Opting into breast screening over the age of 70 years: seeking evidence to support informed choice.

AIM: To provide evidence specific to the Scottish population regarding the risk-benefit balance of women >70 years opting into continued breast screening, which may be used as a basis for patient information documentation. MATERIALS AND METHODS: The present study consisted of a parallel, retrospective data analysis of breast cancer mortality data for breast cancer cases diagnosed between 2009 and 2013 (n=22,013) followed up to 31/12/18, and breast screening programme data from 2010 and 2015 (n=47,235). Screening outcome measures included recall for assessment, oncome of assessment, and tumour features. Tumours were classified as high, intermediate, or low risk according to grade and presence of invasion. Mortality data were linked to age at diagnosis and cause of death was recorded. RESULTS: The proportion of all deaths due breast cancer is inversely related to age at diagnosis. From 77 years, women are more likely to die with breast cancer, than directly due to breast cancer. Mammographic screening accurately identifies breast cancer in older women; however, many of the cancers detected were considered intermediate or low risk. CONCLUSIONS: Harms may outweigh the benefits of continued breast screening in older women. This information should be available to all older women.

Maternal high-fat diet impacts endothelial function in nonhuman primate offspring.

OBJECTIVE: The link between maternal under-nutrition and cardiovascular disease (CVD) in the offspring later in life is well recognized, but the impact of maternal over-nutrition on the offspring's cardiovascular function and subsequent risk for CVD later in life remains unclear. Here, we investigated the impact of maternal exposure to a high-fat/calorie diet (HFD) during pregnancy and early postnatal period on endothelial function of the offspring in a nonhuman primate model. METHODS: Offspring, naturally born to either a control (CTR) diet (14% fat calories) or a HFD (36% fat calories) consumption dam, were breast-fed until weaning at about 8 months of age. After weaning, the offspring were either maintained on the same diet (CTR/CTR, HFD/HFD), or underwent a diet switch (CTR/HFD, HFD/CTR). Blood samples and arterial tissues were collected at necropsy when the animals were about 13 months of age. RESULTS: HFD/HFD juveniles displayed an increased plasma insulin level and glucose-stimulated insulin secretion in comparison with CTR/CTR. In abdominal aorta, but not the renal artery, acetylcholine-induced vasorelaxation was decreased remarkably for HFD/HFD juveniles compared with CTR/CTR. HFD/HFD animals also showed a thicker intima wall and an abnormal vascular-morphology, concurrent with elevated expression levels of several markers related to vascular inflammation and fibrinolytic function. Diet-switching animals (HFD/CTR and CTR/HFD) displayed modest damage on the abdominal vessel. CONCLUSION: Our data indicate that maternal HFD exposure impairs offspring's endothelial function. Both early programming events and postweaning diet contribute to the abnormalities that could be reversed partially by diet intervention.

Molecular regulation of striatal development: a review.

The central nervous system is composed of the brain and the spinal cord. The brain is a complex organ that processes and coordinates activities of the body in bilaterian, higher-order animals. The development of the brain mirrors its complex function as it requires intricate genetic signalling at specific times, and deviations from this can lead to brain malformations such as anencephaly. Research into how the CNS is specified and patterned has been studied extensively in chick, fish, frog, and mice, but findings from the latter will be emphasised here as higher-order mammals show most similarity to the human brain. Specifically, we will focus on the embryonic development of an important forebrain structure, the striatum (also known as the dorsal striatum or neostriatum). Over the past decade, research on striatal development in mice has led to an influx of new information about the genes involved, but the precise orchestration between the genes, signalling molecules, and transcription factors remains unanswered. We aim to summarise what is known to date about the tightly controlled network of interacting genes that control striatal development. This paper will discuss early telencephalon patterning and dorsal ventral patterning with specific reference to the genes involved in striatal development.

The prognostic significance of computerised tomography findings in women with liver metastases from breast cancer.

