Theresa O. Scholl

Early adolescent pregnancy: A comparative study of pregnancy outcome in young adolescents and mature women

Thirty-two adolescents were matched to mature controls for a study of variables known to influence the course and outcome of pregnancy. These included: ethnicity; clinic payment status; year of delivery; parity; and presence or absence of alcohol and tobacco use. The comparative factors examined included: age of menarche; gynecologic age; admission hemoglobin; prepregnant weight and height; weight gain during pregnancy; complications of pregnancy; length of gestation; birth weight; 1- and 5-minute apgar scores; and the presence or absence of congenital defects. There was no significant difference between young adolescents and matched controls in infant birth weight or apgar scores when the above confounding factors were controlled. Young gravidae, however, had significantly shorter gestations, earlier menarche, lower hemoglobin levels, and poorer weight gain during pregnancy than mature women. Multiple-regression analysis suggests that 1) pregnancy weight gain was associated with the trimester the gravida enrolled in the Supplemental Food Program for Women, Infants, and Children (WIC) (p = 0.008) and maternal stature (p = 0.012); 2) length of gestation was associated with maternal stature (p = 0.022) and prepregnant weight (p = 0.011); and 3) maternal hemoglobin was associated with birth weight (p = 0.087). Alternative interpretations are discussed.

Revised Beck Depression Inventory Scores of Inner-City Adolescents: Pre- and Postpartum

The revised Beck Depression Inventory was administered to 109 (69 0%) black, 33 (20 9%) Hispanic, and 16 (10.1%) white adolescents who were attending prenatal and postpartum clinics offered by two inner-city hospitals at 28 wk. of pregnancy, 5 wk. postpartum, and 6 mo. postpartum. The mean Beck scores significantly decreased between 28 wk. of pregnancy and 5 wk. postpartum but did not change between 5 wk. and 6 mo. postpartum. The levels of depression were comparable to those previously reported for nonpregnant adolescent females. Using a Beck cut-off score>20 as indicative of depression, 134 (84.8%) were never depressed; 11 (7.0%) became depressed after delivery; 8 (5 1%) ceased being depressed after delivery; and 5 (3.1%) were depressed throughout.

Early weight gain in pregnant adolescents and fetal outcome

While the contribution of total maternal gain to birthweight is well described, less is known about whether there are specific effects of early weight gain. Early weight gain adequacy may be a particular problem among teenage gravidas who are more likely to have low prepregnant weight and in developing countries where chronic undernutrition is endemic. We studied the effects of early weight gain adequacy on infant birthweight in a geographical cohort of 1,790 adolescents from Camden County, New Jersey. Weight gain was calculated for prepregnant weight to 24 weeks gestation and 24 weeks to delivery. Inadequate early weight gain was defined as gains less than 4.3 kg and inadequate late gains as averaging less than 400 gm/week from 24 weeks gestation to delivery. In regressions predicting birthweight outcome, we found significant independent effects of timing of weight gain inadequacy. Early inadequate gains were associated with a −186.6 ± 31.6 gm decrement in birthweight that was not diminished even when later weight gains were compensatory. Late inadequate (−154.4 ± 29.3 gm) and inadequate gains both early and later (−298.6 ± 49.1 gm) were also associated with birthweight decrements. However, overweight (body mass index >24.5) appeared to buffer some of the effects of inadequate weight gains, reducing the decrement to about −100 gm. Protocols that seek to improve infant outcomes should focus on early weight gain during pregnancy. Affecting weight gain only late in pregnancy may not be able to substantially reduce the risk of fetal growth retardation.

Novel Histopathological Patterns in Cortical Tubers of Epilepsy Surgery Patients with Tuberous Sclerosis Complex.

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.

