Search

In the 5 years after the adoption of state-mandated HIV testing in Connecticut, 33% of HIV-positive pregnant women in the state were newly diagnosed during their pregnancy. Women who first learned that they were HIV-infected during pregnancy comprised of a unique group of people tested, in essence, by state mandate. A total of 11 such women agreed to in-depth interviews to share their personal perspectives regarding the benefits as well as the adverse sequelae of HIV testing for themselves, their children, and the public health. Each woman recalled her initial response to the law, to her HIV diagnosis, and to the seemingly unavoidable challenge to her self-identity and described the ensuing adjustments. There was universal agreement by the study subjects that the law was of overriding and significant benefit. [ABSTRACT FROM AUTHOR]

Objectives: To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC)., Study Design: Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation., Results: A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC., Conclusions: We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease., (Copyright © 2014 Mosby, Inc. All rights reserved.)

Background: Necrotizing enterocolitis (NEC) is a major source of neonatal morbidity and mortality. Since there is no specific diagnostic test or risk of progression model available for NEC, the diagnosis and outcome prediction of NEC is made on clinical grounds. The objective in this study was to develop and validate new NEC scoring systems for automated staging and prognostic forecasting., Study Design: A six-center consortium of university based pediatric teaching hospitals prospectively collected data on infants under suspicion of having NEC over a 7-year period. A database comprised of 520 infants was utilized to develop the NEC diagnostic and prognostic models by dividing the entire dataset into training and testing cohorts of demographically matched subjects. Developed on the training cohort and validated on the blind testing cohort, our multivariate analyses led to NEC scoring metrics integrating clinical data., Results: Machine learning using clinical and laboratory results at the time of clinical presentation led to two nec models: (1) an automated diagnostic classification scheme; (2) a dynamic prognostic method for risk-stratifying patients into low, intermediate and high NEC scores to determine the risk for disease progression. We submit that dynamic risk stratification of infants with NEC will assist clinicians in determining the need for additional diagnostic testing and guide potential therapies in a dynamic manner., Algorithm Availability: http://translationalmedicine.stanford.edu/cgi-bin/NEC/index.pl and smartphone application upon request.

Results from a 13-week inhalation study in rats on a C10-C12 isoparaffinic solvent are compared to the results of repeated inhalation and oral toxicity studies of four other isoparaffinic hydrocarbon solvents. Statistically significant findings which were consistent across all studies included: nephropathy and small but significant changes in hematological parameters in male rats and liver enlargement in both male and female rats. The male rat kidney changes were due to an alpha 2u globulin process and not relevant for human health or risk assessment. The liver enlargement without pathologic changes or elevations in liver enzyme markers was considered to be an adaptive response. The reason for the reductions in hematological parameters that were observed in males only is not clear, but it is suggested that these were either due to normal variation or a secondary consequence of the nephropathy. The overall No Observed Adverse Effect Concentration (NOAEC) was the highest concentration tested in the study, >10,000 mg/m(3). Because of the overall pattern of response, this solvent is considered to be representative of low aromatic C9-C14 aliphatic solvents in general. The data are useful for risk assessment and other purposes including the development of occupational exposure recommendations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The repeat-dose and developmental toxicities of certain petroleum refinery streams are related to their polycyclic aromatic compound (PAC) content (Feuston et al., 1994). Building on this foundation, and working within the context of the US EPA High Production Volume (HPV) Chemical Challenge Program, we: (1) characterized relationships between PAC content and repeat-dose and developmental toxicities of high boiling petroleum substances (HBPS), and (2) developed statistical models that can be used to predict critical effects of similar untested substances. Data from 39 dermal toxicity studies of HBPS were used to develop statistical models to predict the dose-response relationships between the weight percent concentration of each of their 1-7 aromatic ring classes and 4 repeat-dose and 3 developmental endpoints (absolute thymus weight, hemoglobin count, platelet count, liver to body weight, live fetus count, fetal weight, and percent resorptions). The correlations between the observed and model-predicted values are >0.90. The predictive ability of the models was tested via a series of evaluation or corroboration methods. As is shown in the paper, using only compositional data of untested HBPS, the models can be used to predict the effect at a given dose or the dose that causes an effect of a stipulated magnitude., (Copyright © 2012. Published by Elsevier Inc.)

A study was undertaken within the context of the U.S. EPA HPV Chemical Challenge Program to (1) characterize relationships between PAC content and repeat-dose toxicities of high-boiling petroleum substances (HBPS) and (2) develop statistical models that could be used to predict the repeat-dose toxicity of similar untested substances. The study evaluated 47 repeat-dose dermal toxicity and 157 chemical compositional studies. The four most sensitive endpoints of repeat-dose toxicity were platelet count, hemoglobin concentration, relative liver weight and thymus weight. Predictive models were developed for the dose-response relationships between the wt.% concentration of each of seven ring classes of aromatic compounds (the "ARC profile") and specific effects, with high correlations (r=0.91-0.94) between the observed and model-predicted data. The development of the mathematical models used to generate the results reported in this study is described by Nicolich et al. (2013). Model-generated dose-response curves permit the prediction of either the effect at a given dose or the dose that causes a given effect. The models generate values that are consistent with other standard measures. The models, using compositional data, can be used for predicting the repeat-dose toxicity of untested HBPS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

To meet the EPA HPV Chemical Challenge Program requirement for reproductive toxicity data on sponsored high-boiling petroleum substances (HBPS), an analysis was conducted using the results of 39 repeat-dose and 59 developmental rat dermal toxicity studies on HBPS samples spanning the boiling range of the sponsored substances, and the results of three one-generation reproductive toxicity studies on two samples spanning the concentration range of polycyclic aromatic compounds of sponsored substances. The analysis found little evidence of male or female reproductive tract toxicity based on histopathology, reproductive organ weight, and sperm parameters, and no evidence of effects on fertility, while significant developmental toxicity and/or systemic repeat-dose toxicity were frequently observed. Among 14 samples of HBPS tested in both repeat-dose toxicity and developmental toxicity studies, there were no studies in which an adverse reproductive tract finding occurred at a dose lower than that producing developmental toxicity or other adverse effects in repeat-dose toxicity studies. The current analysis supports the hypothesis that effects in developmental and/or repeat-dose toxicity studies of HBPS occur at doses lower than those that might affect fertility in rat one-generation reproductive studies. When adequate developmental and repeat-dose toxicity studies are available, a reproductive toxicity study of HBPS appears unnecessary., (Copyright © 2013 Elsevier Inc. All rights reserved.)