AIMS: While computerised tomography (CT) is used for diagnosis and assessing response to treatment little work has been performed on the prognostic significance of the CT findings in women with liver metastases. The aim of this study was to assess if the CT findings in women diagnosed with liver metastases at the time of first presentation with metastatic breast cancer have any prognostic significance. MATERIALS AND METHODS: The staging CT scans of 78 consecutive women diagnosed with liver metastases at the time of first presentation of metastatic breast cancer were reviewed independently by two radiologists who were blinded to survival and the histological features of the tumour. The number and enhancement characteristics of liver metastases, whether metastases were solitary, multiple or diffuse, the diameter of the largest and the sum of the diameter of the five largest lesions, an estimate of % involvement (<10%, 10-50%, >50%), and the presence of metastases at other sites were assessed. HER-2 and ER status and histological grade of the patient's primary breast cancer were also recorded. Survival was ascertained from hospital records. The prognostic significance of these factors was assessed in a univariate and multivariate fashion. RESULTS: At univariate analysis, number of liver metastases, sum of the diameter of the five largest lesions, percentage estimated involvement, presence of ascites, chest metastases and HER-2 status were significantly associated with reduced survival. Liver metastasis pattern (i.e. whether discrete or multiple), enhancement characteristics, ER status and histological grade were not associated with a significant outcome. At multivariate analysis estimated percentage liver involvement and the presence of chest metastases retained prognostic significance. Estimated percentage involvement was reproducible with 90% concordance between the two observers. CONCLUSIONS: The CT appearances of patients with liver metastases at first presentation with metastatic breast cancer provide prognostic information which may be clinically useful.

The transcobalamin (TCN2) 776C>G polymorphism affects homocysteine concentrations among subjects with low vitamin B(12) status.

BACKGROUND/OBJECTIVES: Methionine synthase catalyzes the conversion of 5-methyltetrahydrofolate to tetrahydrofolate and homocysteine (Hcy) to methionine using vitamin B(12) as a cofactor. Transcobalamin is the main transporter of vitamin B(12) from blood into cells. This study was undertaken to assess the relationship between the transcobalamin P259R (TCN2 776C>G) polymorphism and both serum vitamin B(12) and total Hcy (tHcy) levels. SUBJECTS/METHODS: The population comprised 613 men from Northern Ireland, aged 30-49 years, for whom tHcy, serum vitamin B(12) and serum folate concentrations were available. TCN2 776C>G genotypes were determined using a TaqMan 5' nuclease Real-Time PCR assay. Standard statistical tests of association were applied to assess the relationships between the polymorphism and phenotypic variables. RESULTS: The TCN2 776CC homozygous genotype was associated with lower serum vitamin B(12) concentrations compared with the 776CG (P(unadjusted)=0.01; P(adjusted)=0.03) and 776GG genotypes (P(unadjusted)=0.015; P(adjusted)=0.045). Among individuals with vitamin B(12) concentrations in the lower half of the distribution, tHcy concentrations were higher in TCN2 776GG homozygotes than in individuals with the other genotypes (P(unadjusted)=0.015; P(adjusted)=0.06). CONCLUSIONS: These data suggest that, relative to transcobalamin with arginine at position 259 (776G), transcobalamin with proline at this position (776C) is either more efficient at vitamin B(12) transport from blood to tissues or has higher affinity for vitamin B(12). Furthermore, vitamin B(12) status influences the relationship between TCN2 776C>G genotype and tHcy concentrations. Thus, the TCN2 776C>G polymorphism may contribute to the risk of pathologies associated with a low B(12), and high tHcy phenotype.

Development of multidimensional scales to measure key leaders' perceptions of community capacity and organizational capacity for teen pregnancy prevention.

This study discusses the development of scales to measure key leaders' self-reported involvement in community capacity building, perceptions of organizational capacity for teen pregnancy prevention, and the relationship between capacity and teen pregnancy rates. Data were collected from 1,516 key leaders across a rural southern state. Findings indicate that key leaders' perceptions of organizational capacity are related to their involvement in community capacity building efforts and community capacity is associated with teen pregnancy rates. This research represents progress toward measuring community and organizational capacity and may be used to inform future work focusing on developing quantitative measures of community capacity.

Hypoxia-regulated glucose transporter Glut-1 may influence chemosensitivity to some alkylating agents: results of EORTC (First Translational Award) study of the relevance of tumour hypoxia to the outcome of chemotherapy in human tumour-derived xenografts.

