Jennifer L. Marino

Melatonin receptors activate heteromeric G-protein coupled Kir3 channels.

The effects of melatonin on circadian pacemaker activity in the central nervous system may be the result of melatonin receptor activation of G-protein coupled potassium channels which inhibit the action potential firing of neurons. Xenopus laevis and human1a melatonin receptors stimulated heteromeric G-protein activated inwardly rectifying potassium channels (Kir3.1/Kir3.2) when expressed in vitro in oocytes. Pertussis toxin reduced iodo-melatonin (87.1% reduction) and melatonin (90.3% reduction) stimulated currents in a time-dependent manner for cells expressing X. laevis receptors. A similar pertussis toxin inhibition was observed for human melatonin receptors (melatonin, 78.9% reduction). This suggests a potential role for heteromeric Kir3 channels in the receptor-mediated actions of melatonin in vivo.

Perinatal Outcomes by Mode of Assisted Conception and Sub-Fertility in an Australian Data Linkage Cohort

Background Fertility treatment is associated with increased risk of major birth defects, which varies between in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI), and is significantly reduced by embryo freezing. We therefore examined a range of additional perinatal outcomes for these exposures. Methods All patients in South Australia receiving assisted conception between Jan 1986–Dec 2002 were linked to the state-wide perinatal collection (all births/stillbirths ≥20 weeks gestation or 400 g birth weight, n = 306 995). We examined stillbirth, mean birth weight, low birth weight (<2500 g, <1500 g), small size for gestational age (<10th percentile, <3rd percentile), large size for gestational age (>90th percentile), preterm birth (32–<37 weeks, <32 weeks gestation), postterm birth (≥41 weeks gestation), Apgar <7 at 5 minutes and neonatal death. Results Relative to spontaneous conceptions, singletons from assisted conception were more likely to be stillborn (OR = 1.82, 95% Confidence Interval (CI) 1.34–2.48), while survivors as a group were comprehensively disadvantaged at birth, including lower birth weight (−109 g, CI −129–−89), very low birth weight (OR = 2.74, CI 2.19–3.43), very preterm birth (OR = 2.30, CI 1.82–2.90) and neonatal death (OR = 2.04, CI 1.27–3.26). Outcomes varied by type of assisted conception. Very low and low birth weight, very preterm and preterm birth, and neonatal death were markedly more common in singleton births from IVF and to a lesser degree, in births from ICSI. Using frozen-embryos eliminated all significant adverse outcomes associated with ICSI but not with IVF. However, frozen-embryo cycles were also associated with increased risk of macrosomia for IVF and ICSI singletons (OR = 1.36, CI 1.02–1.82; OR = 1.55, CI 1.05–2.28). Infertility status without treatment was also associated with adverse outcomes. Conclusions Births after assisted conception show an extensive range of compromised outcomes that vary by treatment modality, that are substantially reduced after embryo freezing, but which co-occur with an increased risk of macrosomia.

Burden of Community-Onset Escherichia coli Bacteremia in Seniors

BACKGROUND Although Escherichia coli is a well-recognized cause of urinary tract infection in seniors, little is known about the burden of invasive E. coli infection in this population. METHODS We conducted a population-based cohort study of 46,238 noninstitutionalized Group Health Cooperative members>or=65 years of age to ascertain incidences of community-onset E. coli bacteremia and, for comparison, pneumococcal bacteremia, and we then performed a case-control study to identify risk factors for community-onset E. coli bacteremia. RESULTS The overall rate of community-onset E. coli bacteremia in the study cohort was 150 cases/100,000 person-years, which was approximately 3 times higher than the rate of pneumococcal bacteremia. In the case-control study, urinary catheterization and urinary incontinence were the only factors associated with an increased risk of E. coli bacteremia in men (62 cases), whereas cancer, renal failure, congestive heart failure, coronary artery disease, and urinary incontinence were associated with an increased risk of E. coli bacteremia in women (119 cases). CONCLUSIONS E. coli appears to be the leading cause of community-onset bacteremia in seniors, and, on the basis of these rates, we estimate that 53,476 cases occur in noninstitutionalized seniors each year in the United States. Community-onset E. coli bacteremia in seniors is, therefore, an infection of public health importance.

