From adolescence to parenthood: a multi-decade study of preconception mental health problems and postpartum parent-infant bonds.

PURPOSE: To examine associations between anxiety and depressive symptoms across adolescence and young adulthood with subsequent maternal- and paternal-infant bonding at 1 year postpartum. METHODS: The data were from a prospective, intergenerational cohort study. Participants (381 mothers of 648 infants; 277 fathers of 421 infants) self-reported depression and anxiety at three adolescent waves (ages 13, 15 and 17 years) and three young adult waves (ages 19, 23 and 27 years). Subsequent parent-infant bonds with infants were reported at 1 year postpartum (parent age 29-35 years). Generalised estimating equations (GEE) separately assessed associations for mothers and fathers. RESULTS: Mean postpartum bonding scores were approximately half a standard deviation lower in parents with a history of persistent adolescent and young adult depressive symptoms (maternal ßadj = - 0.45, 95% CI - 0.69, - 0.21; paternal ßadj = - 0.55, 95% CI - 0.90, 0.20) or anxiety (maternal ßadj = - 0.42, 95% CI - 0.66, - 0.18; paternal ßadj = - 0.49, 95% CI - 0.95, 0.03). Associations were still mostly evident, but attenuated after further adjustment for postpartum mental health concurrent with measurement of bonding. CONCLUSIONS: Persistent symptoms of depression or anxiety spanning adolescence and young adulthood predict poorer emotional bonding with infants 1-year postbirth for both mothers and fathers.

Childhood disadvantage and adolescent socioemotional wellbeing as predictors of future parenting behaviour.

INTRODUCTION: In extending work on early life antecedents of parenting, we investigate associations between childhood family history of disadvantage, adolescent socioemotional wellbeing, and age at first parenthood and subsequent parenting behaviour. METHODS: Parent-child interactions were recorded when participants in the longitudinal Dunedin Multidisciplinary Health and Development Study (New Zealand) had a three-year-old child. Data were available for 358 mothers and 321 fathers, aged between 17.7 and 41.5 at the time of their child's birth. Associations between parenting and antecedent data on socioeconomic disadvantage, adolescent wellbeing and mental health, as well as current adult mental health and age at parenting, were tested for using structural equation modelling. RESULTS: Family disadvantage in childhood and lower adolescent wellbeing was associated with less positive future parenting, but only adult (not adolescent) anxiety/depression symptoms were directly associated with parenting behaviour. Childhood family disadvantage was associated with further disadvantage across the life course that included less positive parenting of the next generation. In contrast, socioemotional wellbeing during adolescence and later age of onset of parenting were associated with more positive parenting. CONCLUSIONS: Reducing childhood disadvantage and improving socioemotional wellbeing during childhood and adolescence is likely to have intergenerational benefits through better parenting of the next generation.

The natural history of risky drinking and associated harms from adolescence to young adulthood: findings from the Australian Temperament Project.

BACKGROUND: We aimed to describe the natural history of heavy episodic drinking (HED) and associated harms from adolescence to young adulthood in a large Australian population cohort study. METHOD: The Australian Temperament Project consists of mothers and babies (4-8 months) recruited from Infant Welfare Centres and followed every 2 to 4 years until age 28 years. Analyses were based on data from 1156 young people (497 male; 659 female) surveyed repeatedly at ages 16, 18, 20, 24 and 28 years. We used dual processes latent class growth analysis to estimate trajectories of HED and associated harms, employing a piecewise approach to model the hypothesized rise and subsequent fall across adolescence and the late twenties, respectively. RESULTS: We identified four sex-specific trajectories and observed little evidence of maturing-out across the twenties. In males, a normative pattern of increasing HED across the twenties with little related harm was observed (40% of the male sample). Early and late starter groups that peaked in harms at age 20 years with only minor attenuation in binging thereafter were also observed (6.1% and 35%, respectively). In females, a normative pattern of increasing, but moderate, HED with little related harm was observed (44% of the female sample). Early and late starter groups were also identified (18% and 17%, respectively); however, unlike males, the female late starter group showed a pattern of increasing HED and related harms. CONCLUSIONS: Continued patterns of risky alcohol use and related harms are apparent for both males and females across the twenties.

The natural history of internalizing behaviours from adolescence to emerging adulthood: findings from the Australian Temperament Project.