Tumour hypoxia confers poor prognosis in a wide range of solid tumours, due to an increased malignancy, increased likelihood of metastasis and treatment resistance. Poorly oxygenated tumours are resistant to both radiation therapy and chemotherapy. However, although the link between radiation therapy and hypoxia is well established in a range of clinical studies, evidence of its influence on chemotherapy response is lacking. In this study, a panel of human tumour-derived xenografts that have been characterised previously for in vivo response to a large series of anti-cancer agents, and have been found to show chemosensitivities that correlate strongly with the parent tumour, were used to address this issue. Immunohistochemistry was carried out on formalin-fixed, paraffin-embedded sections of xenograft samples to detect expression of the intrinsic hypoxia marker Glut-1 and adducts of the bioreductive hypoxia marker pimonidazole. Glut-1 scores correlated significantly with T/C values for CCNU sensitivity (r = 0.439, P = 0.036, n = 23) and showed a borderline significant correlation with dacarbazine T/C (r = 0.405, P = 0.076, n = 20). However, there was no correlation between both Glut-1 and pimonidazole scores and T/C obtained for the bioreductive drug mitomycin C. The use of human tumour-derived xenografts offers a potentially useful way of using archival material to determine the influence of hypoxia and other tumour-microenvironmental factors on chemosensitivity without the direct use of human subjects.

Pre-hospital coronary care and coronary fatality in the Belfast and Glasgow MONICA populations.

BACKGROUND: The aim of this study was to describe and compare coronary event case fatality and care pathways in two defined populations with access to different models of pre-hospital care provision. METHODS: Secondary analysis of MONItoring of Trends and Determinants in CArdiovascular Disease (MONICA) population coronary event registers (1988, 1989, 1990, 1992 and 1993). RESULTS: Case fatality at 28 days following an acute coronary event was 6.5% greater in the Glasgow MONICA Project (GMP) population (46.7%) than in the Belfast MONICA Project (BMP) population (40.2%). Pre-hospital case fatality was 33.9% in the GMP population and 28.3% in the BMP population. These differences could not be fully explained by mobile coronary care unit (MCCU) responses in the BMP area. Initial care was provided in hospital for 28.3% of the BMP events and only 7.7% of the GMP events. Additional data collected by the Belfast and Glasgow MONICA investigators support a large difference between the median delay to main medical care in the BMP events (120 min) and the median delay to ward admission in the GMP area (220 min) at this time. CONCLUSIONS: Our findings suggest that the delay between coronary event onset and access to specialist coronary care was the most likely critical difference, irrespective of hospital-based MCCU provision in the BMP area. An established 'culture of early intervention' in Belfast may have been an important factor. As a large proportion of coronary event fatalities continue to occur outside hospital, there is a need to strengthen the evidence base underpinning the provision of appropriate skilled care and treatment at the earliest possible opportunity.

Current smoking and the risk of non-fatal myocardial infarction in the WHO MONICA Project populations.

BACKGROUND: Cohort studies have shown that smoking has a substantial influence on coronary heart disease mortality in young people. Population based data on non-fatal events have been sparse, however. OBJECTIVE: To study the impact of smoking on the risk of non-fatal acute myocardial infarction (MI) in young middle age people. METHODS: From 1985 to 1994 all non-fatal MI events in the age group 35-64 were registered in men and women in the WHO MONICA (multinational monitoring of trends and determinants in cardiovascular disease) project populations (18,762 events in men and 4047 in women from 32 populations from 21 countries). In the same populations and age groups 65,741 men and 66,717 women participated in the surveys of risk factors (overall response rate 72%). The relative risk of non-fatal MI for current smokers was compared with non-smokers, by sex and five year age group. RESULTS: The prevalence of smoking in people aged 35-39 years who experienced non-fatal MI events was 81% in men and 77% in women. It declined with increasing age to 45% in men aged 60-64 years and 36% in women, respectively. In the 35-39 years age group the relative risk of non-fatal MI for smokers was 4.9 (95% confidence interval (CI) 3.9 to 6.1) in men and 5.3 (95% CI 3.2 to 8.7) in women, and the population attributable fractions were 65% and 55%, respectively. CONCLUSIONS: During the study period more than half of the non-fatal MIs occurring in young middle age people can be attributed to smoking.

