatment with DMARDs results in reduction in STAT1 expression in the lining, and STAT1 and STAT6 in the sublining of rheumatoid arthritis synovial tissue. Although the overall expression of STAT4 and Jak3 was not significantly altered by DMARD treatment, there was a significant reduction in the expression of the STAT4 and Jak3 bright cells, thought to be an activated dendritic cell subpopulation.
Results show that Jak3, STAT1, STAT4 expression and STAT6 sublining expression decrease in response to successful treatment of rheumatoid arthritis with standard DMARDs. Therefore, altering the expression of these pathways may represent an alternative treatment option, either through promoting up‐regulation of inhibitory pathways, or suppressing inflammatory paths.
Background: Positron emission tomography (PET) is more accurate than computed tomography (CT) in staging and restaging of lymphoma, but both are considered necessary. Increasingly, PET is carried out with a low-dose CT scan. Many patients undergo both PET/CT and standard diagnostic CT. The clinical utility of performing both studies in patients with lymphoma was evaluated.
Patients and methods: Patients with lymphoma who underwent concurrent PET/CT and diagnostic CT (a scan pair) were identified, and findings detected in either scan but not both were documented. Discrepancies were considered significant if they were related to either lymphoma or another disease process which potentially required intervention.
Results: Eighty-seven scan pairs were identified. PET/CT detected additional lesions over diagnostic CT in 30 patients, of which 11 demonstrated increased clinical stage. Lymphoma therapy changed based on PET/CT in two patients, and one occult rectal cancer was detected. In contrast, diagnostic CT detected five relevant findings, including two incidental findings (venous thrombosis) and three patients with splenic lesions, none of which could be confirmed as lymphoma. No patient had change of stage or lymphoma therapy based on diagnostic CT.
Conclusion: In our series, diagnostic CT did not add value to staging or restaging of lymphoma when carried out concurrently with PET/CT.
lymphoma; PET/CT; staging
Survival from childhood leukaemia has increased, but the proportion of children cured is unknown. The proportion ‘cured' is defined as the proportion of survivors for whom, as a group, there is no longer excess mortality compared to the general population. Average time to cure is defined as the time since diagnosis at which the excess mortality rate has declined to or below a predetermined small value. Data on children diagnosed with leukaemia during 1971–2000 in Great Britain were used to estimate trends in survival, the proportion cured and the average time to cure. Five-year survival for all types of leukaemia combined rose from 33 to 79% by 2000. The percentage cured rose from 25 to 68% by 1995; it is predicted to increase to 73% for those diagnosed more recently. Average time to cure increased from 12 years (95% confidence interval (CI): 11–14) to 19 years (95% CI: 14–26) for lymphoid leukaemia (average annual increase of 0.3 years; P<0.001), but remained at about 5 years for acute nonlymphoblastic leukaemia. The proportion of children cured of leukaemia has risen dramatically, but the period of excess mortality associated with lymphoid leukaemia has also increased, possibly because of late relapse, secondary malignancy and toxicity from treatment.
survival; cure; childhood leukaemia; trends
Modulation of Jak‐STAT signalling may provide an effective therapeutic strategy in inflammatory arthritis.
To document Jak‐STAT expression in a cohort of patients with active rheumatoid arthritis (RA), spondyloarthritis (SpA), and osteoarthritis (OA) and compare these subsets with normal synovial tissue.
Synovial tissue biopsy specimens from patients with RA, OA, and SpA and histologically normal tissue (n = 10 in each arthritis group) were examined for the presence of Jak3, STAT1, STAT4, and STAT6 expression using immunohistochemistry. Phenotyping was performed using immunohistochemistry and immunofluorescence. Clinical and serological characteristics of patients with RA expressing Jak3‐STAT4 were assessed.
STAT1, STAT4, and Jak3 protein expression was generally increased in inflammatory arthritis. In contrast, STAT6 expression was relatively heterogeneous. A subpopulation of CD1a positive dendritic cells unique to seropositive patients with RA was detected. These cells showed intense protein expression for Jak3, STAT4, and STAT6.
CD1a positive dendritic cells intensely express Jak3, STAT4, and STAT6 in seropositive RA tissue and may be an alternative marker for dendritic cells in their early stages of activation as well as providing a tool for identifying RA at the level of the synovium. Jak3 inhibition may be a potential therapeutic target to prevent dendritic cell maturation in RA. STAT1 expression is increased in inflammatory arthritis, suggesting that its pro‐apoptotic and anti‐inflammatory effects cannot effectively counteract inflammation. STAT6 expression is heterogeneous in synovium, suggesting a possible homoeostatic role in addition to any anti‐inflammatory effects.
dendritic cells; rheumatoid arthritis; transcription factors
We provide evidence of a gradual increase in the incidence of childhood leukaemia over the twentieth century from examination of trends in both incidence and mortality in England and Wales. We conclude that much of the recorded increase is likely to be real.