Maternal calcium metabolic stress and fetal growth

BACKGROUNDnSuboptimal maternal calcium intake and vitamin D status may or may not adversely influence fetal growth.nnnOBJECTIVEnIt was hypothesized that maternal calcium metabolic stress in early pregnancy, rather than suboptimal calcium intake or insufficient vitamin D, influences the risk of small-for-gestational-age (SGA) births and other aspects of fetal growth. Stress to calcium metabolism was defined as elevated intact parathyroid hormone (PTH) (>62 pg/mL) accompanied by a very low calcium intake [<60% of the Estimated Average Requirement (EAR)] or insufficient 25-hydroxyvitamin D [25(OH)D] (<20 ng/mL).nnnDESIGNnThis was a prospective cohort study of 1116 low-income and minority gravidae at entry to care of 13.8 ± 5.6 wk (mean ± SD).nnnRESULTSnThe PTH concentration depended on circulating 25(OH)D and total calcium intake. When 25(OH)D was insufficient, even a high calcium intake (which equaled or exceeded the Recommended Dietary Allowance) was unable to maintain PTH or to moderate the proportion of patients with an elevated PTH. When examined one at a time, very low calcium intake (<60% of EAR), very low 25(OH)D (<12 ng/mL), and elevated PTH (>62 pg/mL) each had a small but significant association with birth weight. Elevated PTH was also related to birth length and risk of SGA birth. Elevated PTH accompanied by insufficient 25(OH)D or very low calcium intake was associated with a 2- to 3-fold increased risk of SGA birth and a significantly lower birth weight, birth length, and head circumference, even after women who developed preeclampsia were excluded. Infants born to gravidae with insufficient 25(OH)D or very low calcium intake without elevated PTH or with elevated PTH alone were unaffected.nnnCONCLUSIONnMaternal calcium metabolic stress, rather than low calcium intake or insufficient vitamin D, has an adverse influence on fetal growth. This trial was registered at clinicaltrials.gov as NIH 0320070046.

Maternal Biomarkers of Endothelial Dysfunction and Preterm Delivery

Background Endothelial dysfunction is key to the development of atherosclerosis. Preterm delivery foreshadows later maternal cardiovascular disease (CVD), but it is not known if endothelial dysfunction also occurs. We prospectively measured circulating biomarkers of endothelial dysfunction in pregnant women with preterm or term delivery. Methods We conducted a case-control study nested within a large prospective epidemiological study of young, generally healthy pregnant women. Women who delivered preterm (<37 completed weeks gestation, nu200a=u200a240) and controls who delivered at term (nu200a=u200a439) were included. Pregnancies complicated by preeclampsia were analyzed separately. Circulating endothelial dysfunction biomarkers included soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin). Results Elevated levels of sICAM-1 and sVCAM-1 were positively associated with preterm delivery independent of usual risk factors. At entry (∼16 wks), the adjusted odds ratio (AOR) was 1.73 (95% confidence interval (CI) 1.09–2.74) for the highest quartile of sICAM-1 versus the lowest quartile and for sVCAM-1 the AOR was 2.17 (95% CI 1.36–3.46). When analysis was limited to cases with a spontaneous preterm delivery, the results were unchanged. Similar results were obtained for the 3rd trimester (∼30 wks). Elevated sE-selectin was increased only in preterm delivery complicated by preeclampsia; risk was increased at entry (AOR 2.32, 95% CI 1.22–4.40) and in the 3rd trimester (AOR 3.37, 95% CI 1.78–6.39). Conclusions Impaired endothelial function as indicated by increased levels of soluble molecules commonly secreted by endothelial cells is a pathogenic precursor to CVD that is also present in women with preterm delivery. Our findings underscore the need for follow-up studies to determine if improving endothelial function prevents later CVD risk in women.

Intervention strategies to improve adherence among hypertensives: Review and recommendations

Hypertension is a leading public health problem, which significantly increases the risks of death and disability from cardiovascular and cerebrovascular diseases. Medical treatment is effective for reducing hypertension and the associated risks, but nonadherence to recommendations for treatment has limited the realization of benefits of advances in medical care. This paper reviews recent attempts to improve adherence to medical regimens for the control of high blood pressure. Adherence to antihypertension regimens is defined as a behavioral problem, which includes a series of steps: participation in screening, entering treatment, continuing treatment, and adhering to the prescribed regimen. In the past decade, a wide range of structural and educational interventions attempting to increase adherence have had varying degrees of success. The interventions, their efficacy, study designs, and populations studied are reviewed, and recommendations for future testing and adoption of strategies for improving management of hypertension are advance.

