Prospective association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity.

BACKGROUND: Mitochondria are multifunctional energy-producing and signaling organelles that support life and contribute to stress adaptation. There is a growing understanding of the dynamic relationship between stress exposure and mitochondrial biology; however, the influence of stress on key domains of mitochondrial biology during early-life, particularly the earliest phases of intra-uterine/prenatal period remains largely unknown. Thus, the goal of this study was to examine the impact of fetal exposure to stress (modeled as the biological construct allostatic load) upon mitochondrial biology in early childhood. METHODS: In n = 30 children (range: 3.5-6 years, 53% male), we quantified mitochondrial content via citrate synthase (CS) activity and mtDNA copy number (mtDNAcn), and measured mitochondrial bioenergetic capacity via respiratory chain enzyme activities (complexes I (CI), II (CII), and IV (CIV)) in platelet-depleted peripheral blood mononuclear cells (PBMCs). In a cohort of healthy pregnant women, maternal allostatic load was operationalized as a latent variable (sum of z-scores) representing an aggregation of early-, mid- and late-gestation measures of neuroendocrine (cortisol), immune (interleukin-6, C-reactive protein), metabolic (homeostasis model assessment of insulin resistance, free fatty acids), and cardiovascular (aggregate systolic and diastolic blood pressure) systems, as well as an anthropometric indicator (pre-pregnancy body mass index [BMI]). RESULTS: An interquartile increase in maternal allostatic load during pregnancy was associated with higher mitochondrial content (24% and 15% higher CS and mtDNAcn), and a higher mitochondrial bioenergetic capacity (16%, 23%, and 25% higher CI, CII and CIV enzymatic activities) in child leukocytes. The positive association between maternal allostatic load during pregnancy and child mitochondrial content and bioenergetic capacity remained significant after accounting for the effects of key pre- and post-natal maternal and child covariates (p's < 0.05, except CI p = 0.073). CONCLUSION: We report evidence that prenatal biological stress exposure, modeled as allostatic load, was associated with elevated child mitochondrial content and bioenergetic capacity in early childhood. This higher mitochondrial content and bioenergetic capacity (per leukocyte) may reflect increased energetic demands at the immune or organism level, and thus contribute to wear-and-tear and pathophysiology, and/or programmed pro-inflammatory phenotypes. These findings provide potential mechanistic insight into the cellular processes underlying developmental programming, and support the potential role that changes in mitochondrial content and bioenergetic functional capacity may play in altering life-long susceptibility for health and disease.

Newborn insula gray matter volume is prospectively associated with early life adiposity gain.

BACKGROUND: The importance of energy homeostasis brain circuitry in the context of obesity is well established, however, the developmental ontogeny of this circuitry in humans is currently unknown. Here, we investigate the prospective association between newborn gray matter (GM) volume in the insula, a key brain region underlying energy homeostasis, and change in percent body fat accrual over the first six months of postnatal life, an outcome that represents among the most reliable infant predictors of childhood obesity risk. METHODS: A total of 52 infants (29 male, 23 female, gestational age at birth=39(1.5) weeks) were assessed using structural MRI shortly after birth (postnatal age at MRI scan=25.9(12.2) days), and serial Dual X-Ray Absorptiometry shortly after birth (postnatal age at DXA scan 1=24.6(11.4) days) and at six months of age (postnatal age at DXA scan 2=26.7(3.3) weeks). RESULTS: Insula GM volume was inversely associated with change in percent body fat from birth to six-months postnatal age and accounted for 19% of its variance (ß=-3.6%/S.D., P=0.001). This association was driven by the central-posterior portion of the insula, a region of particular importance for gustation and interoception. The direction of this effect is in concordance with observations in adults, and the results remained statistically significant after adjusting for relevant covariates and potential confounding variables. CONCLUSIONS: Altogether, these findings suggest an underlying neural basis of childhood obesity that precedes the influence of the postnatal environment. The identification of plausible brain-related biomarkers of childhood obesity risk that predate the influence of the postnatal obesogenic environment may contribute to an improved understanding of propensity for obesity, early identification of at-risk individuals, and intervention targets for primary prevention.

