Cyclic adenosine 3',5'-monophosphate-binding proteins in human ovarian cancer: correlations with clinicopathological features.

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.

Isolation of human Leydig cells which are highly responsive to human chorionic gonadotropin.

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.

Inhibin bioactivity in human testicular extracts.

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.

Characterisation of adult Sertoli cell cultures from cryptorchid rats: inhibin secretion in response to follicle-stimulating hormone stimulation.

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.

The role of calcium in luteinizing hormone/human chorionic gonadotrophin stimulation of Leydig cell immunoactive inhibin secretion in vitro.

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.

Prospective cohort study of children born to human immunodeficiency virus-infected mothers, 1985 through 1997: trends in the risk of vertical transmission, mortality and acquired immunodeficiency syndrome indicator diseases in the era before highly active antiretroviral therapy.

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.

Estrogen regulation of transforming growth factor-alpha in ovarian cancer.

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.

A comprehensive evaluation of the mechanism of skin tumorigenesis by straight-run and cracked petroleum middle distillates.

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.

The AIDS epidemic: developing an institutional response.

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)

The carcinogenic response in mice to the topical application of propane sultone to the skin.

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.

Assessment in rats of the reproductive toxicity of gasoline from a gasoline vapor recovery unit.

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.

Decontamination procedures for skin exposed to phenolic substances.

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.

Risk factors for necrotizing enterocolitis totalis: a case-control study.

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.

Clinical parameters do not adequately predict outcome in necrotizing enterocolitis: a multi-institutional study.

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.

A quantitative morphological study of the optic nerve of pre-weanling rats.

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.

Reduction in the risk of vertical transmission of HIV-1 associated with treatment of pregnant women with orally administered zidovudine alone.

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.

A residential summer camp for children with vertically transmitted HIV/AIDS: a six-year experience at the Hole in the Wall Gang Camp.

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.

Rate of transmission of human immunodeficiency virus type 1 infection from mother to child and short-term outcome of neonatal infection. Results of a prospective cohort study.

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.

c-erbB growth-factor-receptor proteins in ovarian tumours.

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.