The Association of Clinical Characteristics and Tumour Markers With Image-Defined Risk Factors in the Management of Neuroblastoma in South Africa.

AIMS: Image-defined risk factors (IDRFs) in neuroblastoma predict surgical complications and management outcomes. As there is a lack of data regarding the association of IDRFs with clinical and pathological factors, this study evaluated the prognostic value of IDRFs to predict neuroblastoma survival outcomes. MATERIALS AND METHODS: This was a retrospective study including 345 patients and reviewed diagnostic imaging for 20 IDRFs, pleural effusions and ascites. The IDRFs were grouped into five 'primary IDRFs' cohorts with vascular encasement, involvement of multiple body compartments, organ infiltration, airway obstruction and intraspinal extension. The association between clinical, histopathological and biological characteristics of neuroblastoma and management was evaluated. RESULTS: More patients without IDRFs had operations compared with patients with IDRFs, with a trend towards significance (64.4% versus 35.6%, P = 0.082). Patients with multiple compartment tumour involvement (P = 0.003) and organ infiltration (P < 0.001) had a higher risk of surgical complications. The 5-year overall survival of the group with more than one IDRF was 0.0% and those with pleural effusions or ascites 6.7%, associated with the worst outcome (P = 0.005). The total number of IDRFs was not predictive of the metastatic remission rate (P = 0.585) or overall survival (P = 0.142), with no conclusive association found between IDRF groups and clinical or biological markers. CONCLUSIONS: Patients with more than one IDRF had the shortest survival time, whereas those with pleural effusions and ascites at diagnosis had a poor outcome. Standardised reporting of IDRFs is crucial for predicting prognosis.

Organic dust-induced lung injury and repair: Bi-directional regulation by TNFα and IL-10.

Exposure to organic dust increases chronic airway inflammatory disorders. Effective treatment strategies are lacking. It has been reported that hog barn dust extracts (HDE) induce TNFα through protein kinase C (PKC) activation and that lung inflammation is enhanced in scavenger receptor A (SRA/CD204) knockout (KO) mice following HDE. Because interleukin (IL)-10 production can limit excessive inflammation, it was hypothesized here that HDE-induced IL-10 would require CD204 to effect inflammatory responses. C57BL/6 wild-type (WT), SRA KO, and IL-10 KO mice were intranasally challenged daily for 8 days with HDE and subsequently rested for 3 days with/without recombinant IL-10 (rIL-10) treatment. Primary peritoneal macrophages (PM) and murine alveolar macrophages (MH-S cells) were treated in vitro with HDE, SRA ligand (fucoidan), rIL-10, and/or PKC isoform inhibitors. HDE induced in vivo lung IL-10 in WT, but not SRA KO mice, and similar trends were demonstrated in isolated PM from same treated mice. Lung lymphocyte aggregates and neutrophils were elevated in in vivo HDE-treated SRA and IL-10 KO mice after a 3-d recovery, and treatment during recovery with rIL-10 abrogated these responses. In vitro rIL-10 treatment reduced HDE-stimulated TNFα release in MH-S and WT PM. In SRA KO macrophages, there was reduced IL-10 and PKC zeta (ζ) activity and increased TNFα following in vitro HDE stimulation. Similarly, blocking SRA (24 hr fucoidan pre-treatment) resulted in enhanced HDE-stimulated macrophage TNFα and decreased IL-10 and PKCζ activation. PKCζ inhibitors blocked HDE-stimulated IL-10, but not TNFα. Collectively, HDE stimulates IL-10 by an SRA- and PKCζ-dependent mechanism to regulate TNFα. Enhancing resolution of dust-mediated lung inflammation through targeting IL-10 and/or SRA may represent new approaches to therapeutic interventions.

Thirty-day postoperative mortality for endometrial carcinoma in England: a population-based study.