Nocturnal secretory dynamics of inhibin B and testosterone in pre- and peripubertal boys.

To investigate the secretory dynamics of testosterone and inhibin B, we collected samples every 20 min from 2000 h to 0800 h in 20 boys. Boys in group 1 (n = 5) were aged less than 8 yr, group 2 (n = 5) were aged more than 8 yr but 1.5 yr or more before pubertal onset, group 3 (n = 5) were studied 1.0 yr or less before pubertal onset, and group 4 (n = 5) were in early puberty. Testosterone increased after midnight in peripubertal boys, coinciding with the onset of LH pulsatility, and showed a pulsatile pattern in 6 of 10 of these boys. Cross-correlation analysis indicated significant temporal coupling between LH and testosterone. Inhibin B was higher in groups 3 and 4, compared with groups 1 and 2 (P < 0.01) and showed a downward trend overnight with no evidence of pulsatility and no evidence of short-term interactions with LH, FSH, or testosterone. Inhibin B and LH nocturnal means were both inversely correlated with time before pubertal onset (r(s) > or = -0.85, P < 0.01). Only LH nocturnal mean and amplitude, respectively, contributed independently to prediction of testosterone and inhibin B nocturnal means, explaining 71 and 65% of their variability. We conclude that both testosterone and inhibin B are related to nocturnal LH release in peripubertal boys but over different time scales.

Development of a youth survey to measure risk behaviors, attitudes and assets: examining multiple influences.

Currently, most surveys assessing adolescent health concerns focus primarily on risk behaviors and negative influences rather than positive influences such as assets. The purpose of this paper is to describe the development and validation of the Adolescent Health Attitude and Behavior Survey (AHABS). This instrument was developed to measure the prevalence of youth health risk behaviors, attitudes towards adolescent sexual behavior and youth assets in a statewide evaluation effort. The questionnaire was completed by 4368 public high school students in Grades 9-12. Content validity was established through an extensive review of literature, a group process and factor analyses. Reliability was established through Cronbach's alpha coefficients. Factor loadings ranged from 0.48 to 0.84 for scales measuring attitudes towards adolescent sexual behavior and alpha coefficients ranged from 0.61 to 0.81. Factor loadings ranged from 0.34 to 0.90 for scales measuring youth assets and alpha coefficients ranged from 0.69 to 0.85. Because of several limitations (e.g. construct validity was not measured), additional development work is needed. Therefore, the AHABS is still in a developing, but promising, state. Additional psychometric work will provide program practitioners and evaluators with a psychometrically sound tool to measure behaviors, attitudes and assets.

Investigation of the C242T polymorphism of NAD(P)H oxidase p22 phox gene and ischaemic heart disease using family-based association methods.

Ischaemic heart disease is a complex phenotype arising from the interaction of genetic and environmental factors. Excessive production of reactive oxygen species leading to endothelial dysfunction is believed to be important in the pathogenesis of ischaemic heart disease. The NAD(P)H oxidase system generates superoxide anions in vascular cells; however, the role of the C242T polymorphism of the NAD(P)H oxidase p22 phox gene in ischaemic heart disease is unclear due to contradictory results from case-control studies. Consequently, we applied family-based association tests to investigate the role of this polymorphism in ischaemic heart disease in a well-defined Irish population. A total of 1023 individuals from 388 families (discordant sibships and parent/child trios) were recruited. Linkage disequilibrium between the polymorphism and ischaemic heart disease was tested using the combined transmission disequilibrium test (TDT)/sib-TDT (cTDT) and pedigree disequilibrium test (PDT). Both cTDT and PDT analyses found no statistically significant excess transmission of either allele to affected individuals (P =0.30 and P =0.28, respectively). Using robust family-based association tests specifically designed for the study of complex diseases, we found no evidence that the C242T polymorphism of the p22 phox gene has a significant role in the development of ischaemic heart disease in our population.

