Contribution of previable live births to disparity in infant mortality of US-born Puerto Ricans compared with infants of other Hispanic origins.

OBJECTIVES: Although US-born Hispanics experience infant mortality rates (IMRs) which are lower than the national rate, within the Hispanic population, infants of Puerto Rican origin experience higher IMRs than other Hispanics. We aimed to describe the contribution of deaths among previable live-born infants to disparity in IMRs comparing Puerto Rican infants to infants of other Hispanic origins. STUDY DESIGN: Retrospective, descriptive analysis. METHODS: We analyzed data from the Centers for Disease Control and Prevention (CDC) WONDER online database representing linked US live births and infant deaths from 2005 to 2014. Data were stratified by race and ethnicity as well as by Puerto Rican and non-Puerto Rican Hispanic origin. Live births <23 weeks of gestation were classified as previable. Ten-year IMRs were calculated as the number of deaths divided by the number of live births for each group over the entire decade. RESULTS: Puerto Rican IMR of 7.34 (per 1000 live births) was higher than the US rate of 6.34 as well as the non-Puerto Rican Hispanic IMR of 5.15. Approximately 22% of US deaths were attributable to previable live births compared with 27% among Puerto Ricans and 20% among non-Puerto Rican Hispanics. The contribution to IMR of previable births among Puerto Ricans measuring 1.96 per 1000 total live births was 42% higher than the US rate of 1.38 and 90% higher than the non-Puerto Rican Hispanic rate of 1.03. CONCLUSIONS: Further research is needed to develop interventions to reduce disparity in previable birth rates, particularly among infants of Puerto Rican origin.

Evaluation of identifier field agreement in linked neonatal records.

OBJECTIVE: To better address barriers arising from missing and unreliable identifiers in neonatal medical records, we evaluated agreement and discordance among traditional and non-traditional linkage fields within a linked neonatal data set. STUDY DESIGN: The retrospective, descriptive analysis represents infants born from 2013 to 2015. We linked children's hospital neonatal physician billing records to newborn medical records originating from an academic delivery hospital and evaluated rates of agreement, discordance and missingness for a set of 12 identifier field pairs used in the linkage algorithm. RESULTS: We linked 7293 of 7404 physician billing records (98.5%), all of which were deemed valid upon manual review. Linked records contained a mean of 9.1 matching and 1.6 non-matching identifier pairs. Only 4.8% had complete agreement among all 12 identifier pairs. CONCLUSION: Our approach to selection of linkage variables and data formatting preparatory to linkage have generalizability, which may inform future neonatal and perinatal record linkage efforts.

Home visiting for first-time mothers and subsequent pregnancy spacing.

OBJECTIVE: The objective of the study was to determine the association of home visiting with subsequent pregnancy outcomes. STUDY DESIGN: Retrospective study of Ohio mothers delivering their first infant from 2007 to 2009. First, we compared mothers enrolled in home visiting with a matched eligible group. Second, we compared outcomes within home visiting based on program participation (low <25% of recommended home visits, moderate 25 to 75%, high 75 to 100% and very high >100%). Time to subsequent pregnancy within 18 months was evaluated using Cox proportional hazards regression; logistic regression tested the likelihood of subsequent preterm birth. RESULTS: Of 1516 participants, 1460 were matched 1:1 to a comparison mother (n=2920). After multivariable adjustment, enrollment was associated with no difference in pregnancy spacing or subsequent preterm birth. Among those enrolled, moderate vs low participants had reduced risk of repeat pregnancy over 18 months (hazard ratio 0.68, P=0.003). CONCLUSION: Increased pregnancy spacing is observed among women with at least moderate home visiting participation.

Estimating community-level costs of preterm birth.

OBJECTIVES: To develop generalizable methods for estimating the economic impact of preterm birth at the community level on initial hospital expenditures, educational attainment and lost earnings as well as to estimate potential savings associated with reductions in preterm birth. STUDY DESIGN: The retrospective, population-based analysis used vital statistics and population demographics from Hamilton County, Ohio, USA, in 2012. METHODS: We adjusted previously reported, mean initial hospital cost estimates (stratified by each week of gestation) to 2012 dollars using national cost-to-charge ratios. Next, we calculated excess costs attributable to prematurity and potential hospital cost savings, which could be realized by prolonging each preterm pregnancy by a single week of gestation. Using reported associations among preterm birth, educational attainment and adult earnings, we developed generalizable formulas to calculate lost academic degrees and lost income estimates attributable to preterm birth. The formulas generated estimates based on local population demographics. RESULTS: The annual initial hospital cost associated with 1444 preterm infants was estimated at $93 million. In addition, over 9000 fewer college degrees and over $300 million in lost annual earnings were attributed to local adults who were born preterm. Prolonging each preterm birth by 1 week could potentially reduce initial hospital expenditures by over $25 million. Additional potential savings could be realized as healthier infants attain higher levels of education and earnings as adults. CONCLUSIONS: The generalizable methods developed for estimating the economic impact of preterm birth at the community level can be used by any community in which vital statistics and population demographics are available. Cost estimates can serve to rally support for local stakeholder investment in developing strategies for preterm birth intervention leading to improved pregnancy outcomes.