OBJECTIVE: To quantify trends in 30-day mortality following surgery for endometrial carcinoma in England, and investigate hospital- and geographical-level variations. DESIGN: Retrospective population-based observational study using cancer registration and Hospital Episodes Statistics data. SETTING: England. POPULATION: Women diagnosed with endometrial carcinoma (ICD10 C54-C55 excluding sarcomas and malignant mixed Mullerian tumours) between 2000 and 2009 who were treated surgically (n = 38 332). METHODS: Random effects logistic regression model of postoperative mortality rates, adjusting for patient- and/or tumour-level factors (namely age, income deprivation, year of diagnosis, FIGO stage and grade). Case-mix adjusted postoperative mortality rates for hospitals and cancer networks were derived from the model. Multiple imputation was used to account for missing stage and grade data. MAIN OUTCOME MEASURES: 30-day postoperative mortality rate. RESULTS: For 2000-2009, the percentage of women dying within 30 days of surgery for endometrial carcinoma was very low at 0.61% (235 deaths), and decreased from 0.70% in 2000-2001 to 0.48% in 2008-2009. Postoperative mortality rates were lower for laparoscopic surgery, and higher for older women, those with advanced stage disease and high-grade tumours. Crude and case-mix adjusted results indicated that one hospital had a higher postoperative mortality rate than expected. CONCLUSIONS: The postoperative mortality rate for endometrial carcinoma in England is low and has improved since 2000, with increasing use of laparoscopic surgery. Postoperative mortality rates differed by surgical approach, patient age, disease stage and tumour grade. Only one hospital had a higher postoperative mortality rate than expected after adjusting for patient case-mix. TWEETABLE ABSTRACT: More women with endometrial cancer but better 30-day survival after surgery since 2000.

Childhood cancer incidence in South Africa, 1987-2007.

BACKGROUND: Childhood cancer is an emerging problem in Africa. Its extent is hazy because data are scarce, but it should be addressed. This is the first report from the South African Children's Tumour Registry (SACTR), which covers the whole of South Africa (SA). It provides minimal estimates of cancer incidence and discusses the challenges of cancer surveillance and control in a child population in a middle-income country. Only about 2% of the African population is covered by cancer registries producing comparable incidence data. OBJECTIVE: To present and interpret incidence patterns and trends of childhood cancer over a 21-year period. The results should raise awareness of the problem of childhood cancer in an African population and provide sensible data for taking this problem in hand. METHODS: All eligible and validated cancer cases registered in the SACTR over the period 1987-2007 and classified according to the International Classification of Childhood Cancer were included. Population data were retrieved from official sources and estimated for the population subcategories. Incidence rates were standardised to the world standard and time trends were evaluated using joinpoint models, adjusting for sex and age. RESULTS: Based on the 11,699 cases, the overall age-standardised average annual incidence rate was 45 per million. Threefold differences in the overall incidence rates were observed between the ethnic groups, ranging from 116 for whites to 37 for black Africans, and they differed by diagnostic group. Differences between the nine provinces of SA relate to the ethnic composition and prevailing socioeconomic status. The overall incidence rate declined by 1.2% per year for the whole country (p<0.01). However, the decline was mainly observed during the first few years of the study period, after which rates stabilised or increased. CONCLUSIONS: Diagnosis and notification of childhood cancer should improve. The differences in incidence between ethnic groups suggest the priorities for cancer control.

Discovery of 4-Amino-8-quinoline Carboxamides as Novel, Submicromolar Inhibitors of NAD-Hydrolyzing Enzyme CD38.

Starting from the micromolar 8-quinoline carboxamide high-throughput screening hit 1a, a systematic exploration of the structure-activity relationships (SAR) of the 4-, 6-, and 8-substituents of the quinoline ring resulted in the identification of approximately 10-100-fold more potent human CD38 inhibitors. Several of these molecules also exhibited pharmacokinetic parameters suitable for in vivo animal studies, including low clearances and decent oral bioavailability. Two of these CD38 inhibitors, 1ah and 1ai, were shown to elevate NAD tissue levels in liver and muscle in a diet-induced obese (DIO) C57BL/6 mouse model. These inhibitor tool compounds will enable further biological studies of the CD38 enzyme as well as the investigation of the therapeutic implications of NAD enhancement in disease models of abnormally low NAD.