Is inhibin B a potential marker of gonadotoxicity in prepubertal children treated for cancer?

BACKGROUND AND OBJECTIVE: Chemotherapy treatment of childhood cancer may impair gonadal function, which may be manifested only in adulthood as permanent sterility. Detection of gonadal dysfunction in prepubertal children has been hampered by the absence of a sensitive marker. Inhibin B is secreted by small antral follicles and Sertoli cells in females and males, respectively, and may be a marker of gonadal function in prepubertal children. The aim of this pilot study was to evaluate inhibin B in relation to sensitive measurements of gonadotrophins as markers of the early gonadotoxic effects of chemotherapy in prepubertal children treated for cancer. STUDY DESIGN AND SUBJECTS: Twenty-five prepubertal children (9 females), median age 4.5 years (range 1.2-12.8 years) with cancer (16 solid tumours, nine acute lymphoblastic leukaemia, ALL) were studied longitudinally. Blood samples were collected before and during chemotherapy (solid tumours) or immediately following induction and first intensification (ALL). Post-treatment (1-6 months) samples were collected in 12 of the patients (5 females). MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA). FSH and LH were measured by sensitive time-resolved immunofluorescence. RESULTS: Girls: Pretreatment inhibin B was slightly high in one girl but normal for age and sex in all others: median 16.1 (range 9.4-186.2) ng/l, median SD score +0.2 (-1.3 to +2.6). Inhibin B decreased to undetectable levels (< 8 ng/l) in 8/9 girls during treatment (P = 0.03), with no accompanying rise in FSH or LH. Post-treatment recovery of inhibin B was variable: median 16.1 (range < 8.0-44.2) ng/l, median SD score +0.1 (range < -2.4 to +1.8). Sustained undetectable inhibin B levels were observed in 2/5 girls with correspondingly elevated FSH concentrations (11.8 and 10.9 U/l). Boys: Inhibin B was normal for age and sex in all boys before treatment with no significant change during or after treatment (medians 93 ng/l, 85 ng/l and 94 ng/l, SD scores -0.3, -0.6 and -0.2, respectively). Inhibin B decreased to undetectable levels in one boy post-treatment with no accompanying increase in FSH or LH. CONCLUSIONS: In prepubertal girls with cancer, chemotherapy is associated with suppression of inhibin B, usually transient, which may indicate arrest of follicle development. Sustained suppression of inhibin B following treatment may be indicative of permanent ovarian damage. In prepubertal boys, chemotherapy had little immediate effect on Sertoli cell production of inhibin B, although one boy showed a delayed effect. Inhibin B, together with sensitive measurements of FSH, may be a potential marker of the gonadotoxic effects of chemotherapy in prepubertal children with cancer.

Smoking, atopy and certain furry pets are major determinants of respiratory symptoms in children: the International Study of Asthma and Allergies in Childhood Study (Ireland).

BACKGROUND: Environmental, cultural and health care differences may account for variation among countries in the prevalence of asthma and respiratory symptoms in teenagers. OBJECTIVE: To examine the prevalence of respiratory symptoms and the level of diagnosis, and to compare determinants of asthma and severe wheeze in two countries. METHODS: Self-completion questionnaires based on the International Study of Asthma and Allergies in Childhood (ISAAC) protocol were provided to school children in Ireland (Republic and Northern Ireland). In the Republic of Ireland, all children in classes largely aged 13-14 years from 30 post-primary schools were selected by random sampling stratified by school size, composition and Health Board in Spring 1995. In Northern Ireland, all children largely aged 13-14 years of age from 26 post-primary schools were selected by random sampling stratified by school type, composition and Education and Library Board in Spring 1996. RESULTS: Questionnaires were completed by 2,364 children from Northern Ireland and 2,671 from the Republic, about 90% of those eligible to participate. The prevalences of wheeze at various levels of severity, of diagnosed asthma and of treated wheeze were very similar in Northern Ireland and the Republic of Ireland. A significant proportion of those reporting more severe symptomatology (four or more attacks of wheeze in the past 12 months and/or one or more nights disturbed and/or moderate or greater disruption of daily activities and/or speech restriction due to wheeze) had been neither diagnosed nor treated for asthma (20-37%). To investigate the determinants of the more severe symptomatology of asthma or treated wheeze a series of stepwise multiple regression analyses was performed. A history of atopy, cigarette smoking, the possession of a furry pet other than a dog or cat and age were each independently associated with severe wheeze, whilst atopy, a furry pet (as above) and gender were each independently associated with asthma or treated wheeze. CONCLUSIONS: Cigarette smoking is closely associated with the reporting of significant respiratory symptoms together with atopy and exposure to furry pets. Some 20-37% of severe symptoms were neither diagnosed nor treated as asthma.

