The JACS prospective cohort study of newly diagnosed women with breast cancer investigating joint and muscle pain, aches, and stiffness: pain and quality of life after primary surgery and before adjuvant treatment.

BACKGROUND: Breast cancer affects one in eight UK women during their lifetime: many of these women now receive adjuvant chemotherapy and hormone therapy. Joint and muscle pains, aches, and stiffness are common but the natural history, aetiology and impact of these symptoms are unknown. A cohort study of newly diagnosed women with primary breast cancer was established to explore this. In this paper we present study methods and sample characteristics, describe participants' experience of musculoskeletal pain at baseline interview, and explore its impact on quality of life. METHODS: Women with non-metastatic breast cancer were recruited following primary surgery into a multi-centre cohort study. They received questionnaires by post five times (baseline, 3, 6 , 9 and 12 months) to investigate prevalence, severity, location and correlates of musculoskeletal pain, and impact on quality-of-life. Pain was measured by the Nordic musculoskeletal questionnaire, the Brief Pain Inventory, and MSK-specific questions, and quality of life by the SF-36 and FACIT scales. RESULTS: 543 women (mean age 57 years, range 28-87, 64% postmenopausal) were recruited following surgery for primary breast cancer from breast cancer clinics in eight hospitals. Fifteen per cent of the eligible cohort was missed; 28% declined to participate. Joint or muscle aches, pains or stiffness were reported by 69% women with 28% specifically reporting joint pain/aches/stiffness. Quality of life, as measured by the FACT-B and adjusted for age, depression, surgery and analgesic use, is significantly worse in all domains in those with musculoskeletal problems than those without. CONCLUSIONS: Our findings highlights the importance of a better understanding of these symptoms and their impact on the lives of women with primary breast cancer so that healthcare professionals are better equipped to support patients and to provide accurate information to inform treatment decisions. Further papers from this study will address these issues.

A survey of joint and muscle aches, pain, and stiffness comparing women with and without breast cancer.

CONTEXT: Joint and muscle aches, pain, and stiffness have been reported to be a problem for some women after adjuvant breast cancer treatment; however, the extent and impact of this problem are unknown. OBJECTIVES: The purpose of this study was to determine the prevalence of this problem in comparison with women of a similar age without breast cancer. METHODS: Two hundred forty-seven women attending breast cancer follow-up clinics were invited to complete pain and quality-of-life measures. A comparison group of 274 women of similar age was drawn from women attending breast screening and benign breast clinics. Prevalence and severity of pain were compared between the two groups. RESULTS: The mean age of all women in the study was 59 years (range 30-86 years). The median time since diagnosis of cancer was 28 months (range 2-184 months). Adjuvant treatments included radiotherapy (79%), chemotherapy (45%), and hormone therapy (81%). Sixty-two percent of women with breast cancer reported pain "today" compared with 53% of women without breast cancer (P = 0.023). Significant predictors of pain in both patient groups were cancer, age, and arthritis. For the cancer cases, significant predictors of pain were age, arthritis, taxane chemotherapy, aromatase inhibitors, and tamoxifen. Quality of life (measured by the Short Form-36) was significantly worse for women with breast cancer compared with controls and was significantly worse in the breast cancer cases with pain. CONCLUSION: Treatment with tamoxifen, taxane chemotherapy, and aromatase inhibitors for breast cancer is predictive of joint pain, which may have an impact on women's lives for some years after breast cancer.

Isolation of Escherichia coli inner membranes by metal affinity two-phase partitioning.

As reduction of sample complexity is a central issue in membrane proteomic research, the need for new pre-fractionation methods is significant. Here we present a method for fast and efficient enrichment of Escherichia coli inner membranes expressing a His-tagged integral membrane L-fucose-proton symporter (FucP). An enriched inner membrane fraction was obtained from a crude membrane mixture using affinity two-phase partitioning in combination with nickel-nitrilotriacetic acid (Ni-NTA) immobilized on agarose beads. Due to interaction between the beads and FucP, inner membranes were selectively partitioned to the bottom phase of a polymer/polymer aqueous two-phase system consisting of poly(ethylene glycol) (PEG) and dextran. The partitioning of membranes was monitored by assaying the activity of an inner membrane marker protein and measuring the total protein content in both phases. The enrichment of inner membrane proteins in the dextran phase was also investigated by proteomic methodology, including sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), trypsin digestion and liquid chromatography in combination with tandem mass spectrometry (LC-MS/MS). Using a high level of significance (99.95%) in the subsequent database search, 36 proteins assigned to the inner membrane were identified in the bottom phase, compared to 29 when using the standard sucrose gradient centrifugation method for inner membrane isolation. Furthermore, metal affinity two-phase partitioning was up to 10 times faster than sucrose gradient centrifugation. The separation conditions in these model experiments provide a basis for the selective isolation of E. coli membranes expressing His-tagged proteins and can therefore facilitate research on such membrane proteomes.

Association of asthma with a functional promoter polymorphism in the IL16 gene.