Vulval cancer incidence, mortality and survival in England: age-related trends.

OBJECTIVE: To explore the trends and age characteristics of vulval cancer incidence, mortality, survival and stage of disease. DESIGN: Retrospective population-based observational study based on cancer registry and Office for National Statistics data. SETTING: England. POPULATION: All women diagnosed with vulval cancer, defined by the site of the tumour (ICD-10 code C51). METHODS: Including all C51 cases, Poisson regression was used to test for trends in incidence and mortality rates, and generalised linear modelling was used to test for trends in relative survival. Excluding women with melanomas, basal cell carcinomas and Paget disease, stage was investigated as a percentage of staged data by age. MAIN OUTCOME MEASURES: Age-standardised incidence and mortality rates, relative survival rates and stage of disease at diagnosis. RESULTS: From 1990, there was a statistically significant increase in overall incidence (P = 0.018) and decrease in mortality (P < 0.001). In addition, there were statistically significant increases in overall survival (1-year, P < 0.001; 5-year, P < 0.001). However, from 1990, incidence increased in women aged 20-39 years (P = 0.002), 40-49 and 50-59 years (both P < 0.001) and 60-69 years (P = 0.030) and decreased in women aged 80 years and above (P < 0.001). There were statistically significant decreases in mortality in women aged ≥60 years (P < 0.001), and statistically significant increases in 1-year survival in women aged ≥40 years (P ≤ 0.047) and in 5-year survival in women aged 40-49 and ≥60 years (P ≤ 0.011). Stage patterns by age highlight diagnosis at an earlier stage in younger women and more advanced stage diagnosis in older women. CONCLUSION: Survival from vulval cancer has improved and mortality has decreased since 1990. The overall incidence of disease has increased as a result of more new diagnoses in the under 70-year age group.

Management of undifferentiated embryonal sarcoma of the liver in children: a case series and management review.

BACKGROUND: Undifferentiated embryonal sarcoma of the liver (UESL) is a rare neoplasm, and the third-most common paediatric hepatic malignancy. However, no treatment guidelines exist. No randomised, controlled trials support specific combinations of therapy. OBJECTIVE: To compare presentation and management of UESL with other series, review the literature, and formulate treatment guidelines. METHODS: A retrospective chart review of all hepatic malignancies was conducted from 1996 to 2007 and 5 children with UESL were identified. Management and outcomes were documented. The literature regarding treatment modalities up to September 2012 was reviewed. RESULTS: Over a period of 11 years, 5 patients presented. All underwent surgery and 4 received chemotherapy. One received radiotherapy at relapse. Three are disease-free with follow-up of 58 - 184 months. One died after relapse, as did the patient whose family declined chemotherapy. CONCLUSION: The improved outcomes are consistent with the international experience and are probably related to combined treatment modalities and advances in supportive care. Pre-operative percutaneous biopsy provides no benefit if the lesion is resectable because it may not prove to be diagnostic, and may cause recurrence in the biopsy tract. If resectable, the recommended treatment is primary excision and adjuvant chemotherapy, with radiotherapy in selected cases. If unresectable, open biopsy is necessary to document histology, and neo- adjuvant chemotherapy is given prior to resection. If deemed unresectable, liver transplantation is considered.

Rural hospital mass casualty response to a terrorist shooting spree.