Influence of maternal thyroid hormones during gestation on fetal brain development.

Thyroid hormones (THs) play an obligatory role in many fundamental processes underlying brain development and maturation. The developing embryo/fetus is dependent on maternal supply of TH. The fetal thyroid gland does not commence TH synthesis until mid gestation, and the adverse consequences of severe maternal TH deficiency on offspring neurodevelopment are well established. Recent evidence suggests that even more moderate forms of maternal thyroid dysfunction, particularly during early gestation, may have a long-lasting influence on child cognitive development and risk of neurodevelopmental disorders. Moreover, these observed alterations appear to be largely irreversible after birth. It is, therefore, important to gain a better understanding of the role of maternal thyroid dysfunction on offspring neurodevelopment in terms of the nature, magnitude, time-specificity, and context-specificity of its effects. With respect to the issue of context specificity, it is possible that maternal stress and stress-related biological processes during pregnancy may modulate maternal thyroid function. The possibility of an interaction between the thyroid and stress systems in the context of fetal brain development has, however, not been addressed to date. We begin this review with a brief overview of TH biology during pregnancy and a summary of the literature on its effect on the developing brain. Next, we consider and discuss whether and how processes related to maternal stress and stress biology may interact with and modify the effects of maternal thyroid function on offspring brain development. We synthesize several research areas and identify important knowledge gaps that may warrant further study. The scientific and public health relevance of this review relates to achieving a better understanding of the timing, mechanisms and contexts of thyroid programing of brain development, with implications for early identification of risk, primary prevention and intervention.

Association of maternal prepregnancy BMI with metabolomic profile across gestation.

BACKGROUND/OBJECTIVES: Elevated prepregnancy body mass index (pBMI) and excess gestational weight gain (GWG) constitute important prenatal exposures that may program adiposity and disease risk in offspring. The objective of this study is to investigate the influence of pBMI and GWG on the maternal metabolomic profile across pregnancy, and to identify associations with birth weight. SUBJECTS/METHODS: This is a longitudinal prospective study of 167 nondiabetic women carrying a singleton pregnancy. Women were recruited between March 2011 and December 2013 from antenatal clinics affiliated to the University of California, Irvine, Medical Center. Seven women were excluded from analyses because of a diagnosis of diabetes during pregnancy. A total of 254 plasma metabolites known to be related to obesity in nonpregnant populations were analyzed in each trimester using targeted metabolomics. The effects of pBMI and GWG on metabolites were tested through linear regression and principle component analysis, adjusting for maternal sociodemographic factors, diet, and insulin resistance. A Bonferroni correction was applied for multiple comparison testing. RESULTS: pBMI was significantly associated with 40 metabolites. Nonesterified fatty acids (NEFA) showed a strong positive association with pBMI, with specificity for mono-unsaturated and omega-6 NEFA. Among phospholipids, sphingomyelins with two double bonds and phosphatidylcholines containing 20:3 fatty acid chain, indicative of omega-6 NEFA, were positively associated with pBMI. Few associations between GWG, quality and quantity of the diet, insulin resistance and the maternal metabolome throughout gestation were detected. NEFA levels in the first and, to a lesser degree, in the second trimester were positively associated with birth weight percentiles. CONCLUSIONS: Preconception obesity appears to have a stronger influence on the maternal metabolic milieu than gestational factors such as weight gain, dietary intake and insulin resistance, highlighting the critical importance of preconception health. NEFA in general, as well as monounsaturated and omega-6 fatty acid species in particular, represent key metabolites for a potential mechanism of intergenerational transfer of obesity risk.

Association of ultrasound-based measures of fetal body composition with newborn adiposity.

