Maternal plasma cortisol's effect on offspring birth weight: a Mendelian Randomisation study.

BACKGROUND: Observational studies and randomized controlled trials have found evidence that higher maternal circulating cortisol levels in pregnancy are associated with lower offspring birth weight. However, it is possible that the observational associations are due to residual confounding. METHODS: We performed two-sample Mendelian Randomisation (MR) using a single genetic variant (rs9989237) associated with morning plasma cortisol (GWAS; sample 1; N = 25,314). The association between this maternal genetic variant and offspring birth weight, adjusted for fetal genotype, was obtained from the published EGG Consortium and UK Biobank meta-analysis (GWAS; sample 2; N = up to 406,063) and a Wald ratio was used to estimate the causal effect. We also performed an alternative analysis using all GWAS reported cortisol variants that takes account of linkage disequilibrium. We also tested the genetic variant's effect on pregnancy cortisol and performed PheWas to search for potential pleiotropic effects. RESULTS: The estimated effect of maternal circulating cortisol on birth weight was a 50 gram (95% CI, -109 to 10) lower birth weight per 1 SD higher log-transformed maternal circulating cortisol levels, using a single variant. The alternative analysis gave similar results (-33 grams (95% CI, -77 to 11)). The effect of the cortisol variant on pregnancy cortisol was 2-fold weaker than in the original GWAS, and evidence was found of pleiotropy. CONCLUSIONS: Our findings provide some evidence that higher maternal morning plasma cortisol causes lower birth weight. Identification of more independent genetic instruments for morning plasma cortisol are necessary to explore the potential bias identified.

Predicting measures of motor performance from multiple cortical spike trains.

Recordings have been obtained simultaneously from several, individually selected neurons in the motor cortex of unanesthetized monkey as the animal performed simple arm movements. With the use of comparatively simple quantitative procedures, the activity of small sets of cells was found to be adequate for rather accurate real-time prediction of the time course of various response measurements. In addition, the results suggest that hypotheses concerning the response variables "controlled" by cortical motor systems may well depend upon whether or not the temporal relations between simultaneously active neurons are taken into account.

Prognosis in human melanoma: PAR-1 expression is superior to other coagulation components and VEGF.

AIMS: Two hundred and four accessible cases of malignant melanoma from the Grampian region of Scotland, collected over a period of 4 years, with minimum follow-up of 2 years, were studied for coagulation factors and vascular endothelial growth factor (VEGF) expression as potential prognostic markers. The aim was to allow comparison with previous work using microvessel density on the same cases. METHODS AND RESULTS: Immunohistochemistry for VEGF, tissue factor (TF), fibrin and protease-activated thrombin receptor (PAR)-1 in 204 cases of melanoma was performed, and intensity of expression scored. Chalkley microvessel counts (MVD) were obtained for the tumour edge. TF expression and presence of fibrin correlated well with Breslow thickness and ulceration, reaching statistical significance, but surprisingly not for metastatic recurrence. Fibrin was variably present in over half the cases, located at the invasive edge, ulcerated surface and between tumour cell surfaces. In a few cases fibrin was within tumour cells, typically co-located with melanin and confirmed by electron microscopy. In contrast, immunohistochemistry for PAR-1 produced statistically significant results, correlating expression with Breslow thickness (P < or = 0.001), ulceration (P = 0.001) and recurrence (P < or = 0.005). Intensity of reactivity of VEGF correlated significantly with Breslow thickness, Clark level, ulceration and MVD, but not for metastatic recurrence. CONCLUSIONS: It appears paradoxical that VEGF expression is not more predictive of recurrence, but even low expression may be sufficient for tumour angiogenesis and other factors must govern tumour aggression. Antagonism of VEGF may still prove a successful adjunct in future therapeutic trials. Both MVD and PAR-1 can be used as adjuncts to Breslow thickness and ulceration as prognostic indicators for melanoma, as they appear to give independent information for all thicknesses. PAR-1 expression is the best antibody marker of recurrence risk from those studied. It remains to be seen whether this methodology can predict response to novel antiangiogenic therapies currently entering trial.

Excising basal cell carcinomas: comparing the performance of general practitioners, hospital skin specialists and other hospital specialists.