BACKGROUND: Civilian mass casualty incidents may occur infrequently and suddenly, and are caused by accidents, natural disasters or human terrorist incidents. Most reports deal with trauma centre management in large cities, and data from small local hospitals are scarce. A rural hospital response to a mass casualty incident caused by a terrorist shooting spree was evaluated. METHODS: An observational study was undertaken to evaluate the triage, diagnosis and management of all casualties received from the Utøya youth camp in Norway on 22 July 2011 by a local hospital, using data from the hospital's electronic records. Descriptive data are presented for patient demographics, injuries and patient flow. RESULTS: The shooting on Utøya youth camp left 69 people dead and 60 wounded. A rural hospital (Ringerike Hospital) triaged 35 patients, of whom 18 were admitted. During the main surge, the hospital triaged and treated 22 patients within 1 h, of whom 13 fulfilled the criteria for activating the hospital trauma team, including five with critical injuries (defined as an Injury Severity Score above 15). Ten computed tomography scans, two focused assessment with sonography for trauma (FAST) scans and 25 conventional X-rays were performed. During the first 24 h, ten surgical procedures were performed and four chest drains inserted. No patient died. CONCLUSION: Critical deviation from the major incident plan was needed, and future need for revision is deemed necessary based on the experience. Communication systems and the organization of radiological services proved to be most vulnerable.

Epithelial cells modulate genes associated with NF kappa B activation in co-cultured human macrophages.

Macrophages located in airways and the alveolar space are continually exposed to different signals from the respiratory mucosa. In this respect, epithelial cells represent an important source of cytokines and mediators modulating the state of activation and/or differentiation of mononuclear phagocytes. Many of the proinflammatory genes induced in macrophages during immune and immunopathological reactions are regulated by transcription factor NF kappa B. The aim of our study was to characterize changes in the expression of genes associated with NF kappa B activation and signalling in THP-1 human macrophages co-cultured with A549 respiratory epithelial cells. At least 4-fold upregulation of mRNA level was found in 29 of 84 tested genes including genes for multiple cytokines and chemokines, membrane antigens and receptors, and molecules associated with NF kappa B signalling. The mRNA induction was confirmed at the level of protein expression by evaluating the release of IL-6 and IL-8 and by ICAM-1 expression. Blocking of one NFκB subunit by p65 siRNA inhibited the production of IL-6 in both cell types while IL-8 release from THP-1 cells did not seem to be affected. We conclude from our data that unstimulated respiratory epithelial cells regulate genes associated with NF kappa B dependent immune responses in human macrophages and that these interactions may play a key role in immediate responses in the respiratory mucosa.

Changes in lung cancer incidence in South Asians in Leicester, 1990-2005.

BACKGROUND: A previous study showed that lung cancer incidence in Leicester's South Asian (SA) population had increased between 1990 and 1999. We expanded the original data set to determine if this increase had continued in recent years. METHODS: All patients diagnosed with lung cancer in Leicester between 1990 and 2005 were identified. Ethnicity was assigned using Nam Pechan software, deprivation by Townsend score. Using Poisson regression, incidence rate ratios (IRRs) were calculated to assess variations in incidence by ethnicity, deprivation and period of diagnosis. RESULTS: Comparing patients diagnosed in 2000-2005 with those in 1990-1994, the risk of lung cancer increased in the SA men (IRR: 1.67 (95% CI: 0.99, 2.78)) whereas in the non-South Asian (NSA) men, it had fallen (IRR: 0.84 (95% CI: 0.76, 0.94)). Comparing patients diagnosed in 2000-2005 with those in 1995-1999 an increase continued in the SA men (IRR: 1.11 (95% CI: 0.71-1.74)). A significant rise was observed in the NSA women comparing those diagnosed from 2000-2005 to 1995-1999 (IRR: 1.16 (95% CI: 1.01, 1.33)). CONCLUSION: Lung cancer is an important public health issue amongst SAs in Leicester and has increased significantly since the early 1990s, with rates sustained in the more recent years of 2000-2005. Changes in the rates of lung cancer in SA and NSA populations are likely to be due to changing smoking habits.

Maternal predictors of neonatal bone size and geometry: the Southampton Women's Survey.