BACKGROUND: Newborns exhibit substantial variation in gestational age-adjusted and sex-adjusted fat mass proportion. The antecedent characteristics of fetal body composition that are associated with newborn fat mass proportion are poorly understood. OBJECTIVE: The aim of this study was to determine whether a composite measure of fetal fat mass is prospectively associated with newborn adiposity. METHODS: In a longitudinal study of 109 low-risk pregnancies, fetal ultrasonography was performed at approximately 12, 20 and 30 weeks gestation. Estimated fetal adiposity (EFA) was derived by integrating cross-sectional arm and thigh per cent fat area and anterior abdominal wall thickness. Newborn per cent body fat was quantified by Dual Energy X-Ray Absorptiometry. The association between EFA and newborn per cent body fat was determined by multiple linear regression. RESULTS: After controlling for confounding factors, EFA at 30 weeks was significantly associated with newborn per cent body fat (standardized ß = 0.41, p < 0.001) and explained 24.0% of its variance, which was substantially higher than that explained by estimated fetal weight (8.1%). The observed effect was driven primarily by arm per cent fat area. CONCLUSIONS: A composite measure of fetal adiposity at 30 weeks gestation may constitute a better predictor of newborn per cent body fat than estimated fetal weight by conventional fetal biometry. Fetal arm fat deposition may represent an early indicator of newborn adiposity. After replication, these findings may provide a basis for an improved understanding of the ontogeny of fetal fat deposition, thereby contributing to a better understanding of its intrauterine determinants and the development of potential interventions.

Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

Abnormal radiological features in a multiple myeloma patient: a case report and radiological review of myelomas.

Multiple myeloma is the prototype of malignant monoclonal gammopathies. The most common skeletal sites are pelvis, skull, spine, ribs and femoral and humeral shafts. The classic radiographic presentation of multiple myeloma is lytic skeletal lesions. Other types of presentation include sclerotic and porotic changes. Primary sclerotic manifestations are rare and occur in only 3% of cases. Although exceptional, multiple myeloma must be borne in mind in the presence of bone sclerosis. This report presents a patient with multiple myeloma with a sunburst/hair-on-end pattern on the radiograph and sclerotic skeletal lesions.

Time-dependent effect of non-Hodgkin's lymphoma grade on disease-free survival of relapsed/refractory patients treated with high-dose chemotherapy plus autotransplantation.

Evaluation of time to event outcomes usually is examined by the Kaplan-Meier method and Cox proportional hazards models. We developed a modified statistical model based on histologic grade and other variables to describe the time-dependent outcome for autologous stem cell transplant (autotransplant) performed for non-Hodgkin's lymphoma (NHL) based on histologic grade and other variables. One hundred and fourteen relapsed or refractory NHL patients were treated using BCNU 600 mg/m2, etoposide 2400 mg/m2, and cisplatin 200 mg/m2 IV followed by autotransplant. Median age was 53.5 (range: 25-70) years, 78 patients had aggressive NHL and 36 indolent NHL. Seventy-five patients received involved-field radiotherapy just prior to transplant. At a median follow-up of 33 (range: 3 to 118) months, the estimated 5-year Kaplan-Meier probabilities of overall survival and disease-free survival were 61% and 51%, respectively. Cox proportional hazards model analysis showed that proportionality did not hold for lymphoma grade, indicating that the relationship between the grade and disease-free survival differed over time. By piece-wise Cox model, the relative risk for experiencing relapse or death after 1 year in patients with indolent compared with patients with aggressive NHL was 2.81 (p=0.019) with 95% confidence interval (1.19, 6.65). The time-dependent effect of lymphoma grade on disease-free survival suggests the need for early (within first year) incorporation of novel therapeutic approaches in management of patients with indolent NHL undergoing autotransplant.

Laparoscopic versus open radical nephrectomy for large renal tumors: a long-term prospective comparison.