BACKGROUND: The aims of the study were to describe the patterning and persistence of anxiety and depressive symptoms from adolescence to young adulthood and to examine long-term developmental relationships with earlier patterns of internalizing behaviours in childhood. METHOD: We used parallel processes latent growth curve modelling to build trajectories of internalizing from adolescence to adulthood, using seven waves of follow-ups (ages 11-27 years) from 1406 participants of the Australian Temperament Project. We then used latent factors to capture the stability of maternal reported child internalizing symptoms across three waves of early childhood follow-ups (ages 5, 7 and 9 years), and examined relationships among these patterns of symptoms across the three developmental periods, adjusting for gender and socio-economic status. RESULTS: We observed strong continuity in depressive symptoms from adolescence to young adulthood. In contrast, adolescent anxiety was not persistent across the same period, nor was it related to later depressive symptoms. Anxiety was, however, related to non-specific stress in young adulthood, but only moderately so. Although childhood internalizing was related to adolescent and adult profiles, the associations were weak and indirect by adulthood, suggesting that other factors are important in the development of internalizing symptoms. CONCLUSIONS: Once established, adolescent depressive symptoms are not only strongly persistent, but also have the potential to differentiate into anxiety in young adulthood. Relationships with childhood internalizing symptoms are weak, suggesting that early adolescence may be an important period for targeted intervention, but also that further research into the childhood origins of internalizing behaviours is needed.

A role for the DRD4 exon III VNTR in modifying the association between nicotine dependence and neuroticism.

INTRODUCTION: Neurotic psychopathology has been extensively examined as a risk factor for nicotine dependence (ND). Genetic stratification may partially explain variability in risk estimates. Genetic variants that compromise dopaminergic neurotransmission may motivate exposure to dopamine-stimulating agents, including nicotine. The 7-repeat allele of a Variable Number Tandem Repeat (VNTR) polymorphism in DRD4 (and evolutionary derivatives 5, 6, and 8 repeats; 7R+) is associated with reduced dopamine receptor function. The purpose of this study was to examine association between both smoking initiation (SI) and progression to ND by young adulthood and (a) history of neuroticism during adolescence, (b) DRD4 7R+, and (c) interaction between neuroticism and DRD4 7R+. METHODS: Participants were drawn from the Victorian Adolescent Health Cohort Study, a longitudinal study of the health and well-being of young Australians across 8 waves (14-24 years). Neuroticism was measured at Waves 3 and 6 (mean 15.9 and 17.4 years). SI was defined as any smoking at any wave. ND was measured at Wave 8 (mean 24.1 years). Genotype data for the DRD4 VNTR were available for 839 participants. RESULTS: While adolescent neuroticism was associated with SI, evidence for association with progression to ND was weak. However, there was evidence of interaction between neuroticism and DRD4 7R+: The odds of progression to ND among those with a history of neuroticism were more than 3.5-fold higher among 7R+ carriers. CONCLUSIONS: Without considering stratification by 7R+, the association between progression to ND and neuroticism would have been assumed barely significant. However, among those carrying DRD4 7R+, risk of progression was considerably intensified.

Psychosocial predictors of binge-drinking residual harm in adolescence and young adulthood: Findings from the Australian Temperament Project.

AIMS: We examine the extent to which adolescent and young adult psychosocial factors are associated with variation in the experience of common types of harm (e.g., injuries, violence, sexual regrets) with respect to binge-drinking frequency - termed residual harm. METHODS: Data were from the Australian Temperament Project, a population-based cohort study that has followed a sample of young Australians from infancy to adulthood since 1983. The current sample comprised 1,081 (565 women). Residual harm was operationalised by saving residuals from models regressing number of alcohol harms onto binge-drinking frequency at each of 5 waves, two in adolescence (15-16 and 17-18 years) and three in young adulthood (19-20, 23-24, and 27-28 years). Psychosocial factors (mental health, social skills, quality of parent and peer relationships) were assessed prior to binge drinking in early adolescence (13-14 years) and then again in young adulthood (19-20 years). RESULTS: Adolescent predictors of decreased residual harm were lower depressive symptoms, and higher cooperation, self-control, and peer and parent attachment. Young adult predictors of decreased residual harm were lower depressive, anxiety, and stress symptoms and peer and parent negative appraisal, and higher responsibility, and peer and parent emotional support. Associations were evident in males and females, although the strength of some associations diminished with age. CONCLUSIONS: Adolescents and young adults with better mental health, social skills, and relationship quality experienced less harm with respect to their binge-drinking frequency. Future research should examine the potential of investment in strength-based interventions for young people.