Functional aspects of early brain development are preserved in tuberous sclerosis complex (TSC) epileptogenic lesions

Tuberous sclerosis complex (TSC) is a rare multi-system genetic disease characterized by several neurological disorders, the most common of which is the refractory epilepsy caused by highly epileptogenic cortical lesions. Previous studies suggest an alteration of GABAergic and glutamatergic transmission in TSC brain indicating an unbalance of excitation/inhibition that can explain, at least in part, the high incidence of epilepsy in these patients. Here we investigate whether TSC cortical tissues could retain GABAA and AMPA receptors at early stages of human brain development thus contributing to the generation and recurrence of seizures. Given the limited availability of pediatric human brain specimens, we used the microtransplantation method of injecting Xenopus oocytes with membranes from TSC cortical tubers and control brain tissues. Moreover, qPCR was performed to investigate the expression of GABAA and AMPA receptor subunits (GABAA α1-5, β3, γ2, δ; GluA1, GluA2) and cation chloride co-transporters NKCC1 and KCC2. The evaluation of nine human cortical brain samples, from 15 gestation weeks to 15years old, showed a progressive shift towards more hyperpolarized GABAA reversal potential (EGABA). This shift was associated with a differential expression of the chloride cotransporters NKCC1 and KCC2. Furthermore, the GluA1/GluA2 mRNA ratio of expression paralleled the development process. On the contrary, in oocytes micro-transplanted with epileptic TSC tuber tissue from seven patients, neither the GABAA reversal potential nor the GluA1/GluA2 expression showed similar developmental changes. Our data indicate for the first time, that in the same cohort of TSC patients, the pattern of both GABAAR and GluA1/GluA2 functions retains features that are typical of an immature brain. These observations support the potential contribution of altered receptor function to the epileptic disorder of TSC and may suggest novel therapeutic approaches. Furthermore, our findings strengthen the novel hypothesis that other developmental brain diseases can share the same hallmarks of immaturity leading to intractable seizures.

Promoter-Specific Hypomethylation Correlates with IL-1β Overexpression in Tuberous Sclerosis Complex (TSC)

In tuberous sclerosis complex (TSC), overexpression of numerous genes associated with inflammation has been observed. Among different proinflammatory cytokines, interleukin-1β (IL-1β) has been shown to be significantly involved in epileptogenesis and maintenance of seizures. Recent evidence indicates that IL-1β gene expression can be regulated by DNA methylation of its promoter. In the present study, we hypothesized that hypomethylation in the promoter region of the IL-1β gene may underlie its overexpression observed in TSC brain tissue. Bisulfite sequencing was used to study the methylation status of the promoter region of the IL-1β gene in TSC and control samples. We identified hypomethylation in the promoter region of the IL-1β gene in TSC samples. IL-1β is overexpressed in tubers, and gene expression is correlated with promoter hypomethylation at CpG and non-CpG sites. Our results provide the first evidence of epigenetic modulation of the IL-1β signaling in TSC. Thus, strategies that target epigenetic alterations could offer new therapeutic avenues to control the persistent activation of interleukin-1β-mediated inflammatory signaling in TSC brain.

Dysregulation of the (immuno)proteasome pathway in malformations of cortical development.

BackgroundThe proteasome is a multisubunit enzyme complex involved in protein degradation, which is essential for many cellular processes. During inflammation, the constitutive subunits are replaced by their inducible counterparts, resulting in the formation of the immunoproteasome.MethodsWe investigated the expression pattern of constitutive (β1, β5) and immunoproteasome (β1i, β5i) subunits using immunohistochemistry in malformations of cortical development (MCD; focal cortical dysplasia (FCD) IIa and b, cortical tubers from patients with tuberous sclerosis complex (TSC), and mild MCD (mMCD)). Glial cells in culture were used to elucidate the mechanisms regulating immunoproteasome subunit expression.ResultsIncreased expression was observed in both FCD II and TSC; β1, β1i, β5, and β5i were detected (within cytosol and nucleus) in dysmorphic neurons, balloon/giant cells, and reactive astrocytes. Glial and neuronal nuclear expression positively correlated with seizure frequency. Positive correlation was also observed between the glial expression of constitutive and immunoproteasome subunits and IL-1β. Accordingly, the proteasome subunit expression was modulated by IL-1β in human astrocytes in vitro. Expression of both constitutive and immunoproteasome subunits in FCD II-derived astroglial cultures was negatively regulated by treatment with the immunomodulatory drug rapamycin (inhibitor of the mammalian target of rapamycin (mTOR) pathway, which is activated in both TSC and FCD II).ConclusionsThese observations support the dysregulation of the proteasome system in both FCD and TSC and provide new insights on the mechanism of regulation the (immuno)proteasome in astrocytes and the molecular links between inflammation, mTOR activation, and epilepsy.