PURPOSE: The role of laparoscopy in the management of large renal tumors (more than 7 cm) is not clearly established. We prospectively evaluated the feasibility, safety and long-term results of laparoscopic radical nephrectomy for large renal tumors (T2N0M0) and compared the results with those of open radical nephrectomy. MATERIALS AND METHODS: Between 1998 and 2006, 112 patients with clinical stage T2N0M0 renal carcinoma underwent radical nephrectomy at our institution. Clinical data were prospectively collected after categorizing the patients into group 1-41 with laparoscopy and group 2-71 with open surgery. The choice of procedure was nonrandomized and it depended on patient and surgeon preference and experience. RESULTS: The 2 groups were contemporary and comparable in terms of age, body mass index and mean tumor size (9.9 and 10.1 cm, respectively). Concomitant adrenalectomy was performed in 14 patients (34%) in group 1 and in 29 (41%) in group 2. Limited (hilar) lymphadenectomy was performed in 30 patients (73%) in group 1 and in 58 (81%) in group 2. Group 1 patients experienced significantly less blood loss, and had a decreased analgesic requirement, shorter hospital stay and more rapid convalescence, although they required longer operative time (180.8 vs 165.3 minutes, p=0.029). The 2 groups were followed for a similar period (mean 51.4 vs 57.2 months) and there was no difference in 5-year survival data. There were no local or port site recurrences. CONCLUSIONS: Laparoscopic radical nephrectomy for clinical stage T2 renal tumors is effective with the advantages of less blood loss, shorter hospital stay, decreased analgesic requirement and rapid recovery compared with open radical nephrectomy. Long-term results are also similar in the 2 groups of patients. Laparoscopic radical nephrectomy for large tumors is a technically difficult, challenging procedure and it should be attempted by surgeons with significant experience.

Primary transitional cell carcinoma of the prostate presenting as a rectal ulcer.

Primary transitional cell carcinoma of the prostate is a rare clinicopathological entity. It is an aggressive tumor with a poor prognosis. Presentation is usually late, with obstructive voiding complaints. Radical surgery offers locoregional control of the disease. We report a case with an atypical presentation of bleeding per rectum and associated obstructive voiding symptoms. Examination revealed a rectal ulcer overlying an enlarged prostate and fixed to it. Histopathology showed a picture of transitional cell carcinoma of the prostate infiltrating the rectum. Imaging studies revealed an enlarged prostate with altered echo pattern with locoregional spread, infiltrating the rectum. Bladder involvement and distant metastases were not evident. External beam radiotherapy achieved good local control. At 3 months of follow-up, the patient was free of urinary symptoms and his rectal ulcer had healed. The patient declined subsequent treatment.

Should involved-field radiation therapy be used as an adjunct to lymphoma autotransplantation?

Relapse at sites of prior disease involvement accounts for the majority of treatment failures following high-dose therapy and autologous transplantation for both Hodgkin's disease and non-Hodgkin's lymphoma. Several studies have demonstrated the utility of 'involved-field' radiation as a treatment modality in this setting to minimize disease bulk prior to transplants, to reduce relapse rates at sites of prior disease involvement and to improve local control for disease resistant to high-dose therapy. Other studies recommend caution due to potential toxicities including radiation-induced pneumonitis and secondary myelodysplasia. Further investigations are needed to better define the optimal extent, dose and timing of radiation in the setting of transplantation, as well as to identify those subsets of patients likely to be at a higher risk of radiation-induced morbidity.

The neurobiology of stress in human pregnancy: implications for prematurity and development of the fetal central nervous system.

Adverse early experience, including prenatal maternal psychosocial stress, has the potential to negatively influence developmental processes through both physiological and behavioral mechanisms. This in turn may have adverse consequences for the mental and physical health, well-being and aging of the individual throughout the entire life-span. We have initiated a program of research on humans to examine the consequences of maternal stress and related factors in pregnancy on the length of gestation, fetal growth, and brain development. We have also investigated the physiological mechanisms that are involved. In this chapter we outline the theoretical rationale for this work and give an overview of our findings to date. These findings support a significant and independent role for behavioral processes such as maternal prenatal stress in the etiology of prematurity-related outcomes, and suggest that these effects are mediated, in part, by the maternal-placental-fetal neuroendocrine axis; specifically by placental corticotropin-releasing hormone. Using a fetal challenge paradigm as a novel method for quantifying fetal neurologic maturity in utero, we have found that the maternal environment exerts a significant influence on the fetal autonomic nervous system and on central nervous system processes related to recognition, memory and habituation. Finally, our findings provide preliminary evidence to support the notion that the influence of prenatal stress and maternal-placental hormones on the developing fetus may persist after birth, as assessed by measures of temperament and behavioral reactivity in the first 3 years of postnatal life. The implications of these studies for life-span development and health are discussed.