Self-reported and laboratory evaluation of late pregnancy nicotine exposure and drugs of abuse.

OBJECTIVE: The objective of this study was to evaluate the prevalence of late pregnancy nicotine exposures, including secondhand smoke exposures, and to evaluate the associated risk of exposure to drugs of abuse. STUDY DESIGN: The study was a retrospective single-center cohort analysis of more than 18 months. We compared self-reported smoking status from vital birth records with mass spectrometry laboratory results of maternal urine using a chi-square test. Logistic regression estimated adjusted odds for detection of drugs of abuse based on nicotine detection. RESULTS: Compared with 8.6% self-reporting cigarette use, mass spectrometry detected high-level nicotine exposures for 16.5% of 708 women (P<0.001) and an additional 7.5% with low-level exposures. We identified an increased likelihood of exposure to drugs of abuse, presented as adjusted odds ratios, (95% confidence interval (CI), for both low-level (5.69, CI: 2.09 to 15.46) and high-level (13.93, CI: 7.06 to 27.49) nicotine exposures. CONCLUSION: Improved measurement tactics are critically needed to capture late pregnancy primary and passive nicotine exposures from all potential sources.

A population study of first and subsequent pregnancy smoking behaviors in Ohio.

OBJECTIVE: The objective of this study is to identify maternal characteristics associated with non-smoking during a subsequent pregnancy after first pregnancy smoking. STUDY DESIGN: We conducted a retrospective population-based analysis of Ohio vital birth records from 2007 to 2013. We used logistic regression to calculate adjusted odds ratios with 95% confidence intervals for detection of characteristics associated with non-smoking during a subsequent pregnancy after first pregnancy smoking. RESULTS: Among 75 190 mothers, 75.6% were non-smokers and 13.7% were smokers during both pregnancies. During their first pregnancy, 49.7% of 15 075 smokers quit. Of them, 50.1% remained non-smokers during their subsequent pregnancy. Women who reduced, but continued smoking during their first pregnancy, were more than five times as likely to smoke during their subsequent pregnancy than women who quit (odds ratio (95% confidence interval): 2.85 (2.43 to 3.35) vs 0.55 (0.45 to 0.67)). CONCLUSION: Interventions targeting complete cessation, rather than reduction in smoking among first-time mothers, may be the most effective at optimizing long-term health benefits.

A Quantitative Method for Determination of Lactide Composition in Poly(lactide) Using (1)H NMR.

A method has been developed to quantitatively determine the composition of d-lactide and meso-lactide stereoisomer impurities in poly(lactide) containing predominantly l-lactide. In this method, the stereosequence information obtained from a few well-resolved resonances in the (1)H NMR spectrum representing RR and R stereogenic defects is used. The d-lactide and meso-lactide as minor components lead to RR and R stereogenic defects, respectively, which influence the isotactic chain length distribution and hence affect the polymer properties. Analytical equations relating the stereosequence probability to the lactide feed composition are not available due the complicated kinetics involved for the melt polymerization; viz. the preference for syndiotactic lactide addition decreases with reducing residual lactide concentration in the batch process. Hence, empirical correlations were determined by least-squares fit to the predictions for the specific stereosequence probabilities provided by Monte Carlo calculations of a number of lactide stereocopolymerizations. The Monte Carlo calculations simulate the kinetics observed for melt polymerization at 180 °C catalyzed by Sn(II) bis(2-ethylhexanoate) (Sn(II) octoate) in a 1:10 000 catalyst/lactide ratio.

Kinesin localizes to the trans-Golgi network regardless of microtubule organization.

Knowledge of the mechanisms of intracellular membrane trafficking is critical for understanding cell function. Here, the microtubule motor kinesin is localized to the Sertoli cell trans-Golgi network with the SUK4 kinesin monoclonal antibody. Using immunoelectron and immunofluorescence microscopy, kinesin was shown to localize to the trans-Golgi network in primary Sertoli cell cultures. Kinesin immunostaining was not observed in brefeldin A-induced trans-Golgi network-derived membrane tubules and remained associated with trans-Golgi network remnants. Despite dramatic differences in microtubule organization between Sertoli cells in vivo and in vitro, kinesin immunostaining was consistently associated with the trans-Golgi network. In cryosections of control testis and testis treated with colchicine to disrupt microtubules, kinesin immunostaining was juxtaposed with immunostaining for a Golgi cisternal protein; however, brefeldin A exposure partitioned the kinesin immunostaining from the Golgi cisternal protein, indicating that kinesin was associated with the trans-Golgi network of Sertoli cells in vivo. These results are discussed in relation to known Golgi-associated microtubule-dependent transport events in other cell types and suggest that kinesin functions locally at the Sertoli cell trans-Golgi network.

Distribution of Sertoli cell microtubules, microtubule-dependent motors, and the Golgi apparatus before and after tight junction formation in developing rat testis.

Sertoli cells are polarized epithelial cells of the seminiferous epithelium which provide structural and physiological support for differentiating germ cells. They establish different basal and adluminal environments for the selective nurturing of pre- and post-meiotic germ cells within the seminiferous epithelium, segregated by the Sertoli-Sertoli cell tight junctional complex, the blood-testis barrier. Tight junction formation between epithelial cells in vitro is a critical polarizing event associated with changes in polarized targeting of membrane-specific proteins and reorganization of microtubules, centrioles, and the Golgi apparatus. To investigate whether tight junction formation is associated with organelle reorganization in Sertoli cells in vivo, we have characterized distribution patterns of Sertoli cell microtubules, the mechanoenzymes kinesin and cytoplasmic dynein, and the Golgi apparatus during tight junction formation in developing rat testis. Immunocytochemistry on samples taken at 5, 10, 15, 20, and 25 days of age was used to examine the distribution of these proteins during the extensive cellular reorganization that culminates in the formation of the blood-testis barrier at 19 days of age. Our data show that the distribution patterns reflect the extensive intercellular repositioning of tubule cells in developing seminiferous tubules, but that changes in intracellular organization are not temporally associated with formation of the blood-testis barrier.

Dialysis survival in a large inner-city facility: a comparison to national rates.

Impoverished patients may represent a high-risk population with poor survival. With 1993 U.S. Renal Data System survival tables (to adjust the risk of death for differences in age, race, and ESRD diagnosis), the mortality rates of patients over 3 yr in a large inner-city dialysis facility using high-flux technique were compared with national averages. At least 93.7% of patients were African-American, 50% had incomes below $7,000 per year, and employment was 5% or less. Observed and expected deaths (the latter derived from the U.S. Renal Data System tables) were used to calculate a standardized mortality ratio (observed deaths/expected deaths); the U.S. average is 1.0. The standardized mortality ratio at this facility for each year was < 0.600 and was significantly lower than the U.S. average in 1991, in 1992 (P < 0.05), and for all 3 yr (P < .001). Over all 3 yr, it was lower for females (0.540, P < 0.05), males (0.620, P < 0.05), patients with diabetes (0.593, P < 0.05), and glomerulonephritis (0.318, P < 0.05). For the 3 yr, a Cox regression analysis revealed independent associations between mortality and age (P = 0.004), serum albumin (P = 0.02), Kt/V (P = 0.02), and dialysis for more than 2 yr (P = 0.01). Patients with economic hardship can attain survival significantly better than the national average with the provision of adequate dialysis, nutrition, and support services.

2,5-Hexanedione exposure alters microtubule motor distribution in adult rat testis.

2,5-Hexanedione (2,5-HD) exposure in rats causes a progressive Sertoli cell injury culminating in testicular atrophy. Morphological injury is preceded by alterations in the assembly characteristics of tubulin isolated from exposed rat testes. This is followed by decreased seminiferous tubule fluid (STF) secretion by Sertoli cells and an increase in the number and size of Sertoli cell vacuoles. The possible involvement of microtubules and microtubule motor-dependent transport processes in STF secretion by Sertoli cells prompted us to examine the immunodistribution of the microtubule motors cytoplasmic dynein and kinesin during and after 2,5-HD exposure in rats. Three weeks following the commencement of exposure (1% 2,5-HD in the drinking water), the intensity of apical Sertoli cell cytoplasmic dynein immunofluorescence declined. This staining deficit became statistically significant by 4 weeks of exposure. Accompanying this change, there was progressive disruption of the immunodistribution of cisternal Golgi elements and associated kinesin immunoreactivity. The decrease in apical Sertoli cell cytoplasmic dynein immunofluorescence and disruption of Golgi and kinesin immunoreactivity suggest that 2,5-HD-induced alterations in Sertoli cell-mediated transport and secretory events could involve deficits in microtubule-dependent motor function.

