Prenatal stress and affective disorders in a population birth cohort.

OBJECTIVES: Pregnant women exposed to an acute traumatic event are thought to produce offspring with an increased incidence of affective disorders. It is not known whether there are specific times in pregnancy which confer increased vulnerability, or if psychosocial stress alone can increase the incidence of affective disorders in offspring. We examined the relationship of the timing of an acute psychosocial threat during pregnancy to the incidence of affective disorders in offspring using data from a large birth cohort. METHODS: Using data on 90079 offspring born in Jerusalem in 1964-1976 and linked to Israel's psychiatric registry, we constructed proportional hazards models to evaluate the link between gestational age during the Arab-Israeli war of June 1967 and incidence of mood disorders. RESULTS: Those in their first trimester of fetal development during the war were more likely to be admitted to hospitals for any mood disorders [relative risk (RR) = 3.01, 95% confidence interval (CI): 1.68-5.39, p = 0.0002]; for bipolar disorder the risk was doubled (RR = 2.44, 95% CI: 0.996-5.99, p = 0.054) and for all 'other' mood disorders the risk was tripled (RR = 3.61, 95% CI: 1.68-7.80, p = 0.001). Mood disorders were also increased in offspring whose mothers had been in the third month of pregnancy in June of 1967 (RR = 5.54, 95% CI: 2.73-11.24, p < 0.0001). CONCLUSIONS: A time-limited exposure to a severe threat during early gestation may be associated with an increased incidence of affective disorders in offspring. The third month of fetal development was a moment of special vulnerability.

Repetitive element DNA methylation levels in white blood cell DNA from sisters discordant for breast cancer from the New York site of the Breast Cancer Family Registry.

Global decreases in DNA methylation, particularly in repetitive elements, have been associated with genomic instability and human cancer. Emerging, though limited, data suggest that in white blood cell (WBC) DNA levels of methylation, overall or in repetitive elements, may be associated with cancer risk. We measured methylation levels of three repetitive elements [Satellite 2 (Sat2)], long interspersed nuclear element-1 (LINE-1) and Alu) by MethyLight, and LINE-1 by pyrosequencing in a total of 282 breast cancer cases and 347 unaffected sisters from the New York site of the Breast Cancer Family Registry (BCFR) using DNA from both granulocytes and total WBC. We found that methylation levels in all markers were correlated between sisters (Spearman correlation coefficients ranged from 0.17 to 0.55). Sat2 methylation was statistically significantly associated with increased breast cancer risk [odds ratio (OR) = 2.09, 95% confidence interval (CI) = 1.09-4.03; for each unit decrease in the natural log of the methylation level, OR = 2.12, 95% CI = 0.88-5.11 for the lowest quartile compared with the highest quartile]. These associations were only observed in total WBC but not granulocyte DNA. There was no association between breast cancer and LINE-1 and Alu methylation. If replicated in larger prospective studies, these findings support that selected markers of epigenetic changes measured in WBC, such as Sat2, may be potential biomarkers of breast cancer risk.

Older paternal age strongly increases the morbidity for schizophrenia in sisters of affected females.

The effect of a family history of schizophrenia on the risk for this disorder in the offspring has rarely been examined in a prospective population cohort accounting for the sex of the proband and the first-degree relatives, and certainly not with respect to later paternal age. The influence of affected relatives on offspring risk of schizophrenia was estimated using Cox proportional hazards regression in models that accounted for sex, relation of affected first degree relatives and paternal age in the prospective population-based cohort of the Jerusalem Perinatal Schizophrenia Study. Of all first-degree relatives, an affected mother conferred the highest risk to male and female offspring among the cases with paternal age <35 years, however, female offspring of fathers ≥35 years with an affected sister had the highest risk (RR = 8.8; 95% CI = 3.9-19.8). The risk seen between sisters of older fathers was fourfold greater than the risk to sisters of affected females of younger fathers (RR = 2.2, 95% CI 0.7-6.7). The test for interaction was significant (P = 0.03). By contrast, the risk of schizophrenia to brothers of affected males was only doubled between older (RR = 3.3, 95% 1.6-6.6) and younger fathers (RR = 1.6, 95% CI 0.7-3.5). The most striking finding from this study was the very large increase in risk of schizophrenia to sisters of affected females born to older fathers. The authors speculate that the hypothesized paternally expressed genes on the X chromosome might play some role in these observations.

Preeclampsia and subsequent risk of cancer: update from the Jerusalem Perinatal Study.

OBJECTIVE: The purpose of this study was to examine the association between preeclampsia and cancer incidence. STUDY DESIGN: The Jerusalem Perinatal Study is a population-based cohort of all births to 41,206 residents of Western Jerusalem from 1964-76. Cancer incidence to 2004 was assessed by linkage of the cohort with the Israel Cancer Registry. Cox's proportional hazards models were constructed to estimate the hazard ratio for cancer among women who had had preeclampsia. RESULTS: Preeclampsia was associated with a 1.23-fold increased risk of cancer at all sites, a 37% increased risk of breast cancer, and more than a doubling of ovarian cancer risk. Analysis by morphologic condition yielded significantly increased risks for malignancies that were classed as cystic mucinous and serous (relative risk, 1.96; 95% CI, 1.00-3.83) and for ductal, lobular, and medullary carcinomas (relative risk, 1.40; 95% CI, 1.07-1.83). No differential association was observed by sex of offspring. CONCLUSION: Our study suggests that the previously described protective effect of preeclampsia on cancer is not universal.

Incidence of schizophrenia among second-generation immigrants in the jerusalem perinatal cohort.