Stress and preterm birth: neuroendocrine, immune/inflammatory, and vascular mechanisms.

A growing literature suggests that maternal psychological and social stress is a significant and independent risk factor for a range of adverse reproductive outcomes including preterm birth. Several issues remain to be addressed about stress and vulnerability to stress during pregnancy. Of these, perhaps one of the most important questions relates to biologic plausibility. Parturition, the process that results in birth, is a biological phenomenon. Very little empirical research to date, however, has examined the role of biological processes, if any, as mediators of the relationship between stress and preterm birth. In this paper we discuss the maternal, placental, and fetal neuroendocrine, immune/inflammatory, and vascular processes that may bridge the experience of social adversity before and during pregnancy and the biological outcome of preterm birth.

Maternal stress is associated with bacterial vaginosis in human pregnancy.

OBJECTIVES: Maternal infection, particularly bacterial vaginosis (BV) in pregnancy, is one of the leading causes of adverse perinatal outcomes. The determinants of individual differences in susceptibility, or vulnerability, to maternal infections are poorly understood. This study examines whether chronic maternal stress predisposes women to infection during pregnancy, and if so, whether the effects of chronic stress on infection are independent of other established risk factors. METHODS: We conducted a cross-sectional, clinical prevalence study of chronic maternal stress and BV status in a sample of 454 pregnant women at 14.3+/-0.3 weeks gestation (+/-SEM). BV was diagnosed by Gram-stain of vaginal fluid samples; chronic maternal stress was assessed using the Cohen Perceived Stress Scale. Other established risk factors for BV, including maternal age, race/ethnicity, marital status, SES, and behaviors related to feminine hygiene, sexual practices, and substance use, were measured using a structured interview. RESULTS: Of the 454 women enrolled in this study, 224 (49%) were BV positive (Nugent score 7-10), 64 (14%) had intermediate vaginal flora (Nugent score 4-6), and 166 (37%) were BV negative (Nugent score 0-3). BV+ women had significantly higher chronic stress levels than BV- women (24.6+/-0.5 vs. 22.2+/-0.6 units (+/-SEM), respectively; t = 3.19; p < .01). Maternal sociodemographic variables (African-American race/ethnicity) and behavioral characteristics (vaginal douching, number of lifetime sexual partners, and use of illicit drugs) also were significantly associated with the presence of BV. After controlling for the effects of these variables, using a multivariable logistic regression model, chronic maternal stress remained a significant and independent predictor of BV status. Women in the moderate-stress group (third quartile) and high-stress (fourth quartile) group were 2.3 times (95% CI = 1.2-4.3) and 2.2 times (95% CI = 1.1-4.2) more likely to be BV+ than women in the low-stress group (bottom quartile). CONCLUSIONS: High levels of chronic stress during pregnancy are associated with bacterial vaginosis. The effect of chronic maternal stress is independent of the effects of other established sociodemographic and behavioral risk factors for BV.

Stress, infection and preterm birth: a biobehavioural perspective.