Inhibin B in boys from birth to adulthood: relationship with age, pubertal stage, FSH and testosterone.

OBJECTIVE: Inhibin B in males is produced principally by Sertoli cells under the influence of FSH and is thought to have a role in feedback regulation of FSH. The aims of our study were to investigate how inhibin B changes from birth to late adolescence in boys, to derive reference data and to explore its relation with pubertal stage, FSH and testosterone. DESIGN AND SUBJECTS: Blood samples were collected from (i) 366 boys aged 0--18 years to obtain age-related reference data; (ii) 195 boys who had full pubertal staging; and (iii) a cohort of 15 boys studied longitudinally as they approached and entered early puberty. MEASUREMENTS: Dimeric inhibin B was measured by double antibody enzyme-linked immunosorbent assay (ELISA), FSH by immunoradiometric assay (IRA) and testosterone by an extraction radioimmunoassay. RESULTS: Inhibin B was high in infant boys, decreased gradually to a nadir at 6--10 years of age, then increased rapidly in early adolescence to reach a new plateau at 12--17 years. It was detectable in all samples. Age-related reference ranges and data for calculation of SD scores are presented. In prepubertal boys, inhibin B correlated positively with age (P < 0.001), but not with FSH. Inhibin B increased progressively from pubertal stages G1 to G3 but then decreased slightly at stages G4 to G5 (P less-than-or-equal 0.01). At stage G2, inhibin B correlated positively with testosterone (P < 0.01) but not with FSH. From stage G3 onwards, inhibin B correlated inversely with FSH (P < 0.01) but lost its relationship with testosterone. In the cohort of boys studied longitudinally, inhibin B increased progressively prior to pubertal onset and further on entry into early clinical puberty (P < 0.05). Testosterone also increased over this period (P < 0.05) but FSH showed no significant change. CONCLUSIONS: The two peaks of inhibin B during infancy and early puberty appear to reflect the two periods of Sertoli cell proliferation in normal human males. During mid-childhood, a relatively constant amount of inhibin B is secreted constitutively. The early FSH-independent increase in inhibin B that precedes clinical puberty and continues to stage G2 may be stimulated by testosterone or other factors from Leydig cells. The inverse relationship between inhibin B and FSH that subsequently develops from mid-puberty onwards is consistent with the establishment of a negative feedback loop at this time.

Dimeric inhibins in girls from birth to adulthood: relationship with age, pubertal stage, FSH and oestradiol.

