"They're kept in a bubble": Healthcare professionals' views on transitioning young adults with congenital heart disease from paediatric to adult care.

BACKGROUND: Due to medical advances, growing numbers of adolescents with congenital heart disease (CHD) survive into adulthood and transferring from paediatric to adult healthcare. This transfer is significant step in a young person's life, and this study examines the views of Irish healthcare professionals' on how best to manage this transition. METHODS: Purposeful sampling was used to invite participation by healthcare professionals (HCPs) from a variety of disciplines whose caseloads include adolescents and young adults with CHD. Fourteen professionals participated in semistructured interviews regarding their experiences of the transition process and their recommendations. Data were collected during Spring 2016 and analysed using thematic analysis. RESULTS: Results indicated that the current approach to transition and transfer could be improved. Professionals identified barriers hindering the transition process such as cultural and attitudinal differences between HCPs dealing with child and adult patients, inadequate preparation and education of patients about their condition, parental reluctance to transfer, and concern about parents' role in on-going treatment. Measures such as better support and education for both the patients and their parents were recommended, in order to facilitate a smoother transition process for all parties involved. Additionally, HCPs identified the need for better collaboration and communication, both between paediatric and adult healthcare professionals and between hospitals, to ensure greater continuity of care for patients. CONCLUSIONS: Action is required in order to improve the current transition process. Measures need to be taken to address the barriers that currently prevent a smooth transition process for young adult CHD patients. Professionals recommended the implementation of a structured transition clinic to deal with the wide variety of needs of transitioning adolescent patients and their families. Recommendations for future research are also made.

Elevated levels of FOXA1 facilitate androgen receptor chromatin binding resulting in a CRPC-like phenotype.

Castration-resistant prostate cancer (CRPC) continues to pose a significant clinical challenge with new generation second-line hormonal therapies affording limited improvement in disease outcome. As the androgen receptor (AR) remains a critical driver in CRPC, understanding the determinants of its transcriptional activity is important for developing new AR-targeted therapies. FOXA1 is a key component of the AR transcriptional complex yet its role in prostate cancer progression and the relationship between AR and FOXA1 are not completely resolved. It is well established that FOXA1 levels are elevated in advanced prostate cancer and metastases. We mimicked these conditions by overexpressing FOXA1 in the androgen-responsive LNCaP prostate cancer cell line and observed a significant increase in AR genomic binding at novel regions that possess increased chromatin accessibility. High levels of FOXA1 resulted in increased proliferation at both sub-optimal and high 5α-dihydrotestosterone (DHT) concentrations. Immunohistochemical staining for FOXA1 in a clinical prostate cancer cohort revealed that high FOXA1 expression is associated with shorter time to biochemical recurrence after radical prostatectomy (hazard ratio (HR) 5.0, 95% confidence interval (CI) 1.2-21.1, P=0.028), positive surgical margins and higher stage disease at diagnosis. The gene expression program that results from FOXA1 overexpression is enriched for PTEN, Wnt and other pathways typically represented in CRPC gene signatures. Together, these results suggest that in an androgen-depleted state, elevated levels of FOXA1 enhance AR binding at genomic regions not normally occupied by AR, which in turn facilitates prostate cancer cell growth.

Minireview: The androgen receptor in breast tissues: growth inhibitor, tumor suppressor, oncogene?

Androgen receptor (AR) signaling exerts an antiestrogenic, growth-inhibitory influence in normal breast tissue, and this role may be sustained in estrogen receptor α (ERα)-positive luminal breast cancers. Conversely, AR signaling may promote growth of a subset of ERα-negative, AR-positive breast cancers with a molecular apocrine phenotype. Understanding the molecular mechanisms whereby androgens can elicit distinct gene expression programs and opposing proliferative responses in these two breast cancer phenotypes is critical to the development of new therapeutic strategies to target the AR in breast cancer.

Biological community structure on patch reefs in Biscayne National Park, FL, USA.