Cellular localization of tissue factor and prothrombin in the estrogen-treated immature rat uterus.

The immediate early responses of the immature rat uterus to estradiol include increases in tissue factor and prothrombin, two proteins of the coagulation cascade. Both attain maximum activity within 3 h after the administration of estradiol and return to control levels after 12-18 h. The presence of the two proteins allows the generation of thrombin (a known growth factor for fibroblasts) in the uterus at the time when uterine growth begins. To further our hypothesis that thrombin is an estrogen-regulated uterine growth factor, we used immunohistochemistry, Western blotting, and coagulation assays to localize the cell types in which these proteins are increased by estradiol. Tissue factor is increased in both the stromal and the epithelial cells. Increased prothrombin is localized primarily along the basement membrane that separates the epithelial and stromal layers and also at the luminal surface of the epithelium.

The cytotoxicity of N-substituted indazolones in murine and human tumor cells.

N-Substituted indazolones are effective cytotoxic agents, causing cell death in a number of tissue culture lines, e.g. L1210, Tmolt3, colon adenocarcinoma and HeLa-S3. Selected agents were also active against the growth of KB, bronchogenic lung, osteosarcoma and glioma. The mode of action of the derivatives involves inhibition of de novo purine synthesis of L1210 cells, which reduces DNA and RNA syntheses. Agents lowered d(NTP) pools, further reducing DNA synthesis. DNA strand scission was evident after incubation with N-substituted indazolones for 24 h at 100 microM, lowering DNA synthesis and causing cell death.

Protein binding and hepatobiliary distribution of valproic acid and valproate glucuronide in rats.

The protein binding and hepatobiliary distribution of valproic acid (VPA) and its glucuronide conjugate (V-G) were examined in rats with a combination of in vitro and ex vivo protocols. VPA was moderately bound to proteins in both serum and hepatic cytosol, and the degree of binding was lower ex vivo than in vitro. V-G, which was more highly bound than VPA ex vivo in serum, may have displaced the parent drug from its binding sites when VPA was administered in vivo. Examination of ex vivo hepatic subcellular distribution revealed that VPA localization tended to be high in cytosol and low in the microsomal fraction; V-G appeared to be distributed evenly throughout the cell although V-G concentrations within the liver were very low. The steady-state elimination rate of VPA did not increase proportionately with increasing steady-state concentrations of unbound VPA in serum, consistent with saturable systemic elimination of the drug. In contrast, steady-state VPA elimination was related linearly to unbound cytosolic VPA concentrations. Moreover, a nonlinear relationship between the unbound concentrations of VPA in hepatic cytosol and serum was observed, consistent with saturable distribution of the unbound drug between the two compartments in vivo. These observations suggest that the nonlinear elimination of VPA in rats may be due to concentration-dependent penetration of the drug into the liver as opposed to saturable biotransformation.

The effects of boron containing peptides on L1210 lymphoid leukemia metabolism.

The purpose of this study was to establish the efficacy and mode of action of peptide boron derivatives as antineoplastic agents and to evaluate their safety in vivo. Boron-containing phenylalanine and tyrosine methyl esters were found to be potent cytotoxic agents in a number of murine and human cancer cell lines. DNA, RNA and protein syntheses were inhibited by selected agents, e.g. [(trimethylamine boryl)carbonyl]-phenylalanine-acetyl ester (9) andN-acetyl-p-boron-phenyl-alanyl-phenlalanine-methyl ester (10), in L1210 lymphoid leukemia cells. IMP dehydrogenase, OMP decarboxylase, m-RNA, t-RNA, r-RNA polymerase and ribonucleoside reductase activities were inhibited. d(CTP) levels were reduced. DNA strand scission occurred after 24 hr incubation. Acute toxicity studies in mice demonstrated that the key derivative was safe at therapeutic levels with no effects on histology of major organs, hematopoietic parameters and clinical values.

Sertoli cells isolated from adult 2,5-hexanedione-exposed rats exhibit atypical morphology and actin distribution.