Shift work, hCLOCK T3111C polymorphism, and endometriosis risk

Background: Endometriosis, a dysplastic disease affecting approximately 5%–10% of US reproductive-age women, has been linked to exposures indicating high circulating estrogen levels. One such exposure may be night shift work, which has been associated with menstrual disruption and increased risk of 2 other estrogen-influenced diseases, breast cancer and adverse coronary events. Methods: In this population-based case-control study, cases were 235 women aged 18 to 49 years who were enrolled in a large health-maintenance organization in the state of Washington, and who were first diagnosed with surgically-confirmed endometriotic disease between April 1, 1996 and March 31, 2001. Controls were 545 randomly selected women enrolled in the same program who did not have a history of endometriosis. Study participants were asked about night shift work in all paid full-time or part-time jobs they had worked from age 18 to the reference date. Genotypes for T3111C hCLOCK were determined for a subset of 218 cases and 456 controls. Results: Any night shift work was associated with a 50% increase in risk of endometriosis (odds ratio = 1.48 [95% confidence interval = 0.96–2.29]), and working more than half of shifts on a job at night was associated with a nearly doubled disease risk (1.98 [1.01–3.85]). Changing sleep patterns on days off was associated with further increases in disease risk. T3111C hCLOCK polymorphism was unrelated to endometriosis status and did not modify the effect of shift work on endometriosis. Conclusions: These findings suggest that some aspects of night shift work may influence the development of endometriosis.

Nature and severity of menopausal symptoms and their impact on quality of life and sexual function in cancer survivors compared with women without a cancer history.

ObjectiveAfter cancer treatment, troublesome menopausal symptoms are common but poorly understood. Using standardized instruments, we measured differences in symptom nature, severity, impact on quality of life, and sexual function between cancer survivors and noncancer participants. MethodsThe Menopause Symptoms After Cancer Clinic operates within the general menopause service in a large women’s hospital, providing menopause advice and management to women with menopausal symptoms and a cancer history. Menopausal symptoms were recorded using the Greene Climacteric Scale, past-week symptoms were recorded using the Functional Assessment of Cancer Therapy breast cancer subscale and endocrine symptom subscale, and sexual symptoms were recorded using Fallowfield’s Sexual Activity Questionnaire. ResultsCancer survivors (n = 934) and noncancer participants (n = 155) did not significantly differ by age at menopause (46 y) or age at first clinic visit (51 y). Cancer survivors were more likely than noncancer participants to be severely troubled by vasomotor symptoms (hot flushes and night sweats; odds ratio, 1.71; 95% CI, 1.06-2.74) and reported more frequent (6.0 vs 3.1 in 24 h; P < 0.001) and more severe (P = 0.008) hot flushes. In contrast, cancer survivors were significantly less troubled by psychological and somatic symptoms and reported better quality of life than noncancer participants. Groups did not differ significantly in physical or functional well-being, gynecologic symptom severity, or sexual function. ConclusionsCancer survivors are more troubled by vasomotor symptoms than noncancer participants, but noncancer participants report greater psychological symptoms. Sexual function does not differ. An improved understanding of the nature and impact of menopause on cancer survivors can be used to direct management protocols.

Cloning and characterization of Kir3.1 (GIRK1) C-terminal alternative splice variants

Southern blot analysis of RT-PCR products from brain and heart revealed multiple products for a C-terminal region of Kir3.1. Sequencing yielded clones for wild-type Kir3.1 and three Kir3.1 C-terminal alternative splice variants, including a unique alternative exon. Two of these variants encoded truncated Kir3.1 molecules. Tissue distribution and electrophysiological characterization of a single truncated variant, Kir3.1(00) were then examined. Kir3.1 channels are gated by G-protein beta gamma-subunits binding to the C-terminal domain, thus, the truncation of Kir3.1(00) removes a major functional domain. When incorporated into heteromeric channels with other family members (Kir3.1, 3.2 or 3.4) several functional changes were observed: (1) Kir3.1(00) changes G-protein activation of Kir3 channels; (2) Kir3.1(00) is restricted in its ability to assemble with other channel subunits as heteromers; and (3) incorporation of Kir3.1(00) into heteromeric channel complexes alters the kinetics of channel re-activation.

Intergenerational associations of chronic disease and polycystic ovary syndrome.

Background Polycystic ovary syndrome (PCOS) is a common female endocrine disorder of heterogeneous clinical presentation, high disease burden, and unknown aetiology. The disease and associated conditions cluster in families, suggesting that PCOS may be the reproductive consequence of underlying chronic disease susceptibility. Objective To determine whether parents of young women with PCOS were more likely to have a history of diabetes or cardiovascular disease in later adult life. Design, Setting and Participants Structured interviews with 715 members of a cohort constructed by tracing female infants born at a single general hospital in Adelaide between 1973 and 1975. Participants were asked whether they had a pre-existing medical diagnosis of PCOS, and whether each parent had ever had high blood pressure, high cholesterol, diabetes, stroke, or heart disease. Maternal high blood pressure during pregnancy was taken from the medical record of the pregnancy with the study participant. Results and Conclusions Mothers of women with PCOS were more likely than mothers of other women to have any cardiovascular disease (RR 1.78, 95% CI 1.29, 2.47), and nearly twice as likely to have high blood pressure (RR 1.95, 95% CI 1.38, 2.76). Fathers of women with PCOS were more than twice as likely to have heart disease (RR 2.36, 95% CI 1.44, 3.88) and over four times as likely to have had a stroke (RR 4.37, 95% CI 1.97, 9.70). Occurrence of cardiovascular disease in both mother and father are associated with the risk of PCOS in daughters. Further detailed study is required to elucidate the precise pathways that may be causally related to the observations.