Coral reef ecosystem management benefits from continual quantitative assessment of the resources being managed, plus assessment of factors that affect distribution patterns of organisms in the ecosystem. In this study, we investigate the relationships among physical, benthic, and fish variables in an effort to help explain the distribution patterns of organisms on patch reefs within Biscayne National Park, FL, USA. We visited a total of 196 randomly selected sampling stations on 12 shallow (<10 m) patch reefs and measured physical variables (e.g., substratum rugosity, substratum type) and benthic and fish community variables. We also incorporated data on substratum rugosity collected remotely via airborne laser surveying (Experimental Advanced Airborne Research Lidar-EAARL). Across all stations, only weak relationships were found between physical, benthic cover, and fish assemblage variables. Much of the variance was attributable to a "reef effect," meaning that community structure and organism abundances were more variable at stations among reefs than within reefs. However, when the reef effect was accounted for and removed statistically, patterns were detected. Within reefs, juvenile scarids were most abundant at stations with high coverage of the fleshy macroalgae Dictyota spp., and the calcified alga Halimeda tuna was most abundant at stations with low EAARL rugosity. Explanations for the overwhelming importance of "reef" in explaining variance in our dataset could include the stochastic arrangement of organisms on patch reefs related to variable larval recruitment in space and time and/or strong historical effects due to patchy disturbances (e.g., hurricanes, fishing), as well as legacy effects of prior residents ("priority" effects).

Epigenetic modification of the X chromosome influences susceptibility to polycystic ovary syndrome.

CONTEXT: The cause of polycystic ovary syndrome (PCOS) is unknown, although genetic and environmental influences are clearly implicated. Some genetic studies have suggested the involvement of X-linked genes in PCOS, but the influence of X chromosome inactivation (XCI) on manifestation of this disorder has not previously been examined. OBJECTIVE: The objective of the study was to test the null hypothesis that XCI has no influence on clinical presentation of PCOS. DESIGN: We examined patterns of XCI between sister pairs with the same genotype at a polymorphic locus on the X chromosome in families with PCOS. SETTING: The study was conducted at a private practice. PARTICIPANTS: PCOS was defined as hyperandrogenemia with chronic anovulation. Forty families were studied in which DNA was obtained from at least one parent, the proband, and one sister that could be accurately diagnosed as being affected or unaffected. MAIN OUTCOME MEASURE(S): Relative expression of two X-linked alleles was determined, and the ratio of one to the other represented the pattern of XCI. RESULTS: The statistical odds on a different clinical presentation between sisters was approximately 29 times higher in sister pairs with different patterns of XCI, compared with sister pairs with the same pattern of XCI (odds ratio 28.9; 95% confidence interval 4.0-206; P = 0.0008). CONCLUSIONS: This study provides evidence to refute the null hypothesis and propose a closer inspection of X-linked genes in PCOS, one in which both genotype and epigenotype are considered. Environmental determinants of PCOS may alter clinical presentation via epigenetic modifications, which currently remain undetected in traditional genetic analyses.

Androgens augment the mitogenic effects of oocyte-secreted factors and growth differentiation factor 9 on porcine granulosa cells.

In this study, we test the hypothesis that the growth-promoting action of androgens on granulosa cells requires paracrine signaling from the oocyte. Mural granulosa cells (MGCs) from small antral (1-3 mm) prepubertal pig follicles were cultured in the presence or absence of denuded oocytes (DO) from the same follicles to determine whether mitogenic and/or steroidogenic responses, to combinations of FSH, insulin-like growth factor 1 (IGF1), and dihydrotestosterone (DHT) were influenced by oocyte-secreted factors (OSFs). To further explore the identity of such factors we performed the same experiments, substituting growth differentiation factor 9 (GDF9), a known OSF, for the DO. OSFs and GDF9 both potently enhanced IGF1-stimulated proliferation, and inhibited FSH-stimulated progesterone secretion. Alone, DHT had little effect on DNA synthesis, but significantly enhanced the mitogenic effects of OSFs or GDF9 in the presence of IGF1. Denuded oocytes, GDF9, and DHT independently inhibited FSH-stimulated progesterone secretion, and androgen, together with DO or GDF9, caused the most potent steroidogenic inhibition. Focusing on mitogenic effects, we demonstrate that both natural androgen receptor (AR) agonists, testosterone and DHT, dose-dependently augmented the mitogenic activity of DO or GDF9. Antiandrogen (hydroxyflutamide) treatment, which is used to block androgen receptor activity, opposed the interaction between androgen and GDF9. In conclusion, androgens stimulate porcine MGC proliferation in vitro by potentiating the growth-promoting effects of oocytes or GDF9, via a mechanism that involves the AR. These signaling pathways are likely to be important regulators of folliculogenesis in vivo, and may contribute to the excess follicle growth that is observed in androgen-treated female animals.

