RESUMO
Objective: Vasomotor symptoms (hot flashes, night sweats) are common during the menopausal transition. Pharmacotherapy is effective but is associated with health risks for some women. There is an increasing demand for non-pharmacological interventions. The CBT-Meno protocol is a psychological intervention targeting a range of common menopausal symptoms. We compared the impact of CBT-Meno vs. waitlist on objective and subjective measures of vasomotor symptoms and on the relationship between vasomotor symptoms and sleep difficulties.Materials: The participants were 36 perimenopausal or postmenopausal women with co-occurring depressive symptoms who participated in the CBT-Meno trial (clinicaltrials.gov NCT02480192). Subjective measures included the Hot Flash Related Daily Interference Scale, the Greene Climacteric Scale, and the Pittsburgh Sleep Quality Inventory. Objective (physiological) and 'in-the-moment' measures of vasomotor symptoms were assessed with sternal skin conductance.Results: Greater improvements in vasomotor 'bothersomeness' and 'interference' were observed in the CBT-Meno condition compared to the waitlist condition. No between-group differences were observed in vasomotor frequency (subjectively or objectively recorded) or severity ratings. Sleep disturbance was unrelated to objectively measured vasomotor symptom frequency.Conclusion: The CBT-Meno trial improved subjective but not objective (physiological) measures of vasomotor symptoms. Self-reported sleep difficulties were unrelated to subjective or objective vasomotor symptoms.
Assuntos
Terapia Cognitivo-Comportamental/métodos , Depressão/terapia , Fogachos/terapia , Perimenopausa/psicologia , Pós-Menopausa/psicologia , Adulto , Idoso , Depressão/fisiopatologia , Feminino , Resposta Galvânica da Pele , Fogachos/fisiopatologia , Humanos , Pessoa de Meia-Idade , Perimenopausa/fisiologia , Pós-Menopausa/fisiologia , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Método Simples-Cego , Sono , Sudorese , Resultado do Tratamento , Sistema Vasomotor/fisiopatologiaRESUMO
The multidisciplinary International Committee for the Advancement of Procedural Sedation presents the first fasting and aspiration prevention recommendations specific to procedural sedation, based on an extensive review of the literature. These were developed using Delphi methodology and assessment of the robustness of the available evidence. The literature evidence is clear that fasting, as currently practiced, often substantially exceeds recommended time thresholds and has known adverse consequences, for example, irritability, dehydration and hypoglycaemia. Fasting does not guarantee an empty stomach, and there is no observed association between aspiration and compliance with common fasting guidelines. The probability of clinically important aspiration during procedural sedation is negligible. In the post-1984 literature there are no published reports of aspiration-associated mortality in children, no reports of death in healthy adults (ASA physical status 1 or 2) and just nine reported deaths in adults of ASA physical status 3 or above. Current concerns about aspiration are out of proportion to the actual risk. Given the lower observed frequency of aspiration and mortality than during general anaesthesia, and the theoretical basis for assuming a lesser risk, fasting strategies in procedural sedation can reasonably be less restrictive. We present a consensus-derived algorithm in which each patient is first risk-stratified during their pre-sedation assessment, using evidence-based factors relating to patient characteristics, comorbidities, the nature of the procedure and the nature of the anticipated sedation technique. Graded fasting precautions for liquids and solids are then recommended for elective procedures based upon this categorisation of negligible, mild or moderate aspiration risk. This consensus statement can serve as a resource to practitioners and policymakers who perform and oversee procedural sedation in patients of all ages, worldwide.
Assuntos
Sedação Consciente/métodos , Sedação Consciente/normas , Jejum , Adolescente , Adulto , Algoritmos , Criança , Pré-Escolar , Sedação Consciente/efeitos adversos , Consenso , Técnica Delphi , Fidelidade a Diretrizes , Humanos , Lactente , Recém-Nascido , Aspiração Respiratória de Conteúdos Gástricos/prevenção & controleRESUMO
BACKGROUND: The number of people with an enteral tube (ET) living at home is increasing globally and services to support them to manage this complex and life-changing intervention vary across regions. The present study aimed to gain an understanding of the experiences of people living at home with an ET and their carers, as well as to explore their views of supporting services and ET-related hospital admissions. METHODS: A qualitative inductive descriptive design was employed. Semi-structured, face-to-face interviews with a purposive sample of people with an ET living at home and carers were undertaken. Interviews were transcribed, initial codes were assigned for salient constructs, and these were then grouped and developed into themes and sub-themes. RESULTS: Nineteen people with ETs and 15 carers of people with ETs were interviewed. Five themes were generated: home better than hospital, feelings about the tube, living with the tube, help when you need it and cost for health service. Participants indicated the ET significantly influenced daily life. Participants described becoming used to coping with the ET at home over time and developing strategies to manage problems, avoid hospital admission and reduce resource waste. Variation in supporting services was described. CONCLUSIONS: People with ETs and their carers need considerable support from knowledgeable, responsive healthcare practitioners during the weeks following initial placement of the ET. Twenty-four hour services to support people with ETs should be designed in partnership with the aim of reducing burden, negative experience, waste and hospital admissions. National frameworks for home enteral nutrition could set the standard for support for people with ETs.
Assuntos
Cuidadores/psicologia , Nutrição Enteral/psicologia , Serviços de Assistência Domiciliar , Intubação Gastrointