Maternal pregnancy weight gain and cord blood iron status are associated with eosinophilia in infancy.

OBJECTIVE: Allergic disease is multifactorial in origin. Because iron nutrition affects immune responses and maternal pregnancy weight gain impairs fetal iron delivery while increasing fetal demands for growth, the study examined maternal pregnancy weight gain, newborn iron status and an index of atopic disease, infant eosinophilia. STUDY DESIGN: Within a larger prospective study of healthy newborns at risk for developing iron deficiency anemia, umbilical cord iron indicators were compared to infant eosinophil counts. RESULT: Infants who developed eosinophilia exhibited higher cord reticulocyte-enriched zinc protoporphyrin/heme ratio, P<0.05 and fewer cord ferritin values in the highest (best) quartile, P<0.05. If cord ferritin was in the upper three quartiles, the negative predictive value for infant eosinophilia was 90%. High maternal pregnancy weight gain predicted infant eosinophil counts, P<0.04, and contributed to cord ferritin predicting eosinophilia, P<0.003. CONCLUSION: Poor fetal iron status may be an additional risk factor for infant eosinophilia.

Sleep quality following hematopoietic stem cell transplantation: longitudinal trajectories and biobehavioral correlates.

The present study examined changes in sleep quality following hematopoietic stem cell transplantation (HSCT) and investigated associations with biobehavioral factors. Individuals undergoing HSCT for hematologic malignancies (N=228) completed measures of sleep quality and psychological symptoms pre-transplant and 1, 3, 6 and 12 months post transplant. Circulating inflammatory cytokines (IL-6, TNF-α) were also assessed. Sleep quality was poorest at 1 month post transplant, improving and remaining relatively stable after 3 months post transplant. However, approximately half of participants continued to experience significant sleep disturbance at 6 and 12 months post transplant. Mixed-effects linear regression models indicated that depression and anxiety were associated with poorer sleep quality, while psychological well-being was associated with better sleep. Higher circulating levels of IL-6 were also linked with poorer sleep. Subject-level fixed effects models demonstrated that among individual participants, changes in depression, anxiety and psychological well-being were associated with corresponding changes in sleep after covarying for the effects of time since transplant. Sleep disturbance was most severe when depression and anxiety were greatest and psychological well-being was lowest. Findings indicate that sleep disturbance is a persistent problem during the year following HSCT. Patients experiencing depression or anxiety and those with elevated inflammation may be at particular risk for poor sleep.

Neonatal iron status is impaired by maternal obesity and excessive weight gain during pregnancy.

OBJECTIVE: Maternal iron needs increase sixfold during pregnancy, but obesity interferes with iron absorption. We hypothesized that maternal obesity impairs fetal iron status. STUDY DESIGN: Three hundred and sixteen newborns with risk factors for infantile iron deficiency anemia (IDA) were studied to examine obesity during pregnancy and neonatal iron status. Erythrocyte iron was assessed by cord blood hemoglobin (Hb), zinc protoporphyrin/heme (ZnPP/H) and reticulocyte-ZnPP/H, and storage iron by serum ferritin. RESULT: Women with body mass index (BMI) ⩾ 30 kg m(-)(2), as compared with non-obese women, delivered larger offspring with higher reticulocyte-ZnPP/H and lower serum ferritin concentrations (P<0.05 for both). With increasing BMI, the estimated body iron was relatively lower (mg kg(-)(1)) and the ratio of total Hb-bound iron (mg) per total body iron (mg) increased. Maternal diabetes compromised infant iron status, but multivariate analysis demonstrated that obesity was an independent predictor. CONCLUSION: Obesity during pregnancy and excessive weight gain are independent risk factors for iron deficiency in the newborn.

Interleukin-8 and interleukin-10, brain volume and microstructure, and the influence of calorie restriction in old rhesus macaques.

Higher systemic levels of the proinflammatory cytokine interleukin-6 (IL-6) were found to be associated with lower gray matter volume and tissue density in old rhesus macaques. This association between IL-6, and these brain indices were attenuated by long-term 30 % calorie restriction (CR). To extend these findings, the current analysis determined if a CR diet in 27 aged rhesus monkeys compared to 17 normally fed controls reduced circulating levels of another proinflammatory cytokine, interleukin-8 (IL-8), and raised levels of anti-inflammatory interleukin-10 (IL-10). Further, these cytokines were regressed onto imaged brain volume and microstructure using voxel-wise regression analyses. CR significantly lowered IL-8 and raised IL-10 levels. Across the two dietary conditions, higher IL-8 predicted smaller gray matter volumes in bilateral hippocampus. Higher IL-10 was associated with more white matter volume in visual areas and tracts. Consuming a CR diet reduced the association between systemic IL-8 and hippocampal volumes. Conversely, CR strengthened associations between IL-10 and microstructural tissue density in the prefrontal cortex and other areas, particularly in a region of dorsal prefrontal cortex, which concurred with our prior findings for IL-6. Consumption of a CR diet lowered proinflammatory and increased anti-inflammatory cytokine concentrations, which lessened the statistical association between systemic inflammation and the age-related alterations in important brain regions, including the hippocampus.

Inflammatory vulnerability associated with the rh5-HTTLPR genotype in juvenile rhesus monkeys.

Individual variation in serotonergic function is associated with reactivity, risk for affective disorders, as well as an altered response to disease. Our study used a nonhuman primate model to further investigate whether a functional polymorphism in the promoter region for the serotonin transporter gene helps to explain differences in proinflammatory responses. Homology between the human and rhesus monkey polymorphisms provided the opportunity to determine how this genetic variation influences the relationship between a psychosocial stressor and immune responsiveness. Leukocyte numbers in blood and interleukin-6 (IL-6) responses are sensitive to stressful challenges and are indicative of immune status. The neutrophil-to-lymphocyte ratio and cellular IL-6 responses to in vitro lipopolysaccharide stimulation were assessed in 27 juvenile male rhesus monkeys while housed in stable social groups (NLL = 16, NS = 11) and also in 18 animals after relocation to novel housing (NLL = 13, NS = 5). Short allele monkeys had significantly higher neutrophil-to-lymphocyte ratios than homozygous Long allele carriers at baseline [t(25) = 2.18, P = 0.02], indicative of an aroused state even in the absence of disturbance. In addition, following the housing manipulation, IL-6 responses were more inhibited in short allele carriers (F1,16 = 8.59, P = 0.01). The findings confirm that the serotonin transporter gene-linked polymorphism is a distinctive marker of reactivity and inflammatory bias, perhaps in a more consistent manner in monkeys than found in many human studies.

Effects of aging and calorie restriction on white matter in rhesus macaques.

Rhesus macaques on a calorie restricted diet (CR) develop less age-related disease, have virtually no indication of diabetes, are protected against sarcopenia, and potentially live longer. Beneficial effects of caloric restriction likely include reductions in age-related inflammation and oxidative damage. Oligodendrocytes are particularly susceptible to inflammation and oxidative stress, therefore, we hypothesized that CR would have a beneficial effect on brain white matter and would attenuate age-related decline in this tissue. CR monkeys and controls underwent diffusion tensor imaging (DTI). A beneficial effect of CR indexed by DTI was observed in superior longitudinal fasciculus, fronto-occipital fasciculus, external capsule, and brainstem. Aging effects were observed in several regions, although CR appeared to attenuate age-related alterations in superior longitudinal fasciculus, frontal white matter, external capsule, right parahippocampal white matter, and dorsal occipital bundle. The results, however, were regionally specific and also suggested that CR is not salutary across all white matter. Further evaluation of this unique cohort of elderly primates to mortality will shed light on the ultimate benefits of an adult-onset, moderate CR diet for deferring brain aging.

Age-related changes in neural volume and microstructure associated with interleukin-6 are ameliorated by a calorie-restricted diet in old rhesus monkeys.

Systemic levels of proinflammatory cytokines such as interleukin-6 (IL-6) increase in old age and may contribute to neural atrophy in humans. We investigated IL-6 associations with age in T1-weighted segments and microstructural diffusion indices using MRI in aged rhesus monkeys (Macaca mulatta). Further, we determined if long-term 30% calorie restriction (CR) reduced IL-6 and attenuated its association with lower tissue volume and density. Voxel-based morphometry (VBM) and diffusion-weighted voxelwise analyses were conducted. IL-6 was associated with less global gray and white matter (GM and WM), as well as smaller parietal and temporal GM volumes. Lower fractional anisotropy (FA) was associated with higher IL-6 levels along the corpus callosum and various cortical and subcortical tracts. Higher IL-6 concentrations across subjects were also associated with increased mean diffusivity (MD) throughout many brain regions, particularly in corpus callosum, cingulum, and parietal, frontal, and prefrontal areas. CR monkeys had significantly lower IL-6 and less associated atrophy. An IL-6xCR interaction across modalities also indicated that CR mitigated IL-6 related changes in several brain regions compared to controls. Peripheral IL-6 levels were correlated with atrophy in regions sensitive to aging, and this relationship was decreased by CR.

Disruptions of social relationships accentuate the association between emotional distress and menstrual pain in young women.

This study examined the effects of social support on dysmenorrhea and whether social support moderates the relationship between negative emotions and painful symptoms. Women (N = 184) completed questionnaires on menstrual symptoms, depression, anxiety, and social networks. Depression and anxiety were strongly associated with menstrual pain. Women who no longer had access to their prior support providers manifested more symptoms than did women with stable social relations. In addition, this disruption in their social networks moderated the relationship between distress and menstrual pain. Results indicate that loss of social support is a significant contributor to menstrual symptoms and point to the importance of considering specific aspects of social support in studying its effect on health.

Intrinsic and environmental influences on immune senescence in the aged monkey.

Several factors associated with the age-related decline in immunity were examined in three studies on aged rhesus monkeys. Natural killer (NK) cell activity was found to be low in many monkeys after 20 years of age, but exceptionally long-lived animals, older than 25 years, often had vigorous cytolytic responses. When NK activity was decreased in an aged monkey, it was predictive of fewer years of survival and a younger age at death. This prediction of mortality was associated with one nonimmune biomarker of aging in the monkey: nail growth rate. Monkeys with very slow nail growth and low NK activity were likely to die sooner. Although these findings might suggest an immutable course for the aging process, the housing conditions of old monkeys also had a pronounced effect on their NK activity. The highest NK responses were found in old monkeys housed with just one other old animal when compared to living alone or with just a young, juvenile monkey. It remains to be determined whether this type of psychosocial influence could have a sustained effect on immunity and ultimately change the pace of aging and time to mortality.

Increased tumor necrosis factor-alpha production by peripheral blood leukocytes from TCDD-exposed rhesus monkeys.

Previous work has shown that exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is associated with a dose-dependent increase in the incidence and severity of endometriosis in the rhesus monkey. Studies also suggest that immune mechanisms participate in TCDD-mediated toxicity and the pathogenesis of endometriosis. Thirteen years after TCDD treatment was terminated, we characterized the phenotypic distribution of peripheral blood mononuclear cells (PBMC) from TCDD-exposed and -unexposed rhesus monkeys and determined the ability of these cells to produce cytokines and exert cytolytic activity against NK and T-cell-sensitive cell lines. We also determined whether elevated serum levels of TCDD, dioxin-like PHAH congeners, and triglycerides correlated with changes in PBMC phenotype or function. For all animals, TCDD exposure correlated with increased PBMC tumor necrosis factor-alpha (TNF-alpha) secretion in response to stimulation by T-cell mitogen and decreased cytolytic activity against NK-sensitive target cells. Furthermore, increased production of this cytokine by PHA-stimulated leukocytes was associated with elevated serum triglyceride levels. Leukocyte TNF-alpha secretion in response to viral antigen and PBMC production of interferon gamma (IFNgamma), IL-6, and IL-10 following exposure to mitogen or antigen were unaffected by previous TCDD treatment. Although TCDD exposure was not associated with changes in PBMC surface antigen expression, elevated serum concentrations of TCDD, 1,2,3,6,7,8-hexachlorodibenzofuran and 3,3',4,4',5-pentachlorobiphenyl correlated with increased numbers of CD3+/CD25- and CD3-/CD25+ leukocytes and enhanced secretion of TNF-alpha by mitogen-stimulated PBMC. These findings indicate that TCDD-exposed rhesus monkeys with endometriosis exhibit long-term alterations in systemic immunity associated with elevated serum levels of specific PHAH congeners.