OBJECTIVE: Increased incidence of schizophrenia is observed among some immigrant groups in Europe, with the offspring of immigrants, ie "second-generation" immigrants particularly vulnerable. Few contemporary studies have evaluated the risk of schizophrenia among second-generation immigrants in other parts of the world. METHODS: We studied the incidence of schizophrenia in relation to parental immigrant status in a population-based cohort of 88 829 offspring born in Jerusalem in 1964-1976. Parental countries of birth were obtained from birth certificates and grouped together as (1) Israel, (2) Other West Asia, (3) North Africa, and (4) Europe and industrialized countries. Cox proportional hazards methods were used in adjusting for sex, parents' ages, maternal education, social class, and birth order. RESULTS: Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. Incidence of schizophrenia was not increased among second-generation immigrants in this birth cohort, neither overall nor by specific group. CONCLUSIONS: The difference in risk of schizophrenia among second-generation immigrants in Europe and in this Israeli birth cohort suggests that the nature of the immigration experience may be relevant to risk, including reasons for migration, the nature of entry, and subsequent position in the host country for immigrants and their offspring. Minority status may be of importance as, in later studies, immigrants to Israel from Ethiopia had increased risk of schizophrenia.

Effect of socioeconomic status and parents' education at birth on risk of schizophrenia in offspring.

Although it is known that schizophrenia is associated with social class, controversy exists as to the nature of this association. The authors studied the incidence of schizophrenia in relation to social class at birth in a population-based cohort of 88,829 offspring born in Jerusalem in 1964-1976. They constructed a six-point scale to index social class, based on paternal occupation at the time of birth, with each of 108 occupations being ranked by mean education. Cox proportional hazards methods were used in adjusting for sex, parents' ages, duration of marriage and birth order. Linkage with Israel's Psychiatric Registry identified 637 people admitted to psychiatric care facilities with schizophrenia-related diagnoses, before 1998. There was no gradient of risk for schizophrenia associated with social class at birth; however, offspring of fathers in the lowest social class showed a modest increase in risk (adjusted Relative Risk = 1.4; 95% Confidence interval = 1.1-1.8, P = 0.002). These data suggest that in contrast to many other health outcomes, there is not a continuous gradient for increasing schizophrenia with decreasing social class of origin. Instead, a modest increase in risk for schizophrenia was observed only for those born at the bottom of the social ladder.

Telomere length and early trauma in schizophrenia.

BACKGROUND: Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects. METHODS: The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR. OUTCOMES: Cases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91±0.74 and 1.83±0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher's R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males' cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma. INTERPRETATION: This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field.

Role of Nursing Competencies for Accelerating Clinical Trials in Stem Cell Clinics.

The California Institute for Regenerative Medicine has formed a group of clinics called the Alpha Stem Cell Clinics Network. Its goal is to accelerate clinical trials of stem cell-based therapies for diseases with unmet medical needs. In this report, we describe our experience in establishing an Alpha Stem Cell Clinic at City of Hope. Implementation and integration of the clinic into the existing institutional structures required collaboration and cooperation with clinical trial units, nursing administration, and creation of new positions. The highlight of this process and the centerpiece to our success has been the definition of the role of the "hybrid nurse," a person with nursing competencies in both clinical care and research. Stem Cells Translational Medicine 2018;7:6-10 Abstract Video Link: https://youtu.be/WOeZrNyXkGU.

Tetrachloroethylene exposure and risk of schizophrenia: offspring of dry cleaners in a population birth cohort, preliminary findings.

Tetrachloroethylene is a solvent used in dry cleaning with reported neurotoxic effects. Using proportional hazard methods, we examined the relationship between parental occupation as a dry cleaner and risk for schizophrenia in a prospective population-based cohort of 88,829 offspring born in Jerusalem from 1964 through 1976, followed from birth to age 21-33 years. Of 144 offspring whose parents were dry cleaners, 4 developed schizophrenia. We observed an increased incidence of schizophrenia in offspring of parents who were dry cleaners (RR=3.4, 95% CI, 1.3-9.2, p=0.01). Tetrachloroethylene exposure warrants further investigation as a risk factor for schizophrenia.

Prepregnancy body mass index, hypertensive disorders of pregnancy, and long-term maternal mortality.

OBJECTIVE: Recent studies have shown increased maternal mortality rates after hypertensive disorders of pregnancy (HDP), but the reasons for this increase remain unclear. This study examines the relationship between elevated prepregnancy body mass index (BMI), HDP, and postpregnancy mortality. STUDY DESIGN: Data came from a 1975-1976 subset (n = 13,722 women) of a population-based cohort. Multiple logistic regression was used to examine the risk of HDP by BMI; age-adjusted Cox proportional hazards models were used to examine survival rates. RESULTS: Overweight (BMI, 25-29.9 kg/m2) and obesity (BMI, > or = 30 kg/m2) were associated with increased HDP (odds ratio [OR], 2.82; 95% confidence interval [CI], 2.40-3.31 and OR, 5.51; 95% CI, 4.15-7.31]) and decreased survival (hazard ratio [HR], 1.42; 95% CI, 1.10-1.83 and HR, 2.43; 95% CI, 1.61-3.68), compared with normal weight (BMI, 18.5-24.9 kg/m2). HDP was significantly associated with increased mortality rates for women who survived > 15 years (HR, 1.94; 95% CI, 1.42-2.67]; HR adjusted for BMI, 1.65; 95% CI, 1.19-2.79]). A greater increase in risk of death after HDP was seen in the overweight women (HR, 1.86; 95% CI, 1.07-3.20) and obese women (HR, 2.90; 95% CI, 1.28-6.58), compared with normal weight women (HR, 1.26; 95% CI, 0.74-2.14). CONCLUSION: Elevated prepregnancy BMI is associated with increased risk of HDP, which are in turn is associated with increased long-term maternal mortality rates. This association between HDP and mortality rates increases with elevated prepregnancy BMI.