childhood leukaemia; incidence; mortality; trends
We analysed trends in 5-year survival of the 18 commonest cancers in Scotland diagnosed between 1986 and 2000 and followed up to 2004 in each of five deprivation groups based on patients postcode of residence at diagnosis. We estimated relative survival up to 5 years after diagnosis, adjusting for the different background mortality in each deprivation group by age, sex and calendar period. We estimated trends in overall survival and in the deprivation gap in survival up to 2004. Five-year survival improved for all malignancies except bladder cancer and was associated with a widening in the deprivation gap in survival. For 25 of 30 cancer–sex combinations examined, 5-year survival was lower among more deprived patients diagnosed during 1996–2000, and the deprivation gap in survival had widened since 1986–1990 for 15 of these 25 cancers, similar to the trends seen in England and Wales.
deprivation; socioeconomic inequalities; relative survival; Scotland
Background: General practitioners state the reason for referring patients in referral letters. The paucity of information in these letters has been the source of criticism from specialist colleagues.
Objective: To invite general practitioners to set standards for referral letters to gastroenterologists and to apply these standards to actual referral letters to one specialist gastroenterology unit.
Methods: A scoring schedule was designed based on the responses to a questionnaire survey of a large sample of all general practitioners in one locality. Altogether 350 consecutive letters to a district general hospital about patients referred for an upper gastrointestinal specialist opinion were subsequently scored using the schedule.
Results: 102 practitioners responded to the survey. Their responses imply that colleagues assess and record findings on 18 potential features of upper bowel disease. In practice most referral letters address fewer than six features of upper bowel disease. The mean number of positive features of upper gastrointestinal disease reported in each letter was one.
Conclusions: This study reported a failure to meet "peer defined" standards for the content of referral letters set by colleagues in one locality. Referral letters serve many purposes, however, encouraging full documentation of specific clinical findings may serve to increase the pre-referral assessments performed in practice.
Study objectives: To estimate ethnic and socioeconomic differences in breast cancer incidence and survival between South Asians and non-South Asians in England and Wales, and to provide a baseline for surveillance of cancer survival in South Asians, the largest ethnic minority.
Setting: 115 712 women diagnosed with first primary invasive breast cancer in England and Wales during 1986–90 and followed up to 1995.
Methods/design: Ethnic group was ascribed by a computer algorithm on the basis of the name. Incidence rates were derived from 1991 census population denominators for each ethnic group. One and five year relative survival rates were estimated by age, quintile of material deprivation, and ethnic group, using national mortality rates to estimate expected survival.
Main results: Age standardised incidence was 29% lower among South Asian women (40.5 per 100 000 per year) than among all other women (57.4 per 100 000). Five year age standardised relative survival was 70.3% (95%CI 65.2 to 75.4) for South Asian women and 66.7% (66.4 to 67.0) for other women. For both ethnic groups, survival was 8%–9% higher for women in the most affluent group than those in the most deprived group. In each deprivation category, however, survival was 3%–8% higher for South Asian women than other women.
Conclusions: This national study confirms that breast cancer incidence is substantially lower in South Asians than other women in England and Wales. It also provides some evidence that South Asian women diagnosed up to 1990 had higher breast cancer survival than other women in England and Wales, both overall and in each category of deprivation.
Trends in long-term relative survival from breast cancer are examined for women diagnosed in England and Wales up to 2001, using both period and hybrid approaches. Large improvements in long-term survival are predicted. Women with breast cancer still experience persistent excess mortality up to at least 20 years after diagnosis.
breast cancer; women; relative survival; long-term; trends; England and Wales
Study objective: To describe the population mortality profile of England and Wales by deprivation and in each government office region (GOR) during 1998, and to quantify the influence of geography and deprivation in determining life expectancy.
Design: Construction of life tables describing age specific mortality rates and life expectancy at birth from death registrations and estimated population counts. Life tables were created for (a) quintiles of income deprivation based on the income domain score of the index of multiple deprivation 2000, (b) each GOR and Wales, and (c) every combination of deprivation and geography.
Setting: England and Wales.
Patients/participants: Residents of England and Wales, 1998.
Main results: Life expectancy at birth varies with deprivation quintile and is highest in the most affluent groups. The differences are mainly attributable to differences in mortality rates under 75 years of age. Regional life expectancies display a clear north-south gradient. Linear regression analysis shows that deprivation explains most of the geographical variation in life expectancy.
Conclusions: Geographical patterns of life expectancy identified within these data for England and Wales in 1998 are mainly attributable to variations in deprivation status as defined by the IMD 2000 income domain score.
Background: Population based colorectal cancer survival among patients diagnosed in 1985–89 was lower in Europe than in the USA (45% v 59% five year relative survival).
Aims: To explain this difference in survival using a new analytic approach for patients diagnosed between 1990 and 1991.
Subjects: A total of 2492 European and 11 191 US colorectal adenocarcinoma patients registered by 10 European and nine US cancer registries.
Methods: We obtained clinical information on disease stage, number of lymph nodes examined, and surgical treatment. We analysed three year relative survival, calculating relative excess risks of death (RERs, referent category US patients) adjusted for age, sex, site, surgery, stage, and number of nodes examined, using a new multivariable approach.
Results: We found that 85% of European patients and 92% of US patients underwent surgical resection. Three year relative survival was 69% for US patients and 57% for European patients. After adjustment for age, sex, and site, the RER was significantly high in all 10 European populations, ranging from 1.07 (95% confidence interval 0.86–1.32) (Modena, Italy) to 2.22 (1.79–2.76) (Thames, UK). After further adjustment for stage, surgical resection, and number of nodes examined (a determinant of stage), RERs ranged from 0.77 (0.62–0.96) to 1.59 (1.28–1.97). For some European registries the excess risk was small and not statistically significant.
Conclusions: US-Europe survival differences in colorectal cancer are large but seem to be mostly attributable to differences in stage at diagnosis. There are wide variations in diagnostic and surgical practice between Europe and the USA.
colorectal cancer; population based cancer registries; surgery; lymph nodes; survival; USA; Europe
This population-based study examines prognostic factors and survival trends among adults (15–99 years) diagnosed with small intestinal cancer in England and Wales during 1971–1990 and followed up to 1995. During this period, the 1- and 5-year age-standardised relative survival rates for small intestinal cancers combined were 42% and 23%, respectively. Duodenal tumours, adenocarcinomas, men, patients with advanced age and the most deprived patients had the poorest prognosis. For all small bowel tumours combined, the excess risk of death fell significantly by 6–9% every 4 years over the 20-year period (adjusted excess hazard ratio (EHR) 0.91 at 1 year after diagnosis, 0.94 at 5 years). For duodenal tumours, the EHR fell by about 14% (95% CI 5–22%) every 4 years between 1979 and 1990, and a similar trend for jejunal tumours was of borderline significance. Further population-based investigations linking survival data to individual data on diagnostic methods and types of treatment are needed.
small intestinal cancers; relative survival; trends; prognostic factors; population-based
Socioeconomic differences in age-standardised crude survival for women diagnosed with breast cancer during 1991–1999 in England were influenced by the population of the geographic area used to assign the deprivation index, but not by the choice of index.
deprivation; ecological studies; small-area geography; socioeconomic status; survival
Background: Synovial biopsies are used to study synovial immunopathology and are increasingly applied for the evaluation of new therapeutic strategies in chronic arthritis. Therefore, it is essential to be informed on the complete spectrum of synovial immunopathology.
Objective: To describe the cellular content, cytokine and cell adhesion molecule expression in synovial tissue from clinically and arthroscopically normal knees.
Methods: Synovial tissue was obtained from 20 normal subjects at the time of knee joint arthroscopy for unexplained knee pain. Tissue sections were studied for basic histopathology and for a range of cell surface markers, cytokines, and cell adhesion molecules by immunoperoxidase staining. Stained sections were evaluated by semiquantitative scoring and digital image analysis.
Results: Normal synovial tissue is composed predominantly of fibrofatty areolar tissue, with a variable thickness of intimal lining, composed of both CD68 positive macrophages and CD55 positive fibroblast-like synoviocytes. Interleukin 1 receptor antagonist (IL1Ra) was frequently detected in the synovial membrane of normal subjects (mean (SD) integrated optical density (IOD)=3809.6 (3893.9)), but both tumour necrosis factor α (TNFα) and interleukin 1ß (IL1ß) were rarely detected. In addition, cell adhesion molecules were rarely detected in the normal synovial membrane, with the exception of intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Osteoprotegerin (OPG) expression was abundant on synovial lining macrophages (mean (SD) IOD=5276 (4716) as well as endothelial cells (mean (SD) IOD=557 (226)), but receptor activator of nuclear factor κ ligand (RANKL) expression was rarely seen.
Conclusions: The normal synovial membrane has a variable architecture, including thickness of the lining and the subintimal cell infiltrate, with little inflammatory cytokine production or expression of cell adhesion molecules. The excess of OPG expression over RANKL and IL1Ra over IL1 may be important for protection against joint damage
Objective: To determine if there is a minimum duration, frequency or quantity of tobacco use required to develop symptoms of dependence.
Design and setting: A retrospective/prospective longitudinal study of the natural history of tobacco dependence employing individual interviews conducted three times annually in two urban school systems over 30 months. Detailed histories of tobacco use were obtained including dates, duration, frequency, quantity, patterns of use, types of tobacco, and symptoms of dependence.
Participants: A cohort of 679 seventh grade students (age 12–13 years).
Main outcome measures: The report of any of 11 symptoms of dependence.
Results: Among 332 subjects who had used tobacco, 40% reported symptoms, with a median latency from the onset of monthly smoking of 21 days for girls and 183 days for boys. The median frequency of use at the onset of symptoms was two cigarettes, one day per week. The report of one or more symptoms predicted continued smoking through the end of follow up (odds ratio (OR) 44, 95% confidence interval (CI) 17 to 114, p < 0.001).
Conclusions: Symptoms of tobacco dependence commonly develop rapidly after the onset of intermittent smoking, although individuals differ widely in this regard. Girls tend to develop symptoms faster. There does not appear to be a minimum nicotine dose or duration of use as a prerequisite for symptoms to appear. The development of a single symptom strongly predicted continued use, supporting the theory that the loss of autonomy over tobacco use begins with the first symptom of dependence.