Sertoli cells were isolated from 2,5-hexanedione (2,5-HD)-exposed, cryptorchid and 21-day-old rats in order to examine alterations in in vitro Sertoli cell transferrin secretion, germ cell adhesion, in vitro morphology, and cytoskeletal organization which might be involved in the irreversibility of 2,5-HD-induced testicular injury. Sertoli cells isolated from 21-day-old, cryptorchid and 2,5-HD-exposed rats exhibited similar transferrin secretion as measured using an enzyme-linked immunosorbent assay. Germ-cell adhesion was measured using [3H]leucine-labeled immature rat germ cells and revealed similar levels of germ-cell binding in Sertoli cell cultures isolated from the three groups of rats. Differential interference contrast microscopy demonstrated that Sertoli cells isolated from 2,5-HD-exposed rats possessed an atypical spindle shape and long cytoplasmic processes. The immunofluorescent distribution of tubulin and vimentin corresponded with the morphological appearance of the cells with well-defined microtubule and intermediate filament networks which, in the cells isolated from 2,5-HD-exposed rats, extended into the cytoplasmic processes. Rhodamine-conjugated phalloidin-labeled actin stress fibers were decreased in density within the 2,5-HD-exposed rat Sertoli cells. The altered morphology and distribution of actin filaments within Sertoli cells isolated from adult 2,5-HD-exposed rats may reflect an underlying insult which is involved in the irreversible nature of 2,5-HD intoxication.

The synthesis and anti-neoplastic activity of N2-isobutyryl-2'-deoxyguanosine-N7-cyanoborane derivatives.

N2-Isobutyryl-2'-deoxyguanosine-N7-cyanoborane derivatives were observed to be potent antineoplastic agents and to be active against a number of human tissue culture tumor cells, e.g. Tmolt3 leukemia, HeLa-S3 uterine carcinoma. Selective agents were active against colon adenocarcinoma, osteosarcoma and glioma growth. These agents preferentially inhibited both DNA and RNA synthesis of L1210 cells. De novo synthesis of purines was significantly inhibited at the regulatory sites of PRPP amido transferase and IMP dehydrogenase. Other sites of inhibition were thymidylate synthetase, OMP decarboxylase and thymidine kinases. The agents also significantly reduced deoxyribonucleotide levels and caused DNA strand scission.

Antineoplastic activity of boron-containing thymidine nucleosides in Tmolt3 leukemic cells.

The sugar boronated thymidine nucleoside, 5' -0-[(triphenylphosphine-boryl) carbonyl]-3'-0-acetyl thymidine 1, and the boron-modified nucleoside phosphotriester, 5'-(diethylphosphite- cyanoborane)-3'-acetylthymidine 2, were successfully synthesized. Both compounds demonstrated differential activity when tested against eight cell lines, with significant cytotoxic activity against the growth of human Tmolt3 leukemia, colon adenocarcinoma, HeLa S3 uterine carcinoma, and osteosarcoma cells. In in vivo studies these agents were found to be active against the growth of Ehrlich ascites carcinoma at 8 mg/kg/day I.P. and to be marginally active against the growth of L1210 and Lewis lung cancers in mice. The mode of action of these thymidine derivatives in Tmolt3 cells was the inhibition of DNA and protein synthesis. Compound 2 was highly effective in inhibiting DNA polymerase alpha and m-RNA, r-RNA and t-RNA polymerase activities. Both compounds inhibited ribonucleoside reductase activity. The de novo purine pathway appeared to be the major site of inhibition of the agents, with IMP dehydrogenase, PRPP amido transferase, and dihydrofolate reductase activities being significantly inhibited. In the pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase activities were inhibited by 1. As expected, d[NTP] levels were significantly reduced by treatment with the agents. DNA strand scission was evident after incubating Tmolt3 cells for 24 hr with the agents.

The antineoplastic and cytotoxicity of benzohydroxamic acids and related derivatives in murine and human tumor cells.

Benzohydroxamic acids proved to be potent cytotoxic agents suppressing the growth of a number of murine and human cell lines grown in tissue culture, e.g. leukemia, colon, uterine and glioma. Selected compounds demonstrated activity against the growth KB nasopharynx, bronchogenic lung, osteosarcoma and skin cancer. In vivo activity against Ehrlich ascites carcinoma growth was shown with certain compounds. In L1210 cells compound 2 inhibited DNA synthesis significantly within 60 min. the site of action of the agent appears to involve the purine de novo synthesis pathway at PRPP amido transferase and IMP dehydrogenase. Dihydrofolate reductase and nucleoside kinase activities were inhibited by the agent. The levels of d(NTP)s in L1210 cells were reduced after drug treatment. The drug did not appear to affect the DNA template directly causing any damage which might alter transcription and replication nor was there any inhibition of HeLa topoisomerase activity by the drug. Thus the drug appears to be a metabolic inhibitor of nucleoside metabolism.