BACKGROUND: General practitioners (GPs) are not encouraged to excise basal cell carcinomas (BCCs). Despite this, as many of 10% of BCCs may be excised by GPs. GPs may be able to have a greater role in the diagnosis and management of BCC, but much needs to be learnt before this can be advocated. OBJECTIVE: To compare the practice of GPs, skin specialists (dermatologists and plastic surgeons) and other hospital specialists in excising BCCs. METHODS: A retrospective analysis of all BCCs excised in the Grampian region between 1 January and 31 December 2005 was carried out In total, 1087 reports were rated for source, quality of clinical information provided and extent of excision. RESULTS: GPs perform significantly less well than skin specialists when diagnosing and excising BCCs, but appear equal in diagnostic skill and better at excision than other hospital specialists. Non-specialized GPs appear to perform as well as GPs with special interest (GPwSI) in adequately excising BCCs. In 18.7% of all cases, the information supplied to the pathologist with the biopsy sample was inadequate to draw a conclusion. CONCLUSIONS: GPs compare unfavourably with skin specialists in diagnosing and excising BCCs. The performance of nonspecialized GPs does not appear to differ markedly from that of GPwSI. There is considerable room to optimize current GP performance, particularly with lesions of the head and neck, and it may be that novel approaches to GP training are required to achieve this. Structured request forms may improve the quality of clinical information provided when skin biopsies are submitted for pathological examination.

Maternal pattern of reproduction and risk of breast cancer in daughters: results from the Utah Population Database.

BACKGROUND: Several studies have found that daughters born to older mothers have an elevated risk of breast cancer, and an endocrine hypothesis, among others, has been developed to explain these findings. Three recent studies have failed to find a consistent maternal age effect, indicating a need for further exploration of this issue. PURPOSE: We used Utah breast cancer records linked to genealogical records to investigate maternal and paternal age and other maternal reproductive factors in relationship to the daughter's risk of breast cancer. METHODS: The study group consisted of 2414 breast cancer case patients and 9138 individually matched control subjects. Breast cancer diagnoses were ascertained through the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The case patients and control subjects were born between 1875 and the end of 1947, and the mean age at diagnosis of the case patients was 65.9 years. RESULTS: No consistent effect for maternal or paternal age was found, except possibly among women who were firstborn children (odds ratio [OR] = 1.42 for a 10-year differential in maternal age; 95% confidence interval [CI] = 1.00-2.00). Further examination of the data indicated that mothers of case patients experienced long intervals between marriage and their first birth but not between subsequent births, and they went on to have fewer children. For each year of delay between the mother's marriage and first birth, the odds of breast cancer in the daughter increased 1.05-fold (95% CI = 1.01-1.10). CONCLUSIONS: We found no evidence of a consistent maternal age effect with regard to breast cancer risk in the daughter, but we did find evidence that the mothers of women who go on to get breast cancer have a reproductive pattern that could suggest some form of underlying infertility. IMPLICATIONS: These findings widen the epidemiologic support for the fetal antigen hypothesis, which is an immunogenetic explanation for the relationships between reproductive factors and breast cancer risk. That hypothesis provides strategies for the identification of breast cancer genes and the eventual development of a breast cancer vaccine.

Hypertension, pregnancy, and risk of breast cancer.

We investigated the relationship between hypertension and breast cancer using data from a large case-control study of women younger than 55 years. Among nulliparous women, there was little evidence of an association between hypertension and breast cancer. Among parous women, hypertension reduced the risk of breast cancer if it had been diagnosed at any time in their lives before the end of the most recent pregnancy (odds ratio = 0.73; 95% confidence interval = 0.59-0.92). Several earlier studies indicate that there is an association between hypertension during pregnancy and elevated levels of maternal serum alpha-fetoprotein. Thus, our results are consistent with the hypothesis that maternal exposure to alpha-fetoprotein during pregnancy protects women against the subsequent occurrence of breast cancer.

Cancer risk among women exposed to exogenous estrogens during pregnancy.

A cohort of 3,139 obstetric patients, who delivered children between 1946 and 1965, was followed retrospectively to assess the relationship between exposure to diethylstilbestrol [(DES) CAS: 56-53-1; alpha, alpha'-diethyl-4,4'-stilbenediol] or other estrogenic substances during pregnancy and subsequent cancer incidence. Among the 1,531 women exposed to DES, the relative risk (RR) for all cancers was 1.46 [95% confidence interval (CI), 1.07-2.00]. The RR for cancers of the breast, cervix, and ovary were 1.37 (adjusted), 1.40, and 2.83, respectively, but none of these estimates was statistically significant. For breast cancer an RR in excess of 2.28 can be excluded, with 95% CI for doses averaging 2,100 mg. Within the exposed group there was no evidence for a dose-response relationship.

Breast cancer in men: aspects of familial aggregation.