Fertility treatments and the young women who use them: an Australian cohort study

BACKGROUND In Australia, fertility treatment is partly or wholly reimbursable under federal benefits schemes, without restrictions on age, number of treatment cycles or existing family size. In this study, we aimed to characterize the potential need for and use of fertility treatments in a population-based cohort of young Australian women. METHODS We conducted structured interviews with 974 members of a cohort constructed by tracing all female infants born at a single general hospital in Adelaide between 1973 and 1975. The main outcome measures were pregnancy history, difficulty becoming pregnant and assistance sought to become pregnant. RESULTS Of 657 women aged 30-32 who had sought pregnancy, 24% reported difficulty becoming pregnant and 26% had lost at least one pregnancy. Ovulatory problems (16%) and male fertility problems (13%) were common among those with difficulty. Over half of the women who had difficulty conceiving (58%) sought assistance, largely from specialists (53%). Consultations, tests and education only were common (22%), as were IVF/ICSI (17%). Close to a third (28%) of those seeking assistance were treated only with clomiphene, as were two-thirds (67%) of women with ovulatory problems. CONCLUSIONS In this study, almost a quarter of women in their early 30s reported difficulty conceiving, and over a quarter reported pregnancy loss. This suggests that a significant proportion of young women experience substantial difficulties becoming pregnant. Our findings highlight the need to continue to document the range of womens reproductive experiences and to monitor fertility and treatment-seeking trends.

Fixed or Rotating Night Shift Work Undertaken by Women: Implications for Fertility and Miscarriage

This review summarizes the evidence concerning effects of night shift work on womens reproductive health, specifically difficulty in conceiving and miscarriage. We distinguish between fixed night shift and rotating night shift, as the population subgroups exposed, the social and biological mechanisms, and the magnitude of effects are likely to differ; of note, women working fixed night shift are known to have high tolerance for this schedule. We identified two relevant systematic reviews with meta-analyses and five additional studies. Night shift work may give rise to menstrual cycle disturbances, but effect sizes are imprecise. Endometriosis may be elevated in night shift workers, but evidence is only preliminary. Adequate data are lacking to assess associations between night shift work and infertility or time to pregnancy. The weight of evidence begins to point to working at night, whether in fixed or rotating shifts, as a risk factor for miscarriage. There are many methodological problems with this literature, with substantial variation in the definitions of night shift and schedule types making comparisons between studies difficult and pooling across studies questionable. Nevertheless, there appears to be grounds for caution and counselling where women have concerns about night shift work and their reproductive health.

Childhood Behavior Problems and Age at First Sexual Intercourse: A Prospective Birth Cohort Study

BACKGROUND AND OBJECTIVES: Early first sexual intercourse (FSI) is a risk factor for unplanned teenage pregnancy, sexually transmitted infection, and adverse social, emotional, and physical health outcomes in adolescence and into adulthood. The aim of this study was to examine relationships between internalizing (eg, anxious/depressed, withdrawn) and externalizing (eg, delinquent, aggressive) behavior problems in childhood and age at FSI. METHODS: We used a large, population-based birth cohort (The Western Australian Pregnancy Cohort [Raine] Study) to address this question. Child behavior was measured by using the Child Behavior Checklist collected from parents at ages 2, 5, 8, 10, and 14 and scores calculated for total, internalizing, and externalizing behavior problems. At age 17, 1200 participants reported sexual behavior. RESULTS: Participants with clinically significant Child Behavior Checklist scores (T ≥60) were at increased risk for earlier first sexual intercourse (FSI) (<16 years). Adjusted odds ratios revealed that total and externalizing behavior problems from age 5 years onward significantly increased the risk of earlier FSI for boys. In girls, externalizing problems from age 10 years increased the risk for earlier FSI. Internalizing problems at ages 8 and 10 were significantly associated with early FSI for boys but not girls. CONCLUSIONS: Externalizing behavior from as early as 5 in boys and 10 in girls is a significant risk factor for earlier age at FSI. Adolescent sexual health promotion should consider early intervention in children with behavior problems, particularly boys.