Exploring a causal model in observational cohort data: The role of parents and peers in shaping substance use trajectories.

AIMS: To explore the process of applying counterfactual thinking in examining causal determinants of substance use trajectories in observational cohort data. Specifically, we examine the extent to which quality of the parent-adolescent relationship and affiliations with deviant peers are causally related to trajectories of alcohol, tobacco, and cannabis use across adolescence and into young adulthood. METHODS: Data were drawn from the Australian Temperament Project, a population-based cohort study that has followed a sample of young Australians from infancy to adulthood since 1983. Parent-adolescent relationship quality and deviant peer affiliations were assessed at age 13-14 years. Latent curve models were fitted for past month alcohol, tobacco, and cannabis use (n = 1590) from age 15-16 to 27-28 years (5 waves). Confounding factors were selected in line with the counterfactual framework. RESULTS: Following confounder adjustment, higher quality parent-adolescent relationships were associated with lower baseline cannabis use, but not alcohol or tobacco use trajectories. In contrast, affiliations with deviant peers were associated with higher baseline binge drinking, tobacco, and cannabis use, and an earlier peak in the cannabis use trajectory. CONCLUSIONS: Despite careful application of the counterfactual framework, interpretation of associations as causal is not without limitations. Nevertheless, findings suggested causal effects of both parent-adolescent relationships and deviant peer affiliations on the trajectory of substance use. Causal effects were more pervasive (i.e., more substance types) and protracted for deviant peer affiliations. The exploration of causal relationships in observational cohort data is encouraged, when relevant limitations are transparently acknowledged.

Patterns of adolescent smoking and later nicotine dependence in young adults: a 10-year prospective study.

OBJECTIVES: There is considerable variability in progression from smoking initiation to established smoking. This paper addresses the extent to which different patterns of adolescent smoking, including periods of cessation, predict smoking status in young adults. STUDY DESIGN: Ten-year, eight-wave prospective cohort study of a state-wide community sample in Victoria, Australia. METHODS: Participants were 1520 students from 44 secondary schools, initially aged 14 to 15 years. Adolescent smoking and quitting patterns were assessed during Waves 1-6 with self-reported frequency of use and a 7-day retrospective diary. The Fagerstrom Test for Nicotine Dependence (ND) was used to assess ND at the age of 24 years (Wave 8). RESULTS: The prevalence of ND in young adults was 16.9% for all adolescent smokers, with prevalence rates of 6.8% and 26.7% for adolescent non-daily and daily adolescent smokers, respectively. Maximum smoking levels, onset of daily smoking, duration of smoking, escalation time and duration of cessation during adolescence predicted later ND. Daily smokers who ceased smoking for at least two waves (> or = 12 months) had a level of risk similar to adolescents who had never smoked. CONCLUSIONS: Quitting smoking as an adolescent substantially alters the risk for later ND. For adolescents who become daily smokers, quitting for 12 months should be the aim in tobacco control and clinical interventions.

A comparison of longitudinal modelling approaches: Alcohol and cannabis use from adolescence to young adulthood.

BACKGROUND: Modelling trajectories of substance use over time is complex and requires judicious choices from a number of modelling approaches. In this study we examine the relative strengths and weakness of latent curve models (LCM), growth mixture modelling (GMM), and latent class growth analysis (LCGA). DESIGN: Data were drawn from the Australian Temperament Project, a 36-year-old community-based longitudinal study that has followed a sample of young Australians from infancy to adulthood across 16 waves of follow-up since 1983. Models were fitted on past month alcohol use (n = 1468) and cannabis use (n = 549) across six waves of data collected from age 13-14 to 27-28 years. FINDINGS: Of the three model types, GMMs were the best fit. However, these models were limited given the variance of numerous growth parameters had to be constrained to zero. Additionally, both the GMM and LCGA solutions had low entropy. The negative binomial LCMs provided a relatively well-fitting solution with fewer drawbacks in terms of growth parameter estimation and entropy issues. In all cases, model fit was enhanced when using a negative binomial distribution. CONCLUSIONS: Substance use researchers would benefit from adopting a complimentary framework by exploring both LCMs and mixture approaches, in light of the relative strengths and weaknesses as identified. Additionally, the distribution of data should inform modelling decisions.

COMT Val(158)Met and 5HTTLPR functional loci interact to predict persistence of anxiety across adolescence: results from the Victorian Adolescent Health Cohort Study.

We investigated whether a composite genetic factor, based on the combined actions of catechol-O-methyltransferase (COMT) (Val(158)Met) and serotonin transporter (5HTTLPR) (Long-Short) functional loci, has a greater capacity to predict persistence of anxiety across adolescence than either locus in isolation. Analyses were performed on DNA collected from 962 young Australians participating in an eight-wave longitudinal study of mental health and well-being (Victorian Adolescent Health Cohort Study). When the effects of each locus were examined separately, small dose-response reductions in the odds of reporting persisting generalized (free-floating) anxiety across adolescence were observed for the COMT Met(158) [odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.76-0.95, P = 0.004] and 5HTTLPR Short alleles (OR = 0.88, CI = 0.79-0.99, P = 0.033). There was no evidence for a dose-response interaction effect between loci. However, there was a double-recessive interaction effect in which the odds of reporting persisting generalized anxiety were more than twofold reduced (OR = 0.45, CI = 0.29-0.70, P < 0.001) among carriers homozygous for both the COMT Met(158) and the 5HTTLPR Short alleles (Met(158)Met + Short-Short) compared with the remaining cohort. The double-recessive effect remained after multivariate adjustment for a range of psychosocial predictors of anxiety. Exploratory stratified analyses suggested that genetic protection may be more pronounced under conditions of high stress (insecure attachments and sexual abuse), although strata differences did not reach statistical significance. By describing the interaction between genetic loci, it may be possible to describe composite genetic factors that have a more substantial impact on psychosocial development than individual loci alone, and in doing so, enhance understanding of the contribution of constitutional processes in mental health outcomes.

Induction of the TRPM-2 gene in cells undergoing programmed death.

RNA and protein products encoded by the testosterone-repressed prostate message-2 gene (TRPM-2) are induced to high levels, coordinate with the onset of cell death, in numerous rodent models of inducible tissue damage. These models include cell death initiated by hormonal stimuli (prostate regression), pressure insult (renal atrophy after ureteral obstruction), developmental stimuli (necrosis of interdigital tissue), and cytotoxic injury (chemotherapeutic regression of a tumor). Sequence analysis of cDNA encoding TRPM-2 revealed its close homology with a product referred to as SGP-2 or clusterin expressed constitutively by Sertoli cells; however, the immunologically related polypeptides expressed in regressing tissues differ in molecular mass from the forms secreted by the testis. Although the function(s) of the products encoded by the TRPM-2 gene remains unclear, their presence provides a remarkable and early indicator of programmed cell death in many types of mammalian cells.

Surface-epitope masking: a strategy for the development of monoclonal antibodies specific for molecules expressed on the cell surface.

BACKGROUND: Producing monoclonal antibodies against specific targets, including tumor-specific antigens, is a tedious and extremely inefficient process. PURPOSE: Our purpose was to determine whether DNA transfection combined with an immunologic masking tactic could be used to efficiently generate hybridomas that secrete monoclonal antibodies. The quest was for monoclonal antibodies that would react with molecules existing on the surface of genetically altered cells. METHODS: We developed a masking technique called surface-epitope masking (SEM). The SEM procedure involves the selective blocking of surface antigens present in a genetically engineered cell (referred to as a "tester") with high-titer polyclonal antibodies that have been produced against the untransfected parental cell (referred to as a "driver"). Surface-epitope-masked tester cells were injected into BALB/c mice; immune spleen cells then taken from these mice were fused with myeloma cells. RESULTS: This process resulted in the efficient generation of hybridomas that secreted monoclonal antibodies that reacted with cell-surface antigens on transfected tester cells and with additional cell types that expressed the same surface molecules. In one case, CREF-Trans 6 cells were engineered to express a typical multidrug-resistant (MDR) phenotype. Using CREF-Trans 6:MDR cells as a tester cell line, we utilized the SEM procedure to produce monoclonal antibodies that displayed surface reactivity to both CREF-Trans 6:MDR cells and MDR human breast carcinoma (MCF7) cells. In a second case, human prostatic carcinoma CREF-Trans 6 cells, which were DNA transfected and derived from nude mouse tumors, were used as the tester cell line. The SEM procedure was again used to produce monoclonal antibodies. These antibodies were designed to and did react with: (a) tumor-associated antigens on the surface of the original LNCaP cell line used to obtain human prostatic carcinoma DNA, (b) primary and secondary nude mouse transfectants derived from tumors, and (c) two additional human prostatic carcinoma cell lines, DU-145 and PC-3. CONCLUSIONS: The SEM approach was used for the efficient and selective development of monoclonal antibodies that react with cell-surface molecules with both known and unknown functions. IMPLICATIONS: The SEM procedure should be useful in producing monoclonal antibodies and identifying genes associated with important cellular processes, including immunologic recognition, tumorigenesis, metastasis, atypical multidrug resistance, and autoimmune diseases.