Early growth is associated with later risk of osteoporosis and fractures. In this study, we aimed to evaluate the relationships between maternal lifestyle and body composition and neonatal bone size, geometry and density in the offspring. Participants were recruited from the Southampton Women's Survey, a unique prospective cohort of 12,500 initially non-pregnant women aged 20-34 years, resident in Southampton, UK. These women were studied in detail before and during pregnancy, and the offspring underwent anthropometric and bone mineral assessment (using dual energy-X-ray absorptiometry) at birth. A total of 841 mother-baby pairs were studied (443 boys and 398 girls). The independent predictors of greater neonatal whole body bone area (BA) and bone mineral content included greater maternal birthweight, height, parity, triceps skinfold thickness and lower walking speed in late pregnancy. Maternal smoking was independently associated with lower neonatal bone mass. Neonatal BA adjusted for birth length (a measure of bone width) was predicted positively by maternal parity and late pregnancy triceps skinfold thickness and negatively by late pregnancy walking speed. These findings were similar in both genders. We have confirmed, in a large cohort, previous findings that maternal lifestyle and body build predict neonatal bone mineral; additionally, maternal parity and fat stores and walking speed in late pregnancy were associated with neonatal bone geometry. These findings may suggest novel public health strategies to reduce the burden of osteoporotic fracture in future generations.

Toll-like receptor 2 is upregulated by hog confinement dust in an IL-6-dependent manner in the airway epithelium.

Hog confinement workers are at high risk to develop chronic bronchitis as a result of their exposure to organic dust. Chronic bronchitis is characterized by inflammatory changes of the airway epithelium. A key mediator in inflammation is Toll-like receptor 2 (TLR2). We investigated the role of TLR2 in pulmonary inflammation induced by hog confinement dust. Normal human bronchial epithelial cells (NHBE) were grown in culture and exposed to hog confinement dust extract. Hog confinement dust upregulated airway epithelial cell TLR2 mRNA in a concentration- and time-dependent manner using real-time PCR. There was a similar increase in TLR2 protein at 48 h as shown by Western blot. TLR2 was upregulated on the surface of airway epithelial cells as shown by flow cytometry. A similar upregulation of pulmonary TLR2 mRNA and protein was shown in a murine model of hog confinement dust exposure. Hog confinement dust is known to stimulate epithelial cells to produce IL-6. To determine whether TLR2 expression was being regulated by IL-6, the production of IL-6 was blocked using an IL-6-neutralizing antibody. This resulted in attenuation of the dust-induced upregulation of TLR2. To further demonstrate the importance of IL-6 in the regulation of TLR2, NHBE were directly stimulated with recombinant human IL-6. IL-6 alone was able to upregulate TLR2 in airway epithelial cells. Hog confinement dust upregulates TLR2 in the airway epithelium through an IL-6-dependent mechanism.

Malignant liver tumors in South African children: a national audit.