Familial aggregation of breast cancer in males was investigated in a population-based case-control study. Cases were ascertained from 10 Surveillance, Epidemiology, and End Results Program registries in the United States between 1983 and 1986. Controls were identified by random-digit dialing and from lists of Medicare recipients. The relative odds of developing breast cancer were similar in men with affected paternal and maternal relatives and in men with affected mothers and sisters. The risk increased with the number of affected relatives. The relative odds of developing breast cancer were greater in men with first-degree relatives who developed their mammary neoplasm before the age of 45 than in men with older first-degree affected relatives; the enhancement of risk in men with an affected sister was greater in those under age 60 than in older men. These results are similar to those observed by others in studies of breast cancer in women.

A linkage analysis of D17S74 (CMM86) in thirty-five families with premenopausal bilateral breast cancer.

We report here results of a linkage analysis of a marker in 35 families in which the proband had premenopausal bilateral breast cancer. This group is of particular interest given their high family risk and the question of etiological heterogeneity. Probands were ascertained from cancer registries in Los Angeles County and Connecticut and major hospitals in Montréal and Québec. Assuming no residual heterogeneity and summing lod scores over all families, we obtained strong evidence against tight linkage (e.g., lod score at theta = 0.000001 is -3.39). To address the issue of heterogeneity, we performed admixture and predivided sample analyses. Using an admixture model we were able to reject the hypothesis of no linkage versus that of linkage with homogeneity (P = 0.045). However, we were unable to reject the hypothesis of no linkage versus linkage with heterogeneity (P = 0.119) or to distinguish between linkage with homogeneity and linkage with heterogeneity (P = 0.500). Predivided sample analyses based upon age of onset, pathological characteristics, time between diagnoses of the breast cancers in each bilateral proband, and the span of ages at diagnoses within a family did not discriminate between apparently linked and unlinked families.

Linkage analysis of DRD2, a marker linked to the ataxia-telangiectasia gene, in 64 families with premenopausal bilateral breast cancer.

Recent reports suggest that subjects who are heterozygous for the ataxia-telangiectasia gene are at increased risk of breast cancer. We conducted linkage analyses of 64 families with premenopausal bilateral breast cancer using DRD2, a marker linked to the ataxia-telangiectasia locus at 11q22-23. We assumed a model with dominant transmission of breast cancer. Lod scores summed over all families provided strong evidence against tight linkage (e.g., a lod score of -6.08 at theta = 0.00001), although a single family provides suggestive evidence of tight linkage to DRD2. Evidence against linkage to 11q was strongest among families that may involve the BRCA1 breast cancer susceptibility gene on 17q21. However, we did not observe evidence of linkage to 11q among the remaining subgroup with neither a family history of ovarian cancer nor the appearance of linkage to 17q21.

Depression and its treatment in a US urban community-1975-1976.

Data on the current prevalence of depression and its treatment derive from a longitudinal community survey conducted in 1975-1976 in New Haven, Conn. The results show the high prevalence of depression based on the Research Diagnostic Criteria. While persons with a depression use the psychiatric and general medical health care systems more frequently than those without a depression, the overall number of those who see a psychiatrist, receive a tricyclic antidepressant, or receive any treatment for their emotional problems from any source is low. Persons with a depression who do not receive treatment especially for their emotional problems make relatively frequent visits to nonpsychiatric physicians. Men and older persons who are depressed receive the least treatment.

An evaluation of the family history method for ascertaining psychiatric disorders.

This methodologic study assessed the accuracy of family history data in ascertaining psychiatric disorders in relatives. Comparison of diagnoses based on family history with diagnoses based on direct interview indicated that the specificity for the family history method is high, but that the sensitivity is generally low. Accuracy was better for affective disorders and alcoholism than for less severe disorders; spouses and offspring provided more accurate information than parents and siblings. The use of multiple information increased sensitivity somewhat, with little adverse effect on specificity. However, because errors were often correlated when more than one person provided information about a particular relative, the use of multiple informants generally did not improve accuracy substantially. Analysis of family-genetic studies should take account of the differential quality of data obtained by the family history method vs direct interview.

Symptom patterns in primary and secondary depression. A comparison of primary depressives with depressed opiate addicts, alcoholics, and schizophrenics.

The primary-secondary distinction in affective disorders has been proposed to reduce the heterogeneity of depression. An investigation of the frequency of secondary depression and its nature in depressed opiate addicts, alcoholics, and schizophrenics was undertaken. Findings show that secondary depression in ambulatory patients with other psychiatric disorders is relatively common. The sociodemographic characteristics of the secondary depressive are consistent with the population from which they derive but differ from primary depressives. The symptom patterns of secondary depressives are similar to primary depressives but are overall less severe. These findings give further support to the value of separating out secondary from primary depression in future research studies.

Sequential patterns of multiple-drug use among high school students.