Preterm birth is currently the most important problem in maternal-child health in the United States. Epidemiological studies have suggested that two factors, maternal stress and maternal urogenital tract infection, are significantly and independently associated with an increased risk of spontaneous preterm birth. These factors are also more prevalent in the population of sociodemographically disadvantaged women who are at increased risk for preterm birth. Studies of the physiology of parturition suggest that neuroendocrine and immune processes play important roles in the physiology and pathophysiology of normal and preterm parturition. However, not all women with high levels of stress and/or infection deliver preterm, and little is understood about factors that modulate susceptibility to pathophysiological events of the endocrine and immune systems in pregnancy. We present here a comprehensive, biobehavioural model of maternal stress and spontaneous preterm delivery. According to this model, chronic maternal stress is a significant and independent risk factor for preterm birth. The effects of maternal stress on preterm birth may be mediated through biological and/or behavioural mechanisms. We propose that maternal stress may act via one or both of two physiological pathways: (a) a neuroendocrine pathway, wherein maternal stress may ultimately result in premature and/or greater degree of activation of the maternal-placental-fetal endocrine systems that promote parturition; and (b) an immune/inflammatory pathway, wherein maternal stress may modulate characteristics of systemic and local (placental-decidual) immunity to increase susceptibility to intrauterine and fetal infectious-inflammatory processes and thereby promote parturition through pro-inflammatory mechanisms. We suggest that placental corticotropin-releasing hormone may play a key role in orchestrating the effects of endocrine and inflammatory/immune processes on preterm birth. Moreover, because neuroendocrine and immune processes extensively cross-regulate one another, we further posit that exposure to both high levels of chronic stress and infectious pathogens in pregnancy may produce an interaction and multiplicative effect in terms of their combined risk for preterm birth. Finally, we hypothesise that the effects of maternal stress are modulated by the nature, duration and timing of occurrence of stress during gestation. A discussion of the components of this model, including a theoretical rationale and review of the available empirical evidence, is presented. A major strength of this biobehavioural perspective is the ability to explore new questions and to do so in a manner that is more comprehensive than has been previously attempted. We expect findings from this line of proposed research to improve our present state of knowledge about obstetric risk assessment for preterm birth by determining the characteristics of pregnant women who are especially susceptible to stress and/or infection, and to broaden our understanding of biological (endocrine, immune, and endocrine-immune interactions) mechanisms that may translate social adversity during pregnancy into pathophysiology, thereby suggesting intervention strategies.

When stress happens matters: effects of earthquake timing on stress responsivity in pregnancy.

OBJECTIVE: The purpose of the study was to assess the effects of the timing of stress during pregnancy on emotional responses and birth outcome. We hypothesized that as pregnancy advanced women would become increasingly resistant to the adverse effects of stress, and so early stress would have more profound effects than later stress. STUDY DESIGN: Forty pregnant women who had experienced an earthquake during pregnancy or shortly afterward were identified. Using regression analyses we determined whether the timing of the earthquake was related to an affective response to this event and to length of gestation. RESULTS: The earthquake was rated as more stressful when it occurred early in pregnancy compared with late in pregnancy, and postpartum ratings were similar to first-trimester ratings (r (quad) =.39; P <.05). Stress experienced early in pregnancy was associated with shorter gestational length (r =.35; P <.05). CONCLUSIONS: As pregnancy advances, women become decreasingly sensitive to the effects of stress. This decrease in vulnerability may reflect increasing protection of the mother and fetus from adverse influences during pregnancy.

Stress and reproduction: introduction to the special section.

This special section on stress and reproduction is devoted to an emerging frontier in interdisciplinary research that merits the attention of health psychologists. The majority of the studies concern the role of stress and emotion on birth outcomes such as low birth weight, fetal growth and preterm delivery, or mechanisms underlying these findings. The implications of this research extend from maternal and infant health to life-span development and adult health and mortality.

Maternal social support predicts birth weight and fetal growth in human pregnancy.

OBJECTIVE: Low birth weight is a primary cause of infant mortality and morbidity. Results of previous studies suggest that social support may be related to higher birth weight through fetal growth processes, although the findings have been inconsistent. The purpose of this investigation was to test a model of the association between a latent prenatal social support factor and fetal growth while taking into account relations between sociodemographic and obstetric risk factors and birth weight. METHOD: A prospective study was conducted among 247 women with a singleton, intrauterine pregnancy receiving care in two university-affiliated prenatal clinics. Measures of support included support from family, support from the baby's father, and general functional support. Sociodemographic characteristics were also assessed. Birth outcome and obstetric risk information were abstracted from patients' medical charts after delivery. RESULTS: Structural equation modeling analyses showed that a latent social support factor significantly predicted fetal growth (birth weight adjusted for length of gestation) with infant sex, obstetric risk, and ethnicity in the model. Marital status and education were indirectly related to fetal growth through social support. The final model with social support and other variables accounted for 31% of the variance in fetal growth. CONCLUSIONS: These findings suggest that prenatal social support is associated with infant birth weight through processes involving fetal growth rather than those involving timing of delivery. Biological and behavioral factors may contribute to the association between support and fetal growth, although these mechanisms need to be further explored. These results pave the way for additional research on fetal growth mechanisms and provide a basis for support intervention research.