OBJECTIVE: Inhibin B is produced by granulosa cells in small antral follicles under the influence of FSH, whilst inhibin A is produced by larger follicles and the corpus luteum. The aims of our study were to investigate how these inhibins change from birth to late adolescence in girls, to derive reference data and to explore their relation with pubertal stage, FSH, oestradiol and each other. STUDY DESIGN AND SUBJECTS: Blood samples were collected from: (a) 345 girls aged 0--18 years to obtain age-related reference data, and (b) 80 pre-menarcheal girls with full pubertal staging, of whom 40 were on GH treatment at the time of sampling. MEASUREMENTS: Dimeric inhibins A and B were measured by double antibody enzyme-linked immunosorbent assay (ELISA), FSH by immunoradiometric assay (IRMA) and oestradiol by radioimmunoassay. RESULTS: Median inhibin B was low until age 6 years, slightly higher from 6 to 10 years, then increased from 10 to 12 years to reach a plateau from 12 to 18 years. Inhibin A was usually detectable in girls younger than 3 months but thereafter became undetectable in most samples until after age 10 years, when median levels rose progressively to 14 years, then stabilized from 14 to 18 years. Both inhibins displayed considerable scatter about the median throughout infancy, childhood and adolescence. Girls aged 0--10 years showed a positive correlation between inhibins A and B (P < 0.0001), whereas those aged 14--18 years showed an inverse relationship (P < 0.001), indicating the onset of ovulatory cycles. Age-related reference ranges and data for calculation of SD scores are presented. GH-treated girls at pubertal stage B2 (but not at B1 or B3--5) had higher inhibin B and FSH levels than untreated girls and were excluded from further analysis. Both inhibins A and B increased during puberty (P < 0.0001) and were positively correlated with each other (P < 0.01). Both inhibins were also positively correlated with FSH in pre-pubertal girls (P < 0.05) but not at pubertal stages B3--5. CONCLUSIONS: Although median levels of inhibins A and B remained low until after age 10 years in girls, the increased levels of both inhibins in individual samples, together with their positive relationship with FSH, provide further evidence of sporadic follicular development throughout infancy and childhood under the influence of FSH. The increase in both inhibins during puberty and their changing relationship with FSH are in keeping with the concept of follicular growth being dependent on the duration of FSH elevation above a critical threshold rather than the degree of elevation per se.

Psychosocial risk factors for heart disease in France and Northern Ireland: the Prospective Epidemiological Study of Myocardial Infarction (PRIME).

BACKGROUND: France has a substantially lower level of premature mortality from cardiovascular diseases (CVD) relative to its comparators. Compared with Northern Ireland, France has one-half the rate, despite having a similar cardiovascular risk profile to Northern Ireland. In this prospective longitudinal study the psychosocial risk hypothesis for CVD was tested. METHOD: A cohort of 9758 men (7359 in France and 2399 in Northern Ireland) aged 50-59 years who were initially free of any CVD were recruited. At baseline the subjects completed a psychosocial questionnaire, measuring hostility, depression, social support, and the Type A behaviour pattern. At 5-years follow-up their clinical status was determined. RESULTS: Multivariate analysis indicated that, contrary to prediction, France had a substantially more negative psychosocial risk profile than Northern Ireland. The psychosocial risk factors were not successful at predicting at 5-years follow-up the hard clinical endpoint of definite fatal/non-fatal myocardial infarction. In the case of the softer clinical endpoint, angina pectoris/unstable angina, only depression predicted outcome with a small effect size. CONCLUSION: The findings provide little support for the psychosocial risk hypothesis. The psychosocial risk profile was more negative in France, the opposite of that predicted. The finding of a relationship between depression and angina may reflect a tendency for individuals who respond negatively on mood state to report more cardiac symptoms irrespective of physical disease state.

[Expression of the neurotrophin-receptor TrkB predicts outcome in nephroblastomas: results of a pilot-study]. / Die Expression des Neurotrophin-Rezeptors TrkB beeinflusst die Prognose von Nephroblastomen: Ergebnisse einer Pilotstudie.

BACKGROUND: The neurotrophin-receptor TrkB plays an important role in pathogenesis, biology and prognosis of neuroblastoma. Expression of TrkB on aggressive neuroblastomas leads to proliferation and survival of the tumor cells and is associated with an unfavorable prognosis. It is now known that Trk receptors are also expressed in extraneural tissues including the kidney. PATIENTS AND METHODS: To study the role of the neurotrophin-receptor TrkB in nephroblastoma/Wilms' Tumor (WT), we determined TrkB mRNA expression by semiquantitative duplex RT-PCR in 39 primary WT. Comparison of mRNA expression levels with clinical variables was performed using Cox regression analysis. RESULTS: The 5-year overall survival was significantly worse for patients with tumors expressing high levels of a functional TrkB-receptor (TrkBfull) in comparison to patients with low levels of TrkBfull (70 % versus 100 %, p=0.005). Conversely, children with tumors expressing high mRNA levels of a functionally inactive truncated TrkB receptor (TrkBtrunc) had a significantly higher 5-year overall survival rate in comparison to patients with low levels of TrkBtrunc (100 % versus 68 %, p=0.003). The hazard ratios for TrkBfull and TrkBtrunc remained significant after adjusting for tumor stage. All WT with high levels of TrkB also expressed the ligand brain-derived neurotrophic factor (BDNF). CONCLUSIONS: Full-length and truncated TrkB appear to be important prognostic factors in WT. Their expression should be assessed prospectively in a larger panel of WT and may have a future role in patient assignment to risk-based treatment strategies. TrkB signaling may be reduced in WT with favorable outcome due to low numbers of TrkB receptors or a competitive effect of functionally inactive TrkBtrunc.