Limitations of DNA histogram analysis by flow cytometry as a method of predicting chemosensitivity in a rat renal cancer model.

Analysis of DNA histograms obtained from rat renal cancer cells stained with propidium iodide and submitted to flow cytometry revealed a tumor cell population with prominent 2C and 4C peaks and with usually less than 10% each of S-phase or hyper-4C cells. The presence of an increased proportion of 4C cells was found to depend on the age and size of the tumor nodule. Sampling replicate portions of the same tumor or different tumors of the same size and age frequently revealed highly variable 4C:2C ratios. Treatment of animals bearing this tumor with a single i.p. injection of cyclophosphamide (CY), under conditions known to reduce the tumor burden by 80% within 1 week, or with 5-fluorouracil (FUra), which is ineffective against this tumor, in many cases did not yield changes in DNA histograms that permitted one to distinguish the effective drug. Either no marked difference in histogram shape occurred after therapy, or FUra induced more striking differences in cell cycle position than did CY. In tumor generations with greater than 15% S-phase cells, treatment with CY resulted in multiple effects on DNA histograms. These included detecting increased numbers of moribund cells (hypo-2C), a decrease in 4C cells, and an increase in hyper-4C cells. These changes did not occur with the ineffective agent FUra. The tumors grown in vitro show no evidence of replication of 4C cells. The DNA histograms of late-log-phase cultures have a major 2C peak and a minor S plus G2 hump. Since neither the untreated tumor in vivo nor that grown in vitro has a major hyper-4C cell population, it is probable that the tumor stem cells are chiefly 2C (diploid-hyperdiploid). Treatment in vitro of late-log-phase cultures with CY or FUra produces DNA histograms which permit identification of the effective agent. After CY, a major part of the cell population was hypo-2C (moribund) cells.

Hormone-regulated apoptosis results from reentry of differentiated prostate cells onto a defective cell cycle.

Castration initiates extensive apoptosis of the secretory epithelial cells lining the ducts of the rat ventral prostate, resulting in the striking regression of this male sexual accessory tissue. We had previously described the paradox of finding similar cascades of gene activity (c-fos greater than c-myc greater than hsp-70) induced during the early period of ventral prostate regression and during the regrowth of the ventral prostate gland initiated by testosterone replenishment. This common pattern of protooncogene expression during periods of predominant cellular apoptosis or proliferation caused us to examine further the possibility that the two cellular events occur through identical early molecular pathways. In the present study we demonstrate that apoptotic prostate epithelial cells incorporate bromodeoxyuridine into nuclear high-molecular-weight DNA prior to nuclear DNA fragmentation. The DNA synthetic activity occurs in coordination with a massive induction of proliferative cell nuclear antigen, a proliferation marker, in the nuclei of androgen-deprived prostatic epithelial cells. Moreover, this activity is also associated with the increased expression of mRNA encoding p53, a suppressor gene well known as a cell cycle-blocking agent. Our data indicate that quiescent (G0) prostate epithelial cells undergo apoptosis due to two sequential events initiated by testosterone depletion. The first event is the active reentry of these cells into the cell cycle. The second event is the apoptotic destruction resulting from the inability of the differentiated cells to successfully complete this cycle.

Gene activity during the early phase of androgen-stimulated rat prostate regrowth.

Androgenic steroids regulate the proliferation rate of normal and malignant prostate cells. In order to investigate the molecular basis of this control, we utilized Northern and Western blot techniques to measure changes in the expression of individual genes during the early phase of prostate regrowth. Vestigial ventral prostate glands of 7-day castrated rats showed increased numbers of replicating cells within 12 h of continuous pharmacological testosterone replacement as demonstrated by flow cytometric procedures. The period prior to the onset of proliferative enhancement was accompanied by the sequential induction of a variety of transcripts encoding gene products often associated with cell growth. Within 1 h of treatment, mature mRNA transcripts for c-fos were induced 6-fold, returning to control levels by 2 h. Other genes showed transiently elevated transcript levels after 2 h (c-Ha-ras, c-Ki-ras) or after 8 h (c-myc,c-myb, beta-actin, and Mr 70,000 heat shock protein) of testosterone replacement. Expression of the polypeptide encoded by c-Ha-ras was coordinately enhanced (2-fold) during this period, but not to the levels of the transcript (20-fold induction). Transcripts encoding basic fibroblast growth factor were increased 16 h and later, subsequent to the earlier enhancement in the proliferation rate. By placing these genes in a defined temporal order with regard to their expression in response to testosterone, we have constructed a map of gene activity during early prostate regrowth. This map shows a number of genes, the products of which might participate in the mechanism by which androgens induce mitogenesis of prostate cells.

Expression of the tumor-associated gene MN: a potential biomarker for human renal cell carcinoma.

MN is a novel cell surface antigen originally detected in human HeLa cells. Although it is also expressed in normal gastric mucosa, this antigen was previously found to be expressed in cells with a malignant phenotype in certain tissues of the female genital tract (cervix and ovary). Using an oligonucleotide primer set specific for MN-complimentary DNA, we performed reverse transcription-PCR assays on RNAs extracted from human cell lines and tissues to evaluate whether this marker might be expressed at other sites. RNA libraries extracted from normal human heart, lung, kidney, prostate, peripheral blood, brain, placenta, and muscle were negative for MN expression. RNAs extracted from liver and pancreatic tissue were positive for MN expression. Three of six renal cancer cell lines tested revealed MN expression. In addition, 12 of 17 samples of human renal cell carcinoma tissue tested positive for MN, all 12 of which were clear cell adenocarcinomas. This survey identified a unique association of MN expression with renal cell cancers, especially those of the clear cell variety, suggesting that MN is a potential marker for the diagnosis, staging, and therapeutic monitoring of renal cell carcinoma in humans.

Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer.

PURPOSE: To evaluate the toxicity, efficacy, and pharmacokinetics of docetaxel when combined with oral estramustine and dexamethasone in a phase I study in patients with progressive metastatic androgen-independent prostate cancer. PATIENTS AND METHODS: Thirty-four men were stratified into minimally pretreated (MPT) and extensively pretreated (EPT) groups. Estramustine 280 mg PO tid was administered 1 hour before or 2 hours after meals on days 1 through 5, with escalated doses of docetaxel from 40 to 80 mg/m2 on day 2. Treatment was repeated every 21 days. RESULTS: Thirty-four patients were assessable for toxicity and 33 for response. In the MPT patients, dose-limiting myelosuppression was reached at 80 mg/m2, with six patients experiencing grade 3/4 granulocytopenia. In EPT patients, escalation above 70 mg/m2 was not attempted. Fourteen MPT (70%) and six EPT (50%) patients had a > or = 50% decline in serum PSA on two consecutive measurements taken at least 2 weeks apart. The overall 50% PSA response rate was 63% (95% confidence interval [CI], 28% to 81%). Of the 18 patients with bidimensionally measurable disease, five (28%; 95% CI, 11% to 54%) achieved a partial response. At the time of entry onto the study, 15 patients required narcotic analgesics for bone pain; after treatment, eight (53%) discontinued their pain medications. The area under the curve for docetaxel increased linearly from 40 to 70 mg/m2. At 80 mg/m2, the measured area under the curve was 8.37 (standard deviation, 0.724), which was significantly higher than the previously reported values. CONCLUSION: The recommended phase II dose of docetaxel combined with estramustine is 70 mg/m2 in MPT patients and 60 mg/m2 in EPT patients. This combination is active in men with androgen-independent prostate cancer.

Steroid effects on protein synthesis in cultured smooth muscle cells from rat aorta.