Interactions between androgen and growth factors in granulosa cell subtypes of porcine antral follicles.

Androgens acting via the androgen receptor (AR) have been implicated in regulation of folliculogenesis in many animal species. These effects are possibly mediated via enhancement of FSH and/or insulin-like growth factor (IGF)-I activity in granulosa cells, which contain high levels of AR protein. We examined the in vitro effect of dihydrotestosterone (DHT) on DNA synthesis and progesterone secretion by follicular cells in response to FSH and IGF-I, alone or in combination. Cells from separate pools of 1- to 3-mm and 3- to 5-mm antral follicles were aspirated from gilt ovaries and fractioned into mural granulosa cells (MGCs) and cumulus-oocyte complexes (COCs) for subsequent cell culture. Androgen alone or with any combination of mitogen had minimal effect on proliferative and no effect on steroidogenic responses of MGCs from 3- to 5-mm antral follicles. Conversely, in MGCs from 1- to 3-mm follicles, DHT significantly enhanced IFG-I-stimulated proliferation and had variable influence on progesterone secretion. The effects of DHT on proliferative responses of COCs were also dependent on follicle size: DHT significantly augmented either IGF-I-stimulated proliferation (1- to 3-mm follicles) or FSH-stimulated proliferation (3- to 5-mm follicles). However, the steroidogenic responses of all COCs were identical, whereby DHT significantly suppressed progesterone secretion, predominantly in the presence of FSH. Addition of an AR antagonist, hydroxyflutamide, generally reversed the proliferative responses invoked by DHT but not the steroidogenic responses. We conclude that androgen-receptor-mediated activity in granulosa cells of antral follicles is dependent on follicle size, is influenced by proximity of cells to the oocyte, and possibly involves both classic and nonclassic steroid mechanisms.

In vivo evaluation of a dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to implantable medical devices.

The purpose of this research effort was to evaluate in vivo a newly developed dexamethasone/PLGA microsphere system designed to suppress the inflammatory tissue response to an implanted device, in this case a biosensor. The microspheres were prepared using an oil/water (O/W) emulsion technique. The microsphere system was composed of drug-loaded microspheres (including newly formulated and predegraded microspheres) and free dexamethasone. The combination of the drug and drug-loaded microspheres provided burst release of dexamethasone followed by continuous release from days 2-14. Continuous release to at least 30 days was achieved by mixing predegraded and newly formulated microspheres. The ability of our mixed microsphere system to control tissue reactions to an implant then was tested in vivo using cotton thread sutures to induce inflammation subcutaneously in Sprague-Dawley rats. Two different in vivo studies were performed, the first to find the dosage level of dexamethasone that effectively would suppress the acute inflammatory reaction and the second to show how effective the dexamethasone delivered by PLGA microspheres was in suppressing chronic inflammatory response to an implant. The first in vivo study showed that 0.1 to 0.8 mg of dexamethasone at the site minimized the acute inflammatory reaction. The second in vivo study showed that our mixed microsphere system suppressed the inflammatory response to an implanted suture for at least 1 month. This study has proven the viability of microsphere delivery of an anti-inflammatory to control the inflammatory reaction at an implant site.

Dexamethasone/PLGA microspheres for continuous delivery of an anti-inflammatory drug for implantable medical devices.

The purpose of this research was to develop polylactic-co-glycolic acid (PLGA) microspheres for continuous delivery of dexamethasone for over a 1-month period, in an effort to suppress the acute and chronic inflammatory reactions to implants such as biosensors, which interfere with their functionality. The microspheres were prepared using an oil-in-water emulsion technique. The oil phase was composed of 9:1 dichloromethane to methanol with dissolved PLGA and dexamethasone. Some microspheres were predegraded for 1 or 2 weeks. Ten percent of polyethylene glycol was added to the oil phase in alternative formulations to delay drug release. The in vitro release studies were performed in a constant temperature (37 C) warm room, in phosphate-buffered saline at sink conditions. Drug loading and release rates were determined by HPLC-UV analysis. The standard microsphere systems did not provide the desired release profile since, following an initial burst release, a delay of 2 weeks occurred prior to continuous drug release. Predegraded microspheres started to release dexamethasone immediately but the rate of release decreased after only 2 weeks. A mixed standard and predegraded microsphere system was used to avoid this delay and to provide continuous release of dexamethasone for 1 month.