Social stress in pregnant squirrel monkeys (Saimiri boliviensis peruviensis) differentially affects placental transfer of maternal antibody to male and female infants.

The capacity of prenatal stress to disrupt the placental transfer of maternal antibody was evaluated in neonatal squirrel monkeys (Saimiri boliviensis peruviensis) gestated under different pregnancy conditions. Normal squirrel monkey offspring (n = 63) were compared with infants generated from pregnancies that involved either a single or 3 periods of disturbance (ns = 21 and 29, respectively). At parturition, levels of antibody (IgG) were determined in mothers and neonates. Only the chronic disturbance condition significantly altered antibody levels in the mothers, resulting in lower IgG. Antibody transfer to the fetus was also affected only by chronic disturbance. In this case the effect was bidirectional, influenced by the sex of the infant. Males were born with lower levels, whereas female infants actually had higher-than-normal IgG, despite lower titers in their mothers. Because virtually all IgG is derived from the prenatal transfer of maternal antibody, it indicates that the sex of the fetus differentially affected this placental process. The IgG receptor may have been up-regulated selectively on the placentas of female fetuses, compensating for reduced antibody in the disturbed mothers.

Antenatal steroid treatment and adverse fetal effects: what is the evidence?

This article reviews current animal and human data regarding possible adverse fetal effects from antenatal steroid treatment. Although it is now well accepted that such treatment is of benefit to fetal lung development, the potential for adverse fetal outcomes as a result of single or multiple glucocorticoid dosing has not been widely recognized. There are now growing concerns, based on animal and some human data, that repeated antenatal doses could lead to a decrease in birth weight, a decrease in fetal brain and other organ size, and abnormal neuronal development. Previous investigations have been hampered by nonstandardization in the type of glucocorticoid, route of delivery, timing of administration, and number of treatment courses. It is recommended that these concerns be addressed through large randomized, controlled clinical trials. In the meantime, it would be prudent to minimize antenatal steroid treatments to a single course with repeated dosing only if there is a persistent threat of preterm delivery. The practice of giving weekly injections of steroids starting at fetal viability and continuing into the third trimester is not supported.

Maternal constraint on fetal growth patterns in the rhesus monkey (Macaca mulatta): the intergenerational link between mothers and daughters.

The gestational experience of a mother can influence the intrauterine environment she provides her own offspring, allowing prenatal events to affect pregnancy outcomes across several generations. Using a multigenerational database, we determined the reproductive consequences for rhesus monkeys descended from small-for-date and large-for-date birth weight matrilines. Both the maternal half-brothers and -sisters of large-for-date infants exhibited enhanced fetal growth, but for small-for-date probands, only the maternal half-sisters experienced significant intrauterine growth constraint. In addition, the growth-restricted females were at higher risk of poor reproductive outcomes in adulthood, and they perpetuated the matrilineal birth weight pattern by selectively constraining the fetal development of their daughters. Collectively, these findings suggest a mechanism for the intergenerational persistence of suboptimal pregnancy outcomes.

Prenatal influences on neuroimmune set points in infancy.