In 1998, the US EPA announced the HPV Challenge Program, a voluntary chemical data collection effort. The Petroleum HPV Testing Group (PHPVTG(1)) volunteered to provide data on approximately 110 high boiling petroleum substances (HBPS), i.e. substances with final boiling points ≥ approximately 650°F (343°C). These HBPS are substances of unknown and variable composition (UVCBs) that are composed of numerous individual constituents. Toxicity studies have shown that some HBPS can produce systemic (repeat-dose) and developmental effects, and some are mutagenic under in vitro conditions. The papers in this supplement show that these effects are related to the profiles of aromatic constituents in these substances. Further, it is shown that the effects on selected repeat-dose and developmental toxicity endpoints and mutagenic activity in bacterial assays can be predicted from compositional information using models based on the aromatic-ring class profile, "ARC profile" as defined by gas chromatographic separation of the DMSO-soluble fraction of the starting materials. This chromatographic method and the predictive models provide an efficient means of characterizing for screening purposes the potential for repeat-dose, developmental effects and bacterial mutagenicity of HBPS and can reduce the number of animal tests that would be required if these tests were conducted on all 110 HBPS., (Copyright © 2012. Published by Elsevier Inc.)

In response to the US EPA HPV Challenge Program, this study was conducted to: (1) evaluate the relationship between PAC content and the developmental toxicity of high-boiling petroleum substances (HBPS) and (2) develop mathematical models to predict the developmental toxicity of similar untested substances based on their aromatic ring class (ARC) profiles. For this investigation, 68 developmental toxicity studies were reviewed. The ARC models relied on data from 21 rat dermal developmental toxicity studies conducted with similar experimental designs to ensure a consistent data set for comparison. The most sensitive general endpoints of developmental toxicity (i.e., decreased fetal survival and growth) were chosen for modeling. The ARC models demonstrated a strong correlation between the predicted vs. observed values for specific sensitive endpoints of these developmental toxicities (percent resorptions, r=0.99; live fetuses per litter, r=0.98; fetal body weight, r=0.94). Such associations provide a promising approach for predicting the developmental toxicity of untested HBPS. Efforts to corroborate the ARC models using test substances that were not used to build the ARC models produced mixed results, and further development and refinement of the ARC models is recommended before they can be reliably applied to all HBPS., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Handlebar injuries are well described in pediatric patients and are frequently associated with internal injuries, including the "classic" duodenal hematoma and solid organ injuries. Before this report, traumatic handlebar hernias were considered rare. They occur when the end of the handlebar (often bare or lacking protective equipment) applies a significant force to a focal area of the abdomen leading to a disruption in the underlying muscle fibers and fascia while sparing the overlying skin. Such nonpenetrating injuries may present with subtle clinical signs and should always be considered in the differential diagnosis. Imaging, with the use of computed tomographic scan or ultrasound will confirm the diagnosis as well as identify any associated injuries. The management plan usually requires surgical exploration and repair of the defect. The prognosis is favorable presuming that there is no significant underlying injury. In this report, we present a series of 5 patients with traumatic handlebar hernia-the most frequently-occurring injury in our series-and review concurrent associated injuries., (Copyright © 2012 Elsevier Inc. All rights reserved.)

An adrenal mass in a newborn usually suggests a diagnosis of neuroblastoma or hemorrhage. A 6-week-old girl was referred for evaluation of a left adrenal mass. The initial findings were most consistent with an adrenal hemorrhage. On surveillance imaging, the lesion was characterized as a complex cystic mass. The patient subsequently developed lesions in the right adrenal gland and liver as well as multiple cutaneous lesions. Although the contralateral adrenal and hepatic lesions resolved spontaneously, the left adrenal and cutaneous lesions persisted. Subsequent imaging revealed that the mural components of the left adrenal mass had increased in size, and at age 13 months, a laparoscopic left adrenalectomy was performed. A benign adrenal adenoma with myxoid changes was reported on surgical pathology. This is the first reported case in a newborn., (Published by Elsevier Inc.)

Objective: The objective of this study was to compare demographic and clinical events in three groups of preterm neonates: those with necrotizing enterocolitis totalis (NEC-T), those with NEC non-totalis (NEC non-T) and in preterm patients without NEC., Study Design: This retrospective case-control study was conducted at Yale New Haven Children's Hospital using patient data from January 1991 to December 2007. Study patients were less than 36 weeks of gestational age (GA) at birth, without gastrointestinal (GI) malformations. Cases (NEC-T) were diagnosed at operation or at autopsy with observation of >80% necrosis of the GI tract. Two control groups were assigned: Group 1 or NEC non-T and Group II or Non-NEC. Two to four controls per case were matched to cases by GA at birth±2 weeks. Demographic and clinical data for the day of diagnosis and retrospectively up to 7 days preceding diagnosis were recorded for those with NEC-T and NEC. Group II controls were matched for date of birth and day of life, in addition to GA at birth., Result: A total of 14 075 patients were admitted to the Newborn Special Care Unit during the study interval. Overall 328 patients (2.3%) developed NEC≥Bell's Stage II; 39 patients met inclusion criteria for NEC-T case status; 148 NEC non-T and 110 non-NEC controls were assigned. In the comparison of NEC T and NEC non-T neonates, use of breast milk was associated with decreased risk of NEC-T, adjusted odds ratio (OR)=0.26, 95% confidence interval (CI) of OR=0.08-0.085, P=0.03. When NEC T and non-NEC patients were compared, having reached full-enteral feeds before the date of diagnosis of the matched case (adjusted OR=28.5, 95% CI of OR=2.7-299, P=0.005) and use of breast milk (adjusted OR=0.09, 95% CI of OR=0.02-0.56, P=0.01) were significantly different between the two groups., Conclusion: Breast milk usage was significantly associated with decreased occurrence of NEC-T in our comparison of NEC-T, NEC non-T and non-NEC patients. Although there were some differences, the majority of demographic and clinical variables assessed were not shown to be significantly different between cases and controls. This highlights the need for more biological data in assessing risk of developing NEC-T.