BACKGROUND: Malignant liver tumors (mostly hepatoblastoma [HB] and hepatocellular carcinoma [HCC]) are uncommon, representing 0.5%-2% of childhood malignancies worldwide. The pattern of liver tumors appears to differ in Southern Africa as a result of infectious factors (e.g., hepatitis B/retroviral disease (HIV). This study aimed to assess recent changes in the prevalence and surgical management of liver tumors in South African children. METHODS: Data were obtained from the tumor registry and pediatric oncology units in South African hospitals to audit and review the epidemiology, treatment, and outcome of malignant hepatic tumors in South African children. RESULTS: Malignant primary hepatic tumors were reported in 274 children (ages 0-14 years) from 1988 through June 2006. Of these 134 (48%) had HB; 77 (27%) had HCC (9 [3%] fibrolamellar subtype); 38 (13%), vascular tumors; and 17 (6%), liver sarcomas. In a further 8 patients (3%) other tumors included lymphoma and endodermal sinus tumor. Vascular tumors included hemangioendotheliomas (12), and there were 5 malignant tumors in children with HIV, including 1 angiosarcoma and 13 Kaposi sarcoma-like tumors. Hepatoblastoma occurred at a mean age of 1.47 years, and none were encountered in patients > 4 years of age. Hepatocellular carcinoma mostly occurred in the older patients (mean age: 10.48 years), but 6% presented in patients < 8 years of age (10 months, 2, 2.6, 5, 5, and 6 years). Hepatic sarcoma occurred at a mean age of 7.66 years and had a female predominance (M:F ratio: 0.4). The relative HCC prevalence (male predominant: hepatitis B related) was reflected in the low HB:HCC (1.67) ratio. However, a significant decrease in HCC was attributed to the effect of hepatitis B inoculation. There appeared to be an increase in the incidence of vascular tumors, presumably the result of an increase in Kaposi-like sarcoma in retrovirus-positive patients. The surgical resection rate was low because most patients presented late, with advanced disease. Survival was 11% and 52% for HB and HCC, respectively, and was related to chemotherapeutic response and complete surgical resection. CONCLUSIONS: Liver tumors appear to have a different epidemiological pattern in South Africa. The observed increased HCC prevalence appears to be decreasing with hepatitis B vaccination. Retroviral disease does not yet appear to have a major influence on the distribution of liver tumors in South Africa, although it possibly affects the vascular tumor prevalence.

Exposure to hog barn dust alters airway epithelial ciliary beating.

Swine confinement workers are at increased risk of airway diseases, including mucus membrane irritation syndrome, chronic rhinosinusitis and chronic bronchitis. Dust extracts from swine confinement facilities stimulate the production of pro-inflammatory cytokines in bronchial epithelial cells, including interleukin (IL)-8. As IL-8 is capable of blocking beta-agonist-stimulated increases in cilia beating, which impacts on mucociliary clearance, it was hypothesised that hog barn-dust exposure might alter cilia responses to stimulation. To test this hypothesis, ciliated bovine bronchial epithelial cell cultures were exposed to hog barn-dust extract (HDE) and ciliary beat frequency (CBF) was assayed. An elevation in baseline CBF was observed. This effect appeared to be independent of endotoxin but dependent upon nitric oxide. HDE also stimulated nitric oxide production in bronchial epithelial cells; however, stimulation of cilia beating by a beta-agonist did not occur in cells pre-exposed to HDE. These data demonstrate that hog barn dust can alter normal stimulation of cilia, suggesting a mechanism for the abrogation of stimulated increases in mucociliary clearance in response to inhaled dust exposure.

An acute haemolytic transfusion reaction caused by anti-Wr.

The Wright (Wr(a)) antigen is found on the red blood cells of approximately 1 : 1000 Caucasians. Anti-Wr(a) has been reported to be present in 1 : 25 to 1 : 100 healthy blood donors and an even higher proportion of hospital patients. Incompatibility due to anti-Wr(a) might therefore be expected to occur in approximately 1 in 50,000 blood transfusions. Reports of haemolytic transfusion reactions (HTR) and haemolytic disease of the newborn due to anti-Wr(a) are, however, rare. We report an acute HTR due to anti-Wr(a) in a 58-year-old man with myelodysplastic syndrome associated with rigors, shortness of breath and a significant rise in serum bilirubin from 16 micromol L(-1) pretransfusion to 110 micromol L(-1) immediately afterwards. This was accompanied by the appearance of bilirubin and urobilinogen in his urine and a fall in haemoglobin of nearly 2 g dL(-1) following the transfusion. Anti-Wr(a) was the only antibody implicated. When tested against the recipients plasma, Wr(a+) panel cells and the transfused unit responsible for the reaction were 2-3+ by indirect antiglobulin test (IAT) and the donation typed as Wr(a+). The recipient had the common Wr(a-) phenotype. The reaction resulted in the patient being admitted to hospital for 2 days. The increasing use of electronic issue may result in more frequent reports of reactions due to anti-Wr(a) using current screening cells.