Many factors during fetal life and early infancy have been found to affect the development of immune responses in animals. This study investigated whether acute exposure of the fetal monkey to high levels of corticosteroids would also have a lingering effect on the expression of immune responses still manifest postpartum in yearling juveniles. One month prior to parturition, pregnant rhesus monkeys were administered dexamethasone for two days. Lymphocyte proliferative responses to mitogen were then examined in their offspring when they were between 1.0-1.5 years of age. In addition, cell sensitivity to corticosteroid feedback was assessed by testing the ability of a gradation of cortisol doses to inhibit proliferation. Monkeys generated from dexamethasone-treated pregnancies tended to have lower responses to concanavalin A. Further, their cells were less sensitive to in vitro incubation with cortisol, suggesting that elevated adrenal activity in vivo had downregulated hormone receptors on their cells. These findings concur with the view that steroidal hormones in utero can influence the fetal immune system, resulting in prolonged effects on immune responses after birth. The similarity of the dexamethasone condition to the clinical treatment used in obstetrical practice raises a potential concern about the widespread antenatal exposure of premature infants to steroidal drugs.

Prenatal stress and immune recognition of self and nonself in the primate neonate.

The capacity of the neonate to respond to nonself antigens was evaluated in infant monkeys born after normal and disturbed pregnancies. Mixed lymphocyte cultures were used to test the infants' proliferative responses to mitomycin-treated stimulator cells, either from a genetically unrelated animal or from a virally transformed monkey cell line. Periods of daily stress for 6 weeks in mid-late pregnancy (months 3.0-4.5) resulted in a significant decrease in proliferative responses, whereas the same stressor early in pregnancy (months 1.5-3.0) increased responses by the neonate's cells. Similar to the late stress effect, an inhibition of proliferative responses by neonatal cells was induced by dexamethasone administered for 2 days late in pregnancy at 4.5 months after conception, 1 month before term. These findings demonstrate that certain immune responses at birth are extremely sensitive to prior prenatal events. Further, the bidirectional changes indicate that there may be critical periods in gestation when the same extrinsic events have radically different effects on the fetus.

In vivo adaptation of attenuated Salmonella typhimurium results in increased growth upon exposure to norepinephrine.

Two studies were conducted to determine whether attenuated strains of Salmonella typhimurium, currently being investigated as possible vectors for mucosal vaccines, are able to respond to norepinephrine (NE). Bacteria were tested for NE responsiveness before and for 1 week after passage through juvenile rhesus monkeys. NE significantly increased the growth of the attenuated bacteria after being shed from the animal, but not before animal infection. Follow-up in vitro tests were performed by passaging the bacteria in Lauria-Bertani (LB) broth with or without selective antibiotic for the attenuation insert and supplementing with NE. NE increased the growth of bacteria passaged in LB broth with no selective antibiotic, but not in bacteria passaged in LB broth with selective antibiotic. These results show that the attenuated bacteria assumed to be safe for use as a vaccine are able to respond to environmental stimuli, such as NE, and change their characteristics. The results suggest that there may be problems with the stability of attenuated bacteria used as vectors for mucosal vaccines.

Maternal separation disrupts the integrity of the intestinal microflora in infant rhesus monkeys.

The integrity of the indigenous microflora of the intestines after maternal separation was investigated in infant rhesus monkeys to determine whether psychological stress may lead to an internal environment conducive to pathogen infection. The stability of the indigenous microflora were estimated by enumeration of total and gram-negative aerobic and facultatively anaerobic bacterial species, specifically Lactobacilli, from coprocultures taken before and after maternal separation. In addition, behavioral and cortisol responses to separation were correlated to the microflora. A significant decrease in fecal bacteria, especially Lactobacilli, was evident on day 3 postseparation, with a return to baseline by the end of the week. The drop in the microflora was correlated with the display of stress-indicative behaviors, but not with cortisol secretion. In addition, infants who displayed numerous stress-indicative behaviors were more susceptible to opportunistic bacterial infection. These results suggest that strong emotional reactions to disruption of the mother-infant bond may increase vulnerability to disease.