The androgen receptor CAG repeat polymorphism and X-chromosome inactivation in Australian Caucasian women with infertility related to polycystic ovary syndrome.

The human androgen receptor (AR) gene contains a polymorphic trinucleotide (CAG) repeat sequence in exon 1. The number of CAG repeats may confer differential receptor activity, and specific ranges of variants have been correlated with androgen-sensitive disease processes. Polycystic ovary syndrome (PCOS) is a female condition characterized by androgen excess and infertility, many features of which are effected through the AR. We compared frequency distributions of CAG repeat alleles and their pattern of expression via X-inactivation analysis among 83 fertile women and 122 infertile women with PCOS, all of Australian Caucasian ethnicity. A population comparison with 831 predominantly fertile Australian women was also used. PCR-based assays were used to genotype each woman and assess allele inactivation patterns after digestion of DNA with methylation-sensitive HpaII. Infertile women with PCOS exhibited a greater frequency of CAG alleles or biallelic means greater than 22 repeats compared with both the fertile control group (P < 0.05) and the general population (P < 0.01). Preferential expression of longer CAG repeat alleles was also observed in PCOS and correlated with increased serum T. We conclude that the AR (CAG)n gene locus and/or its differential methylation patterns influence the disease process leading to PCOS.

Cognitive impairment and functional status in elderly institutionalized patients with schizophrenia.

OBJECTIVE: The relationship of cognitive impairment to functional status in older adults with schizophrenia was investigated. PATIENTS: Ninety-three psychiatric inpatients with schizophrenia between the ages of 65 and 88 years. Two subsets of this sample, consisting of 48 and 24 patients, were studied with a greater number of assessment instruments. MEASURES: The Mini-Mental State Examination (MMSE) was used for brief assessment of overall cognitive functioning, and the Psychogeriatric Dependency Rating Scale (PGDRS) was administered to assess functional status. The cognitive test battery from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) and/or an expanded neuropsychological battery, was given to a subset of the patients. RESULTS: In the overall sample, patients with greater global cognitive impairment had higher levels of rated impairment on the individual items that comprised the Orientation and Physical, but not Behavior, subscales of the PGDRS. Furthermore, in the two subsamples, specific neuropsychological measures of problem-solving, word list learning, naming and constructional praxis were related to overall measures of outcome. CONCLUSIONS: Neuropsychological deficit and psychosocial outcome are multi-dimensional entities that relate to one another in complex ways.

Characterization and biocompatibility studies of novel humic acids based films as membrane material for an implantable glucose sensor.

Multilayered films of humic acids (HAs) (naturally occurring biopolymers) were investigated as a potential semipermeable membrane for implantable glucose sensors. These films were grown using a layer-by-layer self-assembly process of HAs and oppositely charged ferric ions. The growth of these assemblies exhibited strong dependence on the pH and ionic strength of HAs solutions, which correlated with the degree of ionization of the carboxyl groups and neutralization-induced surface spreading. Quartz crystal microbalance (QCM) and ellipsometric studies have shown repeatable, stepwise increase in mass (as high as 5.63 microg/cm(2)) and in film thickness (ca. 24.3 nm per layer) for these assemblies. The permeability of glucose through these membranes can be regulated by varying the number of self-assembled HAs/Fe(3+) layers. Moreover, a 200 nm thick HAs/Fe(3+) film (in its hydrated state) had a shear modulus of about 80 MPa, implying stability upon implantation. These films were determined to be biocompatible since in vivo studies indicated only mild tissue reaction along with some neovascularization.

Campylobacter jejuni cytolethal distending toxin mediates release of interleukin-8 from intestinal epithelial cells.