Background/purpose: In an effort to improve the reporting quality of clinical research, the Journal of Pediatric Surgery instituted specific reporting guidelines for authors beginning June 2006. This study was conducted to evaluate whether these guidelines improved reporting of observational studies., Methods: The Guidelines for the Reporting of Clinical Research Data (Guidelines) included 23 criteria in 3 subcategories: Methods, Results, and More than one treatment group. Reporting quality was evaluated by determining the percentage of criteria met. Seventy-three articles before implementation and 147 articles after implementation were independently assessed by 2 reviewers., Results: Mean global composite scores increased from 72.2 pre-Guidelines to 80.1 post-Guidelines (P < .0001). Scores increased in each subcategory: Methods, 71.9 to 78.6 (P < .0001); Results, 77.2 to 83.0 (P = .002); and More than one treatment group, 40.0 to 70.6 (P = .0003). Post-Guidelines implementation scores have increased over time., Conclusions: The introduction of the Guidelines resulted in significant improvement in the quality of reporting in the Journal. The low cost vs the benefit suggests that the Guidelines can be an effective way to improve reporting quality in nonrandomized studies. We encourage further efforts to increase inclusion of reporting criteria as well as evaluation and improvement of the Guidelines. We suggest that editors of other surgical publications consider implementing analogous guidelines., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: Necrotizing enterocolitis (NEC) remains a major cause of neonatal morbidity and mortality. Some infants recover uneventfully with medical therapy whereas others develop severe disease (that is, NEC requiring surgery or resulting in death). Repeated attempts to identify clinical parameters that would reliably identify infants with NEC most likely to progress to severe disease have been unsuccessful. We hypothesized that comprehensive prospective data collection at multiple centers would allow us to develop a model which would identify those babies at risk for progressive NEC., Study Design: This prospective, observational study was conducted at six university children's hospitals. Study subjects were neonates with suspected or confirmed NEC. Comprehensive maternal and newborn histories were collected at the time of enrollment, and newborn clinical data were collected prospectively, thereafter. Multivariate logistic regression analysis was used to develop a predictive model of risk factors for progression., Result: Of 455 neonates analyzed, 192 (42%) progressed to severe disease, and 263 (58%) advanced to full feedings without operation. The vast majority of the variables studied proved not to be associated with progression to severe disease. A total of 12 independent predictors for progression were identified, including only 3 not previously described: having a teenaged mother (odds ratio, OR, 3.14; 95% confidence interval, CI, 1.45 to 6.96), receiving cardiac compressions and/or resuscitative drugs at birth (OR, 2.51; 95% CI, 1.17 to 5.48), and having never received enteral feeding before diagnosis (OR, 2.41; 95% CI, 1.08 to 5.52)., Conclusion: Our hypothesis proved false. Rigorous prospective data collection of a sufficient number of patients did not allow us to create a model sufficiently predictive of progressive NEC to be clinically useful. It appears increasingly likely that further analysis of clinical parameters alone will not lead to a significant improvement in our understanding of NEC. We believe that future studies must focus on advanced biologic parameters in conjunction with clinical findings.

Editor's note: The study by Simpson and Forsyth published in this issue of JANAC is an evaluation of women's reactions to Connecticut Public Act 99-2, which established mandatory HIV testing for pregnant women in the state. Manuscript reviewers requested further information about the legislation. The authors provide an overview of the legislation in this commentary.

Objectives: This paper describes and compares three innovative methods for preventing perinatal HIV transmission. Each of these strategies has been developed based on an in-depth assessment of the strengths and weaknesses of existing prevention approaches, and the needs of the populations they serve., Methods: Florida expanded an existing outreach program to include women in jails in several high-prevalence counties. Incarcerated women were offered testing for pregnancy and HIV and linked to medical and supportive services. One Connecticut hospital sought to increase prenatal HIV testing rates by requiring HIV test results in the electronic medical records. This program is being expanded to other hospitals throughout the state. Louisiana has implemented a systematic review of perinatal data in order to identify potential programmatic enhancements. This review has led to the perinatal fast track system, designed to quickly identify HIV-infected pregnant women and connect them to care., Results: Each program demonstrated improvements in indicators related to prevention of perinatal HIV transmission, such as increased utilization of prenatal care, increased prenatal testing rates, and decreases in perinatal HIV transmission., Conclusions: These case studies emphasize two key similarities among these programs: the value of collaboration between agencies providing care and services to HIV-infected and high-risk women of childbearing age, and the importance of maximizing opportunities for HIV testing and treatment. These strategies have demonstrated effectiveness in improving health outcomes and reducing perinatal HIV transmission.

Background: There are limited data concerning determinants of varying clinical progression rates in human immunodeficiency virus type 1 (HIV-1)-infected children. Therefore, we sought to determine whether viral or host factors associated with nonprogressive HIV-1 infection in adults play a role in limiting progression of infection in 5 vertically infected youths, ages 12-18 years, who have displayed no signs of advanced HIV-1 disease or acquired immunodeficiency syndrome despite having received minimal treatment with antiretroviral drugs., Results: The 5 individuals, whom we characterize as long term survivors, have maintained low loads of HIV-1 RNA in plasma when compared to many of their peers, and have also maintained normal and stable CD4 T-lymphocyte numbers and percentages throughout their lives. Determination of their predominant HIV-1 sequences revealed that 4 of 5 patients harbor virus with markers of resistance to their therapy (one was never treated). Furthermore 2 harbored viral isolates that contained insertions in Gag or Vif that inhibit HIV-1 replication. Moreover, 2 were found to be heterozygous for the CCR2 polymorphism 64I, a genotype associated with slower progression to acquired immunodeficiency syndrome in adults. All 5 expressed the histocompatibility leukocyte antigen DQ1 and 2 had unusual DR/DQ1 phenotypes., Conclusions: We believe that the limited antiretroviral therapy received by the long term survivors cannot solely account for their benign clinical status. Therefore, we conclude that other factors, including gene polymorphisms that affect viral replicative capacity, account for the long term survival in some, and deduce that, as in adults, no single factor (virologic or host) can account for this clinical phenotype in all cases.

Two novel mutations of the human CLCN1 chloride channel gene, c.592C>G (p.L198V) and c.2255A>G (p.K752R), are described, occurring coincidentally in the one myotonic patient. These individual mutations and a construct with both mutations in the one cDNA were transcribed and expressed in Xenopus oocytes where channel gating parameters were extracted from chloride currents recorded under voltage clamp. We found that the p.L198V mutation has its major effects on the common (or slow) gate of the chloride channel, as do other dominant ClC-1 mutations, and may therefore be causative of the patient's symptoms (when co-expressed with wild-type human ClC-1, the p.L198V mutation exerts a dominant negative effect on common gating) but the p.K752R mutation appears to be innocuous and may be a benign polymorphism. A third mutant, the recently described c.2795C>T (p.P932L), was expressed in HEK 293 cells. Despite the severity of the disease associated with this mutation, chloride currents in cells expressing p.P932L were not significantly different from those of cells expressing wild-type ClC-1., (Copyright 2004 Wiley-Liss, Inc.)

Gasoline (CAS 86290-81-5) is one of the world's largest volume commercial products. Although numerous toxicology studies have been conducted, the potential for reproductive toxicity has not been directly assessed. Accordingly, a two-generation reproductive toxicity study in rats was conducted to provide base data for hazard assessment and risk characterization. The test material, vapor recovery unit gasoline (68514-15-8), is the volatile fraction of formulated gasoline and the material with which humans are most likely to come in contact. The study was of standard design. Exposures were by inhalation at target concentrations of 5000, 10 000, and 20 000 mg/m(3). The highest exposure concentration was approximately 50% of the lower explosive limit and several orders of magnitude above anticipated exposure during refueling. There were no treatment-related clinical or systemic effects in the parental animals, and no microscopic changes other than hyaline droplet nephropathy in the kidneys of the male rats. None of the reproductive parameters were affected, and there were no deleterious effects on offspring survival and growth. The potential for endocrine modulation was also assessed by analysis of sperm count and quality as well as time to onset of developmental landmarks. No toxicologically important differences were found. Therefore, the NOAEL for reproductive toxicity in this study was > or =20 000 mg/m(3). The only systemic effects, in the kidneys of the male rats, were consistent with an alpha-2 u-globulin-mediated process. This is a male rat-specific effect and not relevant to human health risk assessment.

Objectives: To assess changes in the risk of vertical transmission of HIV and changes in both mortality and morbidity among children in southern Connecticut with HIV infection after the introduction of treatment of HIV-infected pregnant women with antiretroviral drugs and of regimens to prevent or to treat AIDS indicator diseases in infected children., Methods: The risk of vertical transmission of HIV, the rates of death and of AIDS indicator diseases and temporal trends in each were determined for children born in the first 5 years of a prospective, longitudinal cohort study (Period 1: December 1, 1985, through November 30, 1990) compared with those for children born during the latter 7 years of the study (Period 2: December 1, 1990, through November 30, 1997)., Results: Of 347 infants enrolled, HIV infection status could be determined for 341; 44 (12.9%) were infected. The risk of vertical transmission declined from 20.7% among children born in Period 1 to 6.5% among children born in period 2 (rate ratio, 3.2; 95% confidence interval, 1.7 to 6.0; P = 0.0001). Of the 21 infected children who died, 11(52%) were < or =18 months of age and 18 (86%) were < or =36 months of age at the times of death. Approximately one-fourth of infected children born during each period died at < or =18 months of age. Among those < or =36 months of age, 15 deaths occurred during 878 person months of observation for those born in Period 1 compared with 3 deaths that occurred during 334 person months for those born in Period 2 (rate ratio, 1.9; 95% confidence interval, 0.5 to 10.3; P = 0.45). Of the 44 children infected with HIV, 32 had one or more AIDS indicator diseases (a total of 67 episodes), 73% of which occurred when the children were < or =36 months of age. Among children born in Period 2, none developed Pneumocystis carinii pneumonia and the rates of Mycobacterium avium complex disease and of wasting syndrome declined, but the differences in rates of disease were not statistically significant., Conclusion: A substantial and statistically significant decline in the risk of vertical transmission of HIV-1 occurred during the 12-year study period. In contrast although there was a trend toward a decrease in mortality among HIV-infected children < or =36 months of age and changes in the overall rates of AIDS indicator diseases among children born in Period 1 compared with Period 2, the differences were not statistically significant.

The modulating effects of the epidermal growth factor (EGF) receptor-specific tyrosine kinase inhibitor ZM 252868 on cell growth and signalling have been evaluated in four ovarian carcinoma cell lines PE01, PE04, SKOV-3 and PE01CDDP. Transforming growth factor alpha (TGF-alpha)-stimulated growth was completely inhibited by concentrations > or =0.3 microM in the PE01 and PE04 cell lines and by > or =0.1 microM in SKOV-3 cells. TGF-alpha inhibition of PE01CDDP growth was reversed by concentrations > or =0.1 microM ZM 252868. TGF-alpha-stimulated tyrosine phosphorylation of both the EGF receptor and c-erbB2 receptor in all four cell lines. The inhibitor ZM 252868, at concentrations > or =0.3 microM, completely inhibited TGF-alpha-stimulated tyrosine phosphorylation of the EGF receptor and reduced phosphorylation of the c-erbB2 protein. EGF-activated EGF receptor tyrosine kinase activity was completely inhibited by 3 microM ZM 252868 in PE01, SKOV-3 and PE01CDDP cells. These data indicate that the EGF receptor-targeted TK inhibitor ZM 252868 can inhibit growth of ovarian carcinoma cells in vitro consistent with inhibition of tyrosine phosphorylation at the EGF receptor.

The role of skin irritation and other factors on the tumorigenic activity of petroleum middle distillates (PMDs) in mice was examined in a comprehensive research program. The program culminated in a 2-year dermal carcinogenicity study which compared the effects of equal weekly doses of irritating and nonirritating PMDs. Modified Ames mutagenicity studies and three- to seven-ring polycyclic aromatic compound (PAC) analyses indicated that the mutagenic activity of PMDs was correlated to PAC content. In subchronic and subacute studies, PMDs produced marked skin irritation which was ameliorated if the test samples were diluted in mineral oil. The reduction in irritation level was not a result of reduced dermal absorption. Straight-run kerosine (SRK), straight-run gas oil (SRGO), and catalytically cracked light cycle oil (LCO) were evaluated in the dermal carcinogenicity study. Test materials were applied either undiluted (2x/week) or as 28.5% (7x/week) or 50% (4x/week) concentrations in mineral oil for a total weekly dose of 100 microliters PMD per animal. All three materials produced moderate to marked skin irritation and increased tumor frequency when applied undiluted. When diluted, the irritant effects of SRK and SRGO, which contain low levels of PACs, were ameliorated, and there were no significant increases in tumors relative to controls. LCO, containing 8.7% three- to seven-ring PACs, increased tumor frequency when diluted, even when skin irritation was limited. These data indicate that the tumorigenic activity of straight-run MDs is likely a consequence of a nongenotoxic process, associated with frequent cell damage and repair. PMDs which contain low levels of three- to seven-ring PACs are unlikely to cause tumors in the absence of prolonged skin irritation. In addition, genotoxic mechanisms may also contribute to tumor formation for other PMDs containing higher levels of PACs, e.g., products blended with cracked stocks.

Transforming growth factor alpha (TGFalpha) may be induced by estrogen in estrogen responsive systems and can contribute to the growth-modulatory effects of this hormone. To test whether TGFalpha contributes to estrogen-regulated growth in ovarian cancers, we have compared the effects of 17beta-estradiol (E2) and TGFalpha in a range of ovarian carcinoma cell lines. Addition of E2 to the estrogen receptor (ER)-positive cell lines (PE01, PE04 and PE01CDDP) produced a 2-4 fold increase in TGFalpha protein concentrations in media conditioned by the cells. Both E2 and TGFalpha stimulated the growth of the PE01 and PE04 lines and inhibited the growth of the PE01CDDP line. Furthermore, the E2-mediated growth effects could be reversed by an epidermal growth factor (EGF) receptor-targeted antibody. E2 also down-regulated EGF receptor expression in ER-positive cell lines. In a series of primary ovarian tumors, higher concentrations of ER were associated with an increased percentage of tumors expressing TGFalpha mRNA and a decreased percentage expressing EGF receptor protein. All these data are consistent with E2 increasing production of TGFalpha in ER-positive ovarian cancer and this in turn acting through the EGF receptor to modulate growth in an autocrine manner.

Residential camping sessions for children with vertically transmitted human immunodeficiency virus/acquired immunodeficiency syndrome have been offered at The Hole In The Wall Gang Camp for the past six summers. More than 600 children 6 to 12 years of age have attended. Such sessions are expensive and require extensive planning. Medical and nursing needs have increased greatly over the 6-year period, reflecting advances in treatment and especially an escalation of prescribed medications. We have found it possible for these children to have a fun-filled camping experience and participate in a wide variety of activities.

In a prospective cohort study of 267 children born to mothers infected with HIV-1 in New Haven, Connecticut, an abrupt decline in the risk of mother-to-child transmission occurred in 1990 and persisted at least through December, 1993. A retrospective, observational study was undertaken to identify factors that might be responsible for this decline. Three variables were assessed: the use of orally administered zidovudine during pregnancy, the CD4+ T-lymphocyte count of the mother, and the mode of delivery. The risk of transmission was 18.6% (36/194; 95% CI: 14.1-24.8%) in infants of all women not treated with zidovudine compared with 5.5% (3/55; 95% CI: 1.1-15.1%) in infants of all women who were treated (odds ratio: 0.25; p = 0.02). In a subgroup of women with known CD4+ cell counts, the risk of transmission was 21.1% (20/95; 95% CI: 13.4-30.6%) in untreated women compared with 5.5% (3/55) in those who received zidovudine (odds ratio: 0.22; p = 0.01). In women with CD4+ T-cell counts < 200/microl, the differences remained significant (39.1% in those not treated vs. 4.2% in those treated; p < 0.004). There was an inverse relationship between CD4+ cell count and risk of transmission: among untreated mothers whose T-lymphocyte counts were > or = 500, 200-499, or < 200/microl, HIV-1 was transmitted to the offspring of 8.2, 30.4, and 39.1% of offspring, respectively (p < 0.002 by the exact trend test). There was no significant association between mode of delivery and vertical transmission of HIV. We conclude that treatment with orally administered zidovudine alone (500 mg/day) in the course of routine prenatal care is associated with a significant reduction in the risk of vertical transmission.

Subchronic 90-day feeding studies were conducted in male and female Fischer-344 (F-344) rats on highly refined white mineral oils and waxes representative of those used for food applications. The goal was to help clarify the mixed results found in other toxicity studies with laboratory animals. Seven white oils and 5 waxes were fed at dietary doses of 20,000, 2,000, 200, and 20 ppm and compared with control groups on untreated diet; toxicity was assessed at 90 days and also after a reversal period of 28 days and/or 85 days. Higher molecular-sized hydrocarbons (microcrystalline waxes and the higher viscosity oils) were without biological effects. Paraffin waxes and low- to midviscosity oils produced biological effects that were inversely related to molecular weight, viscosity, and melting point; oil type and processing did not appear to be determinants. Biological effects were more pronounced in females than in males. Effects occurred mainly in the liver and mesenteric lymph nodes and included increased organ weights, microscopic inflammatory changes, and evidence for the presence of saturated mineral hydrocarbons in affected tissues. Inflammation of the cardiac mitral valve was also observed at high doses in rats treated with paraffin waxes. Further studies are required to elucidate the mechanism for the responses observed and the relevance of these inflammatory responses in the F-344 rat to other species, including humans.

The expression of mRNA for the epidermal growth factor (EGF) receptor, EGF and transforming growth factor alpha (TGF-alpha) was determined in 76 malignant, six borderline and 15 benign primary ovarian tumours using the reverse transcriptase-polymerase chain reaction and related to clinical and pathological parameters. Of the malignant tumours, 70% (53/76) expressed EGF receptor mRNA, 31% (23/75) expressed EGF mRNA and 35% (26/75) expressed TGF-alpha mRNA. For the borderline tumours, four of six (67%) expressed EGF receptor mRNA, 1/6 (17%) expressed TGF-alpha mRNA and none expressed EGF mRNA. Finally, 33% (5/15) of the benign tumours expressed EGF receptor mRNA, whereas 40% (6/15) expressed EGF mRNA and 7% (1/15) expressed TGF-alpha mRNA. The presence of the EGF receptor in malignant tumours was associated with that of TGF-alpha (P = 0.0015) but not with EGF (P = 1.00), whereas there was no relationship between the presence of EGF and TGF-alpha (P = 1.00). EGF receptor mRNA expression was significantly and positively associated with serous histology (P = 0.006) but not with stage or grade. Neither EGF nor TGF-alpha showed any link with histological subtype or stage. The survival of patients with malignant tumours possessing EGF receptor mRNA was significantly reduced compared with that of patients whose tumours were negative (P = 0.030 for all malignant tumours; P = 0.007 for malignant epithelial tumours only). In contrast, neither the expression of TGF-alpha nor EGF was related to survival. These data suggest that the presence of EGF receptor mRNA is associated with poor prognosis in primary ovarian cancer.

The regulatory subunits of protein kinase A, or cyclic AMP-binding proteins, were measured in a series of 107 human ovarian tumors (89 malignant, 7 borderline, and 11 benign tumors) and related to tumor clinicopathological features and patient survival. Total cyclic AMP-binding protein levels were not significantly different between malignant tumors and either borderline or benign tumors. However, serous tumors showed significantly higher levels of total cyclic AMP-binding proteins than other malignant tumors (P = 0.007). Poorly differentiated tumors also possessed significantly higher levels of binding proteins as compared with well/moderately differentiated tumors (P < 0.01). Retrospective analysis of follow-up data also revealed a significant trend for patients with high tumor cyclic AMP-binding proteins to have poorer survival (P = 0.03). Individual binding proteins were identified by photoaffinity labeling, and the RI (Mr 48,000) protein was expressed as a percentage of total cyclic AMP-binding proteins detected. The percentage of the RI protein was not significantly different among malignant, borderline, or benign pathologies and was not associated with tumor stage, differentiation, or debulk status. The percentage of RI was significantly increased in serous tumors compared to other common epithelial malignancies (P = 0.01). In malignant tumors there was a significant positive correlation between the percentage of the RI protein and total cyclic AMP-binding proteins (P = 0.01). These data indicate that high tumor levels of cyclic AMP-binding proteins are associated with serous histology, poor differentiation, and poor patient survival.

Immunohistochemical expression of EGF-R, c-erbB-2 and c-erbB-3, members of the type-1 family of receptor tyrosine kinases, were investigated in 67 primary ovarian-tumour samples (46 malignant, 8 borderline and 13 benign), and related to tumour clinicopathological features. The incidence of all 3 receptor proteins was highest in overtly malignant tumours. No significant correlations were observed between either EGF-R or c-erbB-3 and clinical parameters such as tumour stage, differentiation or extent of debulking surgery, but c-erbB-2 was significantly associated with several indicators of prognosis, including early stage and good/moderate differentiation in optimally debulked tumours. Multiple expression of c-erbB receptor proteins was also significantly higher in malignant tumours compared with borderline and benign tumours. Early-stage tumours were also more likely to express multiple c-erbB-receptor proteins than were late-stage tumours. Co-expression of EGF-R with c-erbB-2, and c-erbB-2 with c-erbB-3 was significantly greater in malignant tumours than in borderline or benign tumours, and within the malignant tumour group, positive associations were observed between EGF-R and c-erbB-3, also between c-erbB-2 and c-erbB-3. Because of the evidence of increased expression of individual c-erbB proteins as well as multiple expression of this family of growth-factor receptors in malignant ovarian tumours, we hypothesize that stimulation by the appropriate ligands may confer a selective advantage to cells expressing more than one receptor. Increased expression of c-erbB growth-factor receptors in malignancy may mediate increased propensity for tumour development.

In this study the expression of c-erbB-3 protein was investigated in a range of human ovarian tumours using a monoclonal antibody (RTJ1) raised to a synthetic peptide from the cytoplasmic domain of the human c-erbB-3 protein. A total of 73 samples from 71 patients were graded as negative, weak, moderate or strong according to the intensity of immunohistochemical staining observed, and this was related to tumour characteristics and other clinical parameters. In terms of positivity vs negativity, of the 73 samples examined, 62 (85%) showed positive immunohistochemical staining for c-erbB-3. The majority of all ovarian tumours studied were positive for c-erbB-3 regardless of whether they were malignant (89%), borderline (100%) or benign (61%), however the incidence of positivity was significantly less in the benign group than in overtly malignant tumours (P = 0.03). c-erbB-3 positivity was not significantly associated with either age at diagnosis, tumour stage, differentiation, ploidy, percentage in S-phase or post-operative tumour bulk in malignant tumours. In terms of intensity of staining no significant difference was observed either within the common epithelial group or between this group and tumours of a benign nature. A significantly more intense pattern of c-erbB-3 staining was observed in tumours of borderline malignancy when compared with their overtly malignant counterparts (P = 0.002). Patients presenting with early-stage malignant tumours (I/II) were more likely to display intense tumour staining than those with late-stage disease (III/IV) (P = 0.04). These investigations suggest that c-erbB-3 protein is frequently expressed in both benign and malignant ovarian tumours, and that overexpression is more common in borderline and early invasive lesions.