Matrilineal transmission of birth weight in the rhesus monkey (Macaca mulatta) across several generations.

OBJECTIVE: To investigate how secular trends in maternal weight characteristics, in response to living in a permissive laboratory environment, influence intergenerational trends in birth weight in the rhesus monkey (Macaca mulatta) and to assess the role of female offspring in perpetuating these matrilineal traits. METHODS: A multigenerational data set was used to evaluate the relationship between familial and contemporaneous pregnancy factors and infant birth weight across several generations. These records provided 25 years of information on the maternal and paternal ancestries and reproductive histories, gestation lengths, and birth weights for 1321 infants. RESULTS: Pregnancy weight gain, gestation length, and maternal familial factors were the most important predictors of infant birth weight, followed by infant sex, paternity, and maternal pregravid weight (P<.001 for each variable). Furthermore, the trend in fetal growth across generations followed a matrilineal pattern of transmission that was much more pronounced for female than male offspring (P<.001). Although secular increases in maternal pregravid weight and pregnancy weight gain were detected, the upward shift in female birth weight was not explained solely by these changes in maternal weight parameters. CONCLUSION: With the delivery of ample nutrition and health care in a laboratory setting, there was a dramatic increase in the birth weight of daughters within certain matrilines, providing evidence that an intrauterine mechanism transmitted through female progeny can regulate fetal development. Further, the upward trend in female birth weight had a beneficial influence on the reproductive performance of female descendants in those lineages.

Brain endothelial cell production of a neuroprotective cytokine, interleukin-6, in response to noxious stimuli.

Brain endothelial cells (BECs), specialized cells of the blood-brain barrier (BBB), are ideally positioned to monitor and respond to events in the periphery. The present study examined their potential role in transducing immune signals to the brain and in responding to noxious stimuli. BECs were isolated from rhesus monkeys at 3 age points (fetal/neonatal, adult, and very old animals). Cells were then challenged in vitro with either an immune stimulus (interleukin-1 beta (IL-1 beta), or lipopolysaccharide (LPS)) or an oxidative challenge (hypoxia). BECs released interleukin-6 (IL-6), which is known to have neurotrophic and neuroprotective functions. Furthermore, higher amounts of IL-6 were released in both baseline and stimulated conditions by BECs derived from aged animals. This research indicates a pathway whereby immune signals may be communicated to the CNS and has revealed one way that the BBB may protect neuronal survival under challenge conditions.

Immune consequences of stroke and cerebral palsy in adults.

The possibility that brain damage results in a sustained dysregulation of lymphocyte responsiveness to the lymphokine, interleukin-2 (IL-2), was investigated in individuals who had experienced a unilateral stroke in adulthood or who presented with spastic hemiparesis since childhood. Following verification of unilateral brain damage via neuromotor assessment, and determination of their health status, blood samples were obtained to evaluate a panel of immune measures. Soluble interleukin-2 receptor (sIL-2R) and lymphocyte proliferative and cytolytic responses in the subjects with stroke or cerebral palsy were compared to age- and gender-matched controls. In addition, lymphocyte populations were enumerated via flow cytometry, and lymphocyte cyclic AMP (cAMP) levels were determined. Circulating blood levels of sIL-2R were significantly elevated in all individuals that had experienced unilateral brain damage. Cytolytic activity also failed to be stimulated to the normal level by in vitro treatment of lymphocytes with IL-2. Further, lymphocytes from the stroke subjects proliferated significantly less after mitogen and IL-2 stimulation. These functional differences were not accounted for by an abnormal leukocyte profile, although phenotypic analyses revealed subtle differences in the natural killer cell subsets. Overall, the findings indicate that individuals with brain damage may not respond appropriately when immune activation is required. These immune differences appear to be a stable trait given that they were manifested after both perinatal and adult brain insult in otherwise healthy, independently living individuals.