Live cells of Campylobacter jejuni and Campylobacter coli can induce release of interleukin-8 (IL-8) from INT407 cells. Additionally, membrane fractions of C. jejuni 81-176, but not membrane fractions of C. coli strains, can also induce release of IL-8. Membrane preparations from 81-176 mutants defective in any of the three membrane-associated protein subunits of cytolethal distending toxin (CDT) were unable to induce IL-8. The presence of the three cdt genes on a shuttle plasmid in trans restored both CDT activity and the ability to release IL-8 to membrane fractions. However, CDT mutations did not affect the ability of 81-176 to induce IL-8 during adherence to or invasion of INT407 cells. When C. jejuni cdt genes were transferred on a shuttle plasmid into a C. coli strain lacking CDT, membrane preparations became positive in both CDT and IL-8 assays. Growth of C. jejuni in physiological levels of sodium deoxycholate released all three CDT proteins, as well as CDT activity and IL-8 activity, from membranes into supernatants. Antibodies against recombinant forms of each of the three CDT subunit proteins neutralized both CDT activity and the activity responsible for IL-8 release. The data suggest that C. jejuni can induce IL-8 release from INT407 cells by two independent mechanisms, one of which requires adherence and/or invasion and the second of which requires CDT.

Sialylation of lipooligosaccharide cores affects immunogenicity and serum resistance of Campylobacter jejuni.

Three genes involved in biosynthesis of the lipooligosaccharide (LOS) core of Campylobacter jejuni MSC57360, the type strain of the HS:1 serotype, whose structure mimics GM(2) ganglioside, have been cloned and characterized. Mutation of genes encoding proteins with homology to a sialyl transferase (cstII) and a putative N-acetylmannosamine synthetase (neuC1), part of the biosynthetic pathway of N-acetylneuraminic acid (NeuNAc), have identical phenotypes. The LOS cores of these mutants display identical changes in electrophoretic mobility, loss of reactivity with cholera toxin (CT), and enhanced immunoreactivity with a hyperimmune polyclonal antiserum generated against whole cells of C. jejuni MSC57360. Loss of sialic acid in the core of the neuC1 mutant was confirmed by fast atom bombardment mass spectrometry. Mutation of a gene encoding a putative beta-1,4-N-acetylgalactosaminyltransferase (Cgt) resulted in LOS cores intermediate in electrophoretic mobility between that of wild type and the mutants lacking NeuNAc, loss of reactivity with CT, and a reduced immunoreactivity with hyperimmune antiserum. Chemical analyses confirmed the loss of N-acetylgalactosamine (GalNAc) and the presence of NeuNAc in the cgt mutant. These data suggest that the Cgt enzyme is capable of transferring GalNAc to an acceptor with or without NeuNAc and that the Cst enzyme is capable of transferring NeuNAc to an acceptor with or without GalNAc. A mutant with a nonsialylated LOS core is more sensitive to the bactericidal effects of human sera than the wild type or the mutant lacking GalNAc.

Effect of adults' self-regulation of diabetes on quality-of-life outcomes.

OBJECTIVE: To examine the relationships among cognitive representations of diabetes, diabetes-specific health behaviors, and quality of life using Leventhal and Diefenbach's self-regulation model of illness (Leventhal H, Diefenbach M: The active side of illness cognition. In Mental Representation in Health and Illness. SkeltonJA, Croyle RT, Eds. New York, Springer-Verlag, 1991, p. 247-272). RESEARCH DESIGN AND METHODS: This research involved secondary analysis of a mailed survey completed by 296 adults (ages 20-90 years). Structural equation modeling was conducted to investigate relationships among cognitive representations, diabetes-specific health behaviors, and quality of life. Model differences by diabetes type were also investigated. RESULTS: Findings indicated that certain cognitive representation constructs were related to increased diabetes-specific health behaviors, decreased sense of burden, and positive quality-of-life outcomes. Individuals levels of understanding of diabetes and their perceptions of control over diabetes were the most significant predictors of outcomes. However, diabetes-specific health behaviors were related to an increased sense of burden that was negatively associated with quality of life. Multigroup analyses indicated that this self-regulatory model provided a good fit for individuals with type 1 diabetes, those with type 2 diabetes who take insulin, and those with type 2 diabetes who do not take insulin. CONCLUSIONS: These findings advance what is known about cognitive representations of illness and the self-regulation of diabetes as well as the relationships between cognitive representations of illness, quality of life, and behavioral factors. In particular, results from this study suggest the need for further study to address ways of reducing the burden of diabetes associated with health behaviors and decreased quality of life.