Testes from adult (90-120-day-old) rats, which had been made cryptorchid 28 days previously, were dispersed by successive treatment with trypsin, collagenase and hyaluronidase. The resulting crude cell suspension was fractionated on discontinuous Percoll density gradients to yield five distinct cell bands (1-5), at the interface between successive layers of Percoll. Crude cells and purified fractions were cultured for up to 7 days, and inhibin was subsequently measured in the media by radioimmunoassay and in vitro bioassay. Sertoli cells from density gradient bands 2 (1.03-1.04 g/ml) and 3 (1.04-1.05 g/ml) showed minimal germ cell or peritubular cell contamination, as determined by morphological and histochemical techniques. Cells from these bands secreted significantly higher levels of immunoactive inhibin/microgram DNA/48 h under both basal and either follicle-stimulating hormone (FSH)- (100 ng/ml) or dibutyryl cAMP-stimulated (100 micrograms/ml) conditions than did cells from the other bands. While there was a decline in basal secretion of inhibin with increasing duration of culture, the capacity of the purified Sertoli cells (bands 2 and 3) to respond to both FSH and dibutyryl cAMP increased over the culture period. The addition of dibutyryl cAMP (31.25-500 micrograms/ml) to the purified Sertoli cells also caused a stimulation of bioactive inhibin. Immunoactive inhibin production by purified Sertoli cells was unaffected by the addition of either rat LH (8 ng/ml) or testosterone (10(-6) M). The data describe a method for the isolation of adult Sertoli cells from cryptorchid testes, and demonstrate their responsiveness to both FSH and dibutyryl cAMP in vitro using the measurement of immunoactive inhibin as a marker of Sertoli cell function.

This investigation compared the effects of feeding rats diets containing food grade white oil processed by either conventional oleum treatment or the more modern method of catalytic hydrogenation. In two separate experiments, male or female Fischer-344 rats were given free access for 90 days to diets containing 0, 10, 100, 500, 5,000, 10,000, or 20,000 ppm of either oleum-treated white oil (OTWO) or hydrotreated white oil (HTWO). There were no mortalities and no adverse clinical signs associated with feeding either white oil. Treatment-related effects evidenced by hematological, clinical chemical, and pathological changes were generally dose-related and more marked in female than in male rats, and the OTWO caused a greater pathological response than the HTWO. Tissue residues of saturated hydrocarbons were up to 5.2 times higher in female rats than in males. Rats fed 5,000 ppm or more of either white oil showed dose-related alterations in several hematological and clinical chemistry variates associated mainly with hepatic damage or functional alteration. At necropsy, mesenteric lymph nodes were enlarged, and increases in weight of liver, kidney, and spleen were significant. Microscopic changes were characterized by multifocal lipogranulomata in mesenteric lymph node and liver. No changes were observed in rats fed OTWO or HTWO for 90 days at dietary concentrations of 10 or 100 ppm, equivalent to a minimum intake of 0.65 and 6.4 mg/kg/day, respectively. Differences in degree of pathological response associated with each oil may have been due to their differences in specification rather than processing method.

The mechanism by which luteinizing hormone (LH) stimulates Leydig cell immunoactive inhibin (I-inhibin) secretion was investigated using Percoll-purified adult rat Leydig cells. Using a maximally stimulating dose of LH (16 ng/ml). Leydig cell I-inhibin secretion was non-detectable at 1-2 h of incubation, but subsequently increased at all time points during a 25 h incubation period. LH stimulated both Leydig cell content and release of I-inhibin. Increasing concentrations of LH stimulated both inhibin and testosterone immunoactivity in the incubation media over a similar dose-response range, with a 2- to 4-fold rise in I-inhibin secretion at maximal doses of LH. Dibutyryl cAMP stimulated testosterone secretion in a manner similar to that of LH, but I-inhibin secretion was less sensitive than testosterone and a significant stimulation was observed only at the highest doses (200-1000 micrograms/ml). LH-stimulated I-inhibin secretion was significantly decreased when Leydig cells were incubated in calcium-depleted (0.15 mM Ca2+ + 1 mM EGTA) or low [Ca2+] media (0.15 mM) as compared to normal (1.15 mM) or high [Ca2+] (2-5 mM) media. In contrast, LH-stimulated testosterone secretion remained unchanged by altering extracellular [Ca2+], and although decreased in the presence of EGTA, testosterone secretion remained significantly greater than basal levels. Furthermore both diltiazem and verapamil completely blocked the LH and dibutyryl cAMP-stimulated increase in Leydig cell I-inhibin, but did not reduce either LH or dibutyryl cAMP-stimulated testosterone production to basal levels. We conclude that LH stimulates both I-inhibin synthesis and release by adult rat Leydig cells in culture, by mechanisms involving calcium.

In an attempt to determine the rate of transmission of infection from human immunodeficiency virus type 1 (HIV-1) antibody-positive women to their offspring and to describe the short-term outcome of perinatal infection, we enrolled 62 infants in a prospective cohort study during a 30-month period and followed them up for an additional 6 months. The clinical, immunologic, and serologic status of the children was assessed prospectively. Fourteen subjects were symptomatic: 3 had acquired immunodeficiency syndrome, 5 had signs and symptoms that were compatible with HIV-1 infection (Centers for Disease Control, Atlanta, Ga, class P2A), and 6 had ill-defined symptoms that could not be definitely attributed to HIV. Our data indicated that the maximum rate of vertical transmission of HIV-1 infection in New Haven, Conn, was less than 30%, and the rate of HIV-1-associated disease occurring during the first 3 years of life was 16%. The mean and median time to loss of maternal antibody, as detected by Western blot in seroreverters, was approximately 7 months, and the half-life of passive antibody was 38 days. A continued close follow-up of children in the cohort studied, and others like it, is critical to learn the full range of outcomes of HIV infection in the pediatric population.