Only recently have multiple-drug use studies involving more than heroin and marijuana begun to be reported in the literature. Four of these studies have found evidence that multiple-drug use is a progressive phenomenon, although the particular pattern of multiple-drug use reported in different populations varies somewhat. This study examines the patterns of multiple-drug use reported by a random sample of 1,094 high school students living in greater New Haven, Conn in the 1972-1973 academic school year. Scalogram analysis reveals a progressive relationship for nine drugs: alcohol, marijuana, hashish, barbiturates, amphetamines, LSD, mescaline, cocaine, and heroin. Cigarettes and glue were not found to play a part in this pattern. The temporal order in which respondents reported that they had begun using each drug supports the results of scalogram analysis only in part.

Screening for depression in a community sample. Understanding the discrepancies between depression symptom and diagnostic scales.

Discrepancies between the symptoms of depression, as found in a self-report questionnaire (Center for Epidemiologic Studies--Depression Scale [CED-D]), and the diagnosis of major depression as made by the Research Diagnostic Criteria (RDC) occurred in a community survey. The discrepancies can be explained by the subject's psychiatric or medical disorders other than depression, by nay saying during the interview, or by the exclusion criteria of the RDC (duration of symptoms, role impairment, or help seeking) that are not part of the CES-D. Results show that the discrepancies can be readily explained.

Best estimate of lifetime psychiatric diagnosis: a methodological study.

It is important for genetic, epidemiologic, and nosological studies to determine accurate rates of lifetime psychiatric diagnoses in patient and nonpatient populations. As part of a case-control family study of major depression, lifetime psychiatric diagnoses were made for 1,878 individuals. Sources of information used in making diagnostic estimates included direct interview, medical records, and family history data systematically obtained from relatives. Diagnostic estimates were made by trained interviewers, experienced clinicians, and by computer program. The results indicate that it is possible to make lifetime best estimate diagnoses reliably among both interviewed and noninterviewed individuals for most diagnostic categories and that diagnoses based on interview data alone are an adequate substitute for best estimate diagnoses based on all available information in a limited number of diagnostic categories.

Psychiatric disorders in the relatives of probands with affective disorders. The Yale University--National Institute of Mental Health Collaborative Study.

A family study of psychiatric disorders in 2,003 first-degree relatives of 335 probands found increased rates of bipolar I disorder and major depression (MD) in the relatives of probands with bipolar disorder and increased rates of MD in the relatives of probands with MD. There was a similarity in rates of affective disorders in the relatives of ambulatory and of hospitalized depressed probands (suggesting that ambulatory depressed patients may be as suitable as hospitalized ones for biological studies) and a comparability of rates of illness in relatives between centers for most disorders when comparable diagnostic criteria and procedures were used.

Different definitions of alcoholism, I: Impact of seven definitions on prevalence rates in a community survey.

The authors applied seven different sets of diagnostic criteria for alcoholism to data obtained by using the Schedule of Affective Disorders and Schizophrenia (SADS) in a community sample. They found that the different diagnostic schemes for alcoholism are hierarchical in the sense that some definitions identify smaller groups of subjects as alcoholic than do other definitions. This study illustrates a potentially useful empirical approach to comparing diagnostic criteria for psychiatric disorders in epidemiologic or clinical studies.

A population-based study of endometrial cancer and familial risk in younger women. Cancer and Steroid Hormone Study Group.

Endometrial cancer remains an important cause of morbidity and mortality in the United States, and recent genetic evidence supports the hypothesis that hormonal dysregulation is not the only important risk factor for this tumor. This multicenter, population-based case-control study investigated familial aggregation of endometrial cancer and other cancers. Cases were 455 women 20-54 years of age diagnosed with histologically confirmed primary epithelial carcinoma of the endometrium. Controls consisted of 3216 women 20-54 years of age identified by random-digit dialing. Family histories of cancer in female relatives were obtained by interview of cases and controls. Endometrial cancer in a first-degree female relative increased the risk of endometrial cancer by nearly 3-fold [odds ratio (OR), 2.8; 95% confidence interval (CI), 1.9-4.2]. Cases also reported significantly more colorectal cancer in family members than did controls (OR, 1.9; 95% CI, 1.1-3.3). Family history of cancer of the cervix, lung, ovary, and thyroid was not significantly associated with endometrial cancer, and breast cancer was not related unless more than one relative was affected. Family history of endometrial cancer is an independent risk factor for cancer of the endometrium. In addition, the observed association with a family history of colorectal cancer suggests that genes important in familial colorectal cancer may have substantial implications for endometrial cancer. Nearly 5% of incident endometrial cancer among women between the ages of 20 and 54 may be attributable to a family history of endometrial cancer, and 2% may be related to colorectal cancer.