Effect of CEP-751 (KT-6587) on neuroblastoma xenografts expressing TrkB.

BACKGROUND: The compound CEP-751 (KT-6587), a potent and selective inhibitor of the Trk family of tyrosine kinases, has been shown to inhibit the growth of human neuroblastoma (NB) xenografts in nude mice [1]. PROCEDURE: To address its mechanism of action, we studied SY5Y, a human NB cell line with no detectable Trk expression, and two subclones transfected with TrkB. The transfected clones, SY5Y (G8) and SY5Y (G12), expressed moderate and high levels, respectively, of TrkB mRNA and protein. These TrkB-expressing subclones and the parental line were then grown as xenografts in nude mice, and CEP-751 was used to inhibit TrkB tyrosine kinase activity in these xenografts. Animals were treated twice a day with CEP-751 (21 mg/kg), or with the carrier vehicle as a control. TrkB expression in the resultant tumors was examined by quantitative RT-PCR. The effect of CEP-751 on TrkB activation by BDNF was examined in G12 cells in culture by immunoprecipitation with antipan Trk antiserum, followed by Western blot analysis using antiphosphotyrosine antibodies. To determine if CEP-751 was causing apoptosis, the TUNEL assay was used. RESULTS: CEP-751 had little effect on the growth of SY5Y tumors, but did slow the growth rate of the C8 and G12 tumors. The daily growth rate of the treated tumors was 0.16, 0.13, and 0.10 cm3, respectively, for the SY5Y, G8, and G12 tumors. RT PCR analysis confirmed the expression of TrkB in G8 and G12, but not in SY5Y tumors. Activation of TrkB by BDNF in G12 cells was inhibited by CEP-751 in a dose dependent fashion. The treated tumors showed marked evidence of apoptosis. CONCLUSIONS: These data suggest that the effect of CEP-751 is due, at least in part, to its inhibition of TrkB kinase, and that CEP-751 may become a useful therapeutic tool for the treatment of aggressive neuroblastomas, which often express TrkB.

Association among EPHB2, TrkA, and MYCN expression in low-stage neuroblastomas.

BACKGROUND: The EPH family is the largest subfamily of receptor protein-tyrosine kinases, consisting of EPHA and EPHB subgroups. Ligands of EPH family receptors are called ephrins, which include ephrin-A and ephrin-B subgroups. We recently found that transcripts encoding the EPHB subgroup (EPHB) and the ephrin-B subgroup (EFNB) were expressed together in neuroblastoma (NB) cell lines. PROCEDURE: In this study, we examined the expression of EPHB and EFNB transcripts in 24 NB specimens representing all clinical stages. We found that several EPHB and EFNB transcripts were expressed together in all NBs examined. RESULTS: Among the transcripts examined, EPHB6 expression was most significantly associated with low stage tumors (stages 1, 2, and 4S; P = 0.0048). TrkA expression was significantly correlated with EPHB6, EFNB2, and EFNB3 expression (P < 0.01 in each case). Taken together, these data indicate that the expression of EPHB6, EFNB2, and EFNB3 may serve as prognostic indicators of favorable NBs. In the low-stage NBs without MYCN amplification, EPHB2 expression was correlated both with MYCN expression and with TrkA expression (P < 0.01 in each case). Moreover, MYCN expression was correlated with TrkA expression (P < 0.01) in the low-stage NBs. CONCLUSIONS: This observation points to the possibility that MYCN expression might contribute to favorable outcome of low-stage NBs.