A quantitative histological estimation of the optic nerve of pre-weanling rats has revealed that the total fiber number decreases rapidly between 7 and 25 days of age.

Inhibin bioactivity was measured in human testicular extracts by a sensitive sheep pituitary cell bioassay. The relationship between testicular inhibin bioactivity, daily sperm production (DSP) and plasma concentrations of FSH, LH, testosterone and oestradiol were examined. The mean level of testicular inhibin bioactivity was 4.4 +/- 1.3 U/g (mean +/- SD) with a significantly lower value in those who received radiotherapy (3.2 +/- 1.4 U/g) than in the untreated group (4.8 +/- 1.1 U/g). In contrast to the rat, human testicular inhibin bioactivity was not significantly correlated to FSH or DSP. These findings suggest that inhibin may have a complex role in normal and/or pathological testicular function.

Spraying or swabbing with a mixture of polyethylene glycol 300/industrial methylated spirits (PEG-300/IMS) (2:1 by volume) has been shown to substantially reduce mortality, systemic effects, and skin burns resulting from skin contamination by phenol, cumene hydroperoxide, or phenol/acetone cleavage product. The skin-damaging potentials of sodium hydroxide and sulfuric acid have also been investigated. PEG-300/IMS(2:1 by volume) mixture was found, in rats, to be slightly less effective than water as means of decontamination. The PEG-300/IMS mixture has been shown not to cause eye irritation, and so should not present a hazard where this mixture is used as a decontaminant spray.

The AIDS epidemic presents the health care delivery system with a number of diverse and complex challenges. Some institutions will perceive the problems associated with this disease as being overwhelming and insurmontable. Others will be stimulated by the scientific and ethical issues presented. The need to strike a balance, which incorporates the needs of the institution and the population to be served, cannot be stressed enough. The proper planning of an institutional response to this epidemic should involve an evaluation of internal resources, the investigation of existing models of AIDS care, and an assessment of the patient population. The departments of nursing, medicine, pediatrics, and social work can provide invaluable input into this process. Consultation with community-based agencies is also stressed, as these organizations provide an important source of supportive care to outpatients. A number of concerns are raised when institutions begin to plan and develop responses to the AIDS epidemic. These concerns often center on the perception that a visible commitment to persons with AIDS-related illnesses will keep other patients away or that attention and resources will be diverted from other equally serious conditions. Such concerns are reasonable and must be taken into account when planning any type of dedicated services. Particular care must be taken to avoid diverting resources from other programs. For institutions already providing care to large numbers of AIDS patients, the decision to centralize services and provide a more comprehensive approach to care is often a matter of relocation as opposed to introduction of a new patient care service.(ABSTRACT TRUNCATED AT 250 WORDS)

Leydig cells were purified on discontinuous Percoll gradients after collagenase digestion of human or rat testes. Leydig cells from both species were found in three bands. As determined by positive staining for 3 beta-hydroxysteroid dehydrogenase, band 1 (lowest density cells) from both species contained only 12-28% Leydig cells. However, while band 3 was the most Leydig cell-enriched fraction in rat cell preparations (70-90% Leydig cells), human band 2 (48-70% Leydig cells) was consistently more Leydig cell enriched than was band 3 (30-56% Leydig cells). Despite their slightly different fractionation pattern, Leydig cells prepared from five men with prostatic carcinoma were similar to those from the rat, both in terms of the amount of testosterone produced basally per 10(6) Leydig cells (80-234 ng/20 h) and in terms of the magnitude of their response to hCG (764-1342 ng/10(6) Leydig cells X 20 h; 5- to 17-fold stimulation above basal). Cells prepared from five other men with prostatic carcinoma produced much lower amounts of testosterone, but still had up to a 6-fold response to hCG. Plasma LH, FSH, and testosterone concentrations in the latter group could not be distinguished from those in the group whose Leydig cells produced large amounts of testosterone in vitro. Morphologically, the testes from the latter group appeared to contain more darkly staining than lightly staining Leydig cells than did the former group. Rat Leydig cells responded in a dose-dependent fashion to hCG over the range 0.03-0.5 mU/mL, whereas human Leydig cells were 10- to 100-fold less sensitive, responding to hCG in the range 0.4-100 mU/mL. The number and affinity of Leydig cell LH (hCG) receptors were assessed from Scatchard analysis of [125I]hCG binding. Compared with rat cells, human Leydig cells contained approximately 20% of the number of LH receptors, while the affinity of the receptors (Kd, approximately 10(-10) M) was similar to that in rats. In conclusion, a method for the isolation of highly responsive human Leydig cells has been developed. The results so far suggest that the function of human Leydig cells may be more similar to that of the rat than thought previously.

The carcinogenic effects of limited and repeated skin applications of propane sultone were investigated in three strains of mice, CF1, C3H and CBah (a hairless strain). Propane sultone was shown to be carcinogenic when given as a single application of a 25% w/v solution in toluene and also following twice weekly application of a 2.5% w/v solution for up to 58 weeks. More limited exposure to 2.5% w/v solutions of propane sultone resulted in a few skin tumours, although the incidences were not statistically significant. Most neoplasms were papillomas or carcinomas, although a small number of mesenchymal tumours of dermal origin also developed. No skin neoplasms were found in any control mice. The skin application of propane sultone was associated with a statistically significant increase in the incidence of systematic neoplasia in CFl and C3H mice. The exposed CFl mice had a higher incidence of neoplasms of lymphoreticular and lung origin, while female C3H mice showed a higher incidence of mammary gland and uterine tumours. In mice exposed to beta-propiolactone as a positive control, neoplasms developed at the site of application but, there was no evidence of increased systemic neoplasis in contrast to the findings with ptopane sultone.