To examine the direct effects of steroids on vascular smooth muscle, we have incubated rat aortic vascular smooth muscle cells in culture either steroid-free, or with natural and synthetic corticosteroids (RU26988, dexamethasone, corticosterone, 9 alpha-fluorocortisol, aldosterone, deoxycorticosterone) or sex steroids (estradiol, 5 alpha-dihydrotestosterone). At the end of 24 h, cultures were pulsed with [35S]methionine for 2 h, the cells lysed, and patterns of incorporation of isotope into protein determined by two-dimensional gel electrophoresis and autoradiography. Neither estradiol nor 5 alpha-dihydrotestosterone altered protein synthetic profiles compared with control (steroid-free) incubations. In contrast, cultures exposed to the six corticosteroids at 10(-7) M showed an identical pattern of response (6 proteins increased, 6 proteins decreased). This response appears to be glucocorticoid specific, since the mineralocorticoids (9 alpha-fluorocortisol, aldosterone, and deoxycorticosterone) did not have any effects over and above those seen with the pure glucocorticoid RU26988. We interpret these data as evidence for a putative glucocorticoid domain of at least 12 proteins in rat vascular smooth muscle cells. In contrast, there appear to be no comparable estrogen-, androgen-, or mineralocorticoid-specific changes in these cells.

Metastatic infection secondary to genitourinary tract sepsis.

Metastatic infections arising from sepsis in the genitourinary tract are reviewed in 175 cases, including five in which we treated the patients. The skeleton was the most common site of metastasis (59 per cent). The endocardium was next most frequently involved (28 per cent). Gram-negative organisms were implicated in less than two-thirds of the cases (59 per cent). Impaired host defense mechanisms were noted in 25 per cent of the patients experiencing metastatic infections. The lower urinary tract was the source of metastasis in 75 per cent of the patients, particularly after urologic manipulation in men. Women were more likely to experience metastatic infection from the upper urinary tract. Anatomic and pathologic considerations explaining these sex differences are presented.

Which patients with newly diagnosed prostate cancer need a radionuclide bone scan? An analysis based on 631 patients.

PURPOSE: Although radionuclide bone scans are frequently recommended as part of the staging evaluation for newly diagnosed prostate cancer, most scans are negative for metastases. We hypothesized that Gleason score, prostate-specific antigen (PSA), and clinical stage could predict for a positive bone scan (BS), and that a low-risk group of patients could be identified in whom BS might be omitted. METHODS: All patients who had both pathologic review of their prostate cancer biopsies and radionuclide BS at our institution between 1/90 and 5/96 were studied. Gleason score, PSA, and clinical stage (AJCC, 4th edition) were evaluated by univariate and multivariate analyses for their ability to predict a positive BS. Groups analyzed were Gleason of 2-6 vs. 7 vs. 8-10; PSA of 0-15 vs. greater than 15-50 vs. greater than 50; and clinical stage of T1a-T2b vs. T2c-T4. Univariate analysis using chi(2) and multivariate analysis using logistic regression were performed. RESULTS: Of the 631 consecutive patients, 88 (14%) had positive BS. Multivariate analysis (64 excluded due to missing PSA and/or clinical stage) showed Gleason score, PSA, and clinical stage to be significant independent predictors for positive BS (p < 0.002, p < 0.001, p < 0.001, respectively). The odds ratios were 5.25 (confidence interval [CI], 3.43-8.04) for PSA > 50 vs. 0-15; 2.25 (CI, 1.43-3.54) for Gleason of 8-10 vs. 2-6; 2.15 (CI, 1.54-2.99) for clinical stage T2c-T4 vs. T2b or less. Three of 308 (1%) had a positive BS in patients with Gleason 2-7, PSA of 50 or less, and clinical stage of T2b or less. In the subset of the same risk group with PSA of 15 or less, all 237 had negative bone scans. In patients with PSA greater than 50, 49/99(49.5%) had positive BS. CONCLUSION: Gleason score, PSA, and clinical stage were independent predictors for a positive radionuclide BS in newly diagnosed prostate cancer patients. PSA is the major predictor for positive BS. About one-half of the patients analyzed were in the low-risk group (Gleason 2-7, PSA < or = 50, clinical stage < or = T2b) and elimination of BS in these patients would result in considerable economic savings.