Enteropathogens and other factors associated with severe disease in children with acute watery diarrhea in Lima, Peru.

To evaluate enteropathogens and other factors associated with severe disease in children with diarrhea, 381 children <5 years of age with diarrhea and moderate to severe dehydration (in-patients) and 381 age-, sex-, and date-of-visit-matched children with mild diarrhea (out-patients) presenting to a hospital in Peru, were studied. Rotavirus was detected in 52% of the in-patients and 35% of the out-patients (odds ratio [OR]=2.3, 95% confidence interval [95% CI]= 1.6-3.2); 95% of the rotaviruses among in-patients were of serotypes G1-G4. The risk of severe diarrhea was particularly great in children who were not exclusively breast-fed in early infancy and who also lacked piped water in their homes (for children with both characteristics OR=6.8, 95% CI=3.6-12.8). The high prevalence of rotavirus and its association with severe diarrhea underscores the need for rotavirus vaccines. Interventions to educate mothers and improve access to safe water should augment the impact of rotavirus vaccines in preventing severe diarrhea.

Campylobacter jejuni-stimulated secretion of interleukin-8 by INT407 cells.

Incubation of INT407 cells with various clinical isolates of Campylobacter jejuni resulted in secretion of interleukin-8 (IL-8) at levels ranging from 96 to 554 pg/ml at 24 h. The strains which produced the highest levels of IL-8 secretion were 81-176 and BT44. Induction of IL-8 secretion required live cells of 81-176 and was dependent on de novo protein synthesis. Site-specific mutants of 81-176, which were previously shown to be defective in adherence and invasion, resulted in reduced levels of secretion of IL-8, and cheY mutants of strains 81-176 and 749, which are hyperadherent and hyperinvasive, resulted in higher levels of IL-8 secretion. Another mutant of 81-176, which adheres at about 43% of the wild-type levels but is noninvasive, also showed marked reduction in IL-8 levels, suggesting that invasion is necessary for high levels of IL-8 secretion. When gentamicin was added to INT407 cells at 2 h after infection with 81-176, IL-8 secretion 22 h later was equivalent to that of controls without gentamicin, suggesting that the events which trigger induction and release of IL-8 occur early in the interactions of bacteria and eukaryotic cells.

Designing a system for ambulatory obstetric case management.

The authors describe the development of critical pathways for ambulatory obstetric case management. When case management was identified as needed, but published work in outpatient obstetrics could not be found, four nurses used this opportunity to design a cost-effective system leading to quality outcomes. The driving force was the need for a format that directed comprehensive consistent care delivered by a large multidisciplinary health care team. Design issues included capturing leading edge standards of care and user friendly formats for all caregivers. Throughout a period of 2 years, a trifold format was developed for all obstetric patients, and 15 bifold formats were developed for patients with specific high-risk diagnoses. The format design facilitated cost-effective quality care and is expected to improve patient outcomes. A research study has been initiated to measure effectiveness of the design.

The pattern of change in leisure activity behavior among older adults with arthritis.

This study employed a "ceasing participation" framework to examine changing leisure activity patterns. Respondents of the Living With Arthritis project were classified into four participation pattern categories. Results confirmed that older adults with arthritis are more likely to experience changes to their activity regimen than older adults without arthritis. A multi-group discriminant function analysis showed that arthritis severity distinguished those who tend to cease activity. Social network and age best distinguished those who quit activities without replacement. Results are placed in the context of coping strategies. Those who do not replace forfeited activities with other activities are least flexible in their response to their chronic condition and face challenges to their well-being.

Effects of a one-year physical activity intervention for older adults at congregate nutrition sites.

The effects of a physical activity intervention on strength, balance, motor coordination, and mobility were tested in a quasi-experiment at rural congregate nutrition sites. Twice-weekly sessions of low intensity movements were conducted for one year. Logistic regression results showed significant differences between intervention (n = 61) and comparison (n = 49) groups on several performance-based measures. Intervention subjects perceived significantly greater improvements in physical functioning over the previous year than did comparison subjects. A qualitative evaluation revealed perceived program benefits of pain reduction, increased flexibility, muscle strengthening, increased walking speed, and improved mental outlook.