Experience and outcomes of nephroblastoma in Johannesburg, 1998 - 2003.

INTRODUCTION: Outcomes for children with cancer in the developing world are compromised by the difficulties for patients in accessing health services and by competition for resources between oncological services and the myriad other health problems of emerging nations. The purpose of this study is to document and analyse our experience and the outcomes of children with nephroblastoma over recent years. METHODS: This is a retrospective review of all patients who underwent combined oncological and surgical treatment for nephroblastoma in the Paediatric Oncology Unit between 1998 and 2003. RESULTS: Sixty-three patients were treated for Wilms' tumour; the mean age was 3 years 8 months (range 4 months to 11 years). The majority of children presented with an abdominal swelling or mass. Preoperative chemotherapy was given in forty-six cases (73 %). The tumour stage distribution was 11/63 stage I (17 %), 11/63 stage II (17 %), 21/63 stage III (33 %), 16/63 stage IV (25 %) and 4/63 stage V (6 %). Postoperative chemotherapy and radiotherapy was given according to the SIOP protocol. During the study period, thirteen patients (21 %) died (7 cancer-specific, 2 postoperative, 4 sepsis related), thirteen (21 %) were lost to follow-up and thirty-seven (59 %) are free of disease with a mean follow-up period of 3.67 years. Children with stage I and stage II had a disease-free survival at 4 years of 89 %. However, those with stage III, IV and V disease had 4-year survival of 66.75 % (p = 0.07). Overall, four-year post-nephrectomy survival was 76 %. CONCLUSION: Outcomes for children with cancer have improved dramatically over recent years; however, in the developing world, the scarcity of hospital resources and the overwhelming burden of non-cancer diseases can mean that oncological treatment is extremely challenging. In our society, children tend to present with nephroblastoma at an advanced stage; however, treatment by dedicated, multidisciplinary teams can achieve good results.

Placental calcium transporter (PMCA3) gene expression predicts intrauterine bone mineral accrual.

Evidence is accruing that environmental exposures during critical periods of early development induce persisting changes in skeletal growth, and alter fracture risk in later life. We have previously demonstrated that placental calcium transport, partly determined by maternal 25-(OH) vitamin D status, may underlie this phenomenon. However, the precise relationship between expression of calcium transport proteins in the human placenta, and neonatal bone mineral accrual in the offspring, remains unknown. Tissue samples from 70 human placentae were fast frozen in liquid nitrogen and stored at -70 degrees C. A quantitative real time reverse transcriptase polymerase chain reaction was used to measure the mRNA expression of PMCA isoforms 1-4, using beta-actin as a control gene. Neonatal whole body bone area, mineral content and areal density (BA, BMC, BMD) were measured within 2 weeks of birth using DXA. PMCA3 mRNA expression predicted BA (r=0.28, p=0.02), BMC (r=0.25, p=0.04), placental weight (r=0.26, p=0.04) and birth weight (r=0.33, p=0.006) of the neonate. In a multivariate model, the relationship between placental PMCA3 expression and neonatal BMC was independent of maternal height, pre-pregnant fat stores, parity, physical activity, smoking, and calcium intake (p<0.05). Expression of the placental calcium transporter PMCA3 mRNA predicts neonatal whole body bone mineral content. This association may explain, in part, the mechanism whereby a mother's 25(OH)-vitamin D stores influence her offspring's bone mass.

A prospective cohort study of arm pain in primary care and physiotherapy--prognostic determinants.