BACKGROUND: IL-16, a multifunctional cytokine with increased expression in the airways of asthmatic subjects, inhibits allergic airway inflammation in animal models. A T-->C single nucleotide polymorphism (SNP) at the -295 position in the promoter region of the IL16 gene has been described. OBJECTIVE: We sought to examine the functional significance of this promoter SNP and its relationship to asthma. METHODS: We examined the effect of the -295 SNP on promoter activity in cell-line (HBE4-E6/E7) transfection experiments. We investigated the association of the IL16 -295 genotype with asthma among 341 affected sib-pair white families and 184 unrelated nonasthmatic control subjects. We analyzed the association between the IL16 genotype and asthma using family-based association test and case-control analyses. RESULTS: In in vitro transfection experiments the T allele in the -295 position was associated with substantially reduced promoter activity compared with the C allele. In the family study the more common T allele at the -295 position was significantly associated with all asthma phenotypes (P = .002 to P = .015). In the case-control analysis asthmatic subjects were more likely than unrelated nonasthmatic control subjects to have the -295 TT genotype, but this did not reach statistical significance (odds ratio, 1.36; 95% CI, 0.92-2.02). CONCLUSIONS: The T allele at the -295 position in the IL16 promoter region is associated with reduced promoter activity relative to the C allele and with asthma in this white population. Further investigation is needed to delineate the mechanisms underlying these findings and the relationship of the IL16 -295 genotype to asthma in other populations.

Gas cooking and smoking habits and the risk of childhood and adolescent wheeze.

The authors investigated the risk of wheezing illnesses in relation to contemporaneous pollutant exposures (gas cooking, heating, and smoking) in childhood and adolescence in a cohort of 2,289 United Kingdom subjects. Data from two questionnaires assessing wheezing at ages 7-8 and 15-17 years and one questionnaire on current and past pollutant exposures at age 16-18 years were studied (1987-1996). The 1,868 subjects returning all three questionnaires were divided into three groups representing childhood (10.5%), adolescent (10.9%), and persistent (i.e., both; 16.3%) wheezing and compared with 1,165 controls (62.4%) without wheezing. The estimated risks of childhood wheezing were increased by exposure to any gas in childhood (odds ratio (OR) = 1.47, 95% confidence interval (CI): 1.05, 2.04) and exposure to a gas hob in childhood (OR = 1.56, 95% CI: 1.13, 2.16) and were increased further in those persistently exposed. Risk of persistent wheezing in adolescence was paradoxically reduced by exposure to a gas hob (OR = 0.67, 95% CI: 0.50, 0.91), possibly because of selection avoidance. Contemporaneous exposure to combined smoking by both parents was associated with wheezing in all groups (odds ratios ranged from 1.62 (95% CI: 1.06, 2.46) to 1.93 (95% CI: 1.10, 3.38)). Maternal smoking alone was associated with persistent wheezing and with both childhood (OR = 1.90, 95% CI: 1.06, 3.39) and persistent (OR = 2.18, 95% CI: 1.15, 4.14) wheezing if smoking occurred throughout childhood and adolescence. The authors conclude that exposures to gas cooking and smoking in childhood and adolescence increase the overall risk of wheezing.

Small size at birth and greater postnatal weight gain: relationships to diminished infant lung function.

Recent evidence suggests that impaired lung development is linked with diminished lung function and an increased risk of chronic obstructive airway disease in adulthood. To examine environmental influences on early lung development, we measured lung function in 131 normal-term infants aged 5-14 weeks. Adjusting for age at measurement, FEV at 0.4 seconds fell by 4.4% for each standard deviation decrease in birth weight (p = 0.047); when adjusted for FVC, FEV at 0.4 seconds was not related to birth weight but fell by 3.2% per standard deviation increase in infant weight gain (p = 0.001). Age- and sex-adjusted total respiratory system compliance fell by 7.0% per standard deviation decrease in birth weight (p < 0.001) but was not related to infant weight gain. In univariate analyses, age-adjusted forced expiratory flow at functional residual capacity was not related to birth weight, but decreased by 11.0% per standard deviation increase in infant weight gain (p = 0.007). The respiratory rate rose by 5.1% per standard deviation increase in infant weight gain (p = 0.001). Lung function measurements were not related to infant feeding. The observations suggest that lower rates of fetal growth and higher rates of early infancy weight gain are associated with impaired lung development.

Collection and characterisation of bacterial membrane proteins.

A general strategy for the amplified expression in Escherichia coli of membrane transport and receptor proteins from other bacteria is described. As an illustration we report the cloning of the putative alpha-ketoglutarate membrane transport gene from the genome of Helicobacter pylori, overexpression of the protein tagged with RGS(His)6 at the C-terminus, and its purification in mg quantities. The retention of structural and functional integrity was verified by circular dichroism spectroscopy and reconstitution of transport activity. This strategy for overexpression and purification is extended to additional membrane proteins from H. pylori and from other bacteria.

Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness.

Asthma is a common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness. Although environmental factors such as allergen exposure are risk factors in the development of asthma, both twin and family studies point to a strong genetic component. To date, linkage studies have identified more than a dozen genomic regions linked to asthma. In this study, we performed a genome-wide scan on 460 Caucasian families and identified a locus on chromosome 20p13 that was linked to asthma (log(10) of the likelihood ratio (LOD), 2.94) and bronchial hyperresponsiveness (LOD, 3.93). A survey of 135 polymorphisms in 23 genes identified the ADAM33 gene as being significantly associated with asthma using case-control, transmission disequilibrium and haplotype analyses (P = 0.04 0.000003). ADAM proteins are membrane-anchored metalloproteases with diverse functions, which include the shedding of cell-surface proteins such as cytokines and cytokine receptors. The identification and characterization of ADAM33, a putative asthma susceptibility gene identified by positional cloning in an outbred population, should provide insights into the pathogenesis and natural history of this common disease.