OBJECTIVE: To investigate outcome and prognostic determinants for arm pain presenting to primary care and physiotherapy services. METHODS: Patients with arm pain were recruited as they presented to primary care and physiotherapy services, and were followed for 12 months. At baseline, they were classified by diagnosis using a validated examination schedule. Depression, somatizing tendency, health anxiety, fear-avoidance beliefs and chronic pain outside the arm were ascertained using standard definitions. Three outcomes were considered: same-site pain during the final month of follow-up (continuing pain); pain present on most days of that month; and pain present without a break of 7 days over follow-up ('unremitting' pain). Associations were explored in multi-level logistic regression models and summarized as odds ratios (ORs) with 95% confidence intervals (95% CIs). RESULTS: Altogether, 313 (83%) of 375 subjects completed follow-up, including 53% with 'continuing' and 24% with 'unremitting' pain. 'Continuing' pain was predicted most strongly by male sex (OR 1.9, 95% CI 1.2-3.2) (this association was restricted largely to the elbow), higher frequency of pain in the past month at baseline (OR 2.5, 95% CI 1.1-5.6), chronic pain at sites outside the arm (ORs 1.6-2.4 for different sites) and current smoking (OR 3.3, 95% CI 1.6-6.6). There were also indications that mental health and fear-avoidance beliefs influenced prognosis. Predictors for the other two adverse outcomes were similar. CONCLUSION: Arm pain often persists in patients who consult medical services. Predictors of persistence include male sex (elbow only), frequency of pain at baseline, chronic pain at other sites and smoking.

Parental determinants of neonatal body composition.

BACKGROUND: The prevalence of both childhood and adult obesity is rising in the developed world, and there is increasing interest in its underlying causes. A number of studies suggest a positive relationship between birth weight and childhood body mass index, but less is known about specific prenatal environmental influences on more direct measures of obesity. We used data from the Southampton Women's Survey to investigate parental influences on neonatal body composition ascertained by dual x-ray absorptiometry. METHODS: Participating mothers were characterized in detail (anthropometry, lifestyle, diet) before and during pregnancy; information was also obtained on their partners. The offspring underwent assessment of fat and lean body mass by dual x-ray absorptiometry within 2 wk of birth. Linear regression methods were used to explore the parental determinants of neonatal body composition. RESULTS: Complete data were available for 448 mother-offspring pairs. Taller women and those with higher parity had offspring with increased birth weight, fat, and lean mass (P < 0.05). Mothers who were taller, of greater parity, had greater fat stores, or walked more slowly also had offspring with greater proportionate body fat at birth (all P < 0.05). There was a weaker trend toward lower percentage fat and greater percentage lean in the offspring of mothers who smoked during pregnancy. CONCLUSION: Maternal size, parity, smoking history, walking speed, and fat stores are independent determinants of neonatal body composition. If these influences are shown to have persisting effects on body composition through to adulthood, they point to novel public health interventions early in life to prevent later obesity.

Inflammatory responses to the occupational inhalation of metal fume.

Occupational exposure to metal fume promotes a reversible increase in the risk of pneumonia, but by mechanisms which are unclear. To investigate, the current authors measured various markers of host defence function in welders and nonwelders. Induced sputum and venous blood samples were collected from 27 welders with regular long-term exposure to ferrous metal fume and 31 unexposed matched controls. In sputum, the present authors measured cell counts, the soluble and cellular iron concentration, and levels of interleukin-8, tumour necrosis factor-alpha, myeloperoxidase, matrix metalloproteinase-9, immunoglobulin (Ig)A, alpha(2)-macroglobulin and unsaturated iron-binding capacity. Blood samples were assayed for evidence of neutrophil activation and pneumococcal IgG antibodies. Welders had significantly higher iron levels and a substantially lower unsaturated iron-binding capacity in their sputum, but, despite a high iron challenge, there was a noteworthy absence of an inflammatory response. Only blood counts of eosinophils and basophils were significantly related to the extent of welding. Weak nonsignificant trends were observed for several other measures, consistent with low-grade priming of neutrophils. In conclusion, these data suggest that chronic exposure to metal fume blunts responsiveness to inhaled particulate matter. However, the mechanism behind the lack of detectable local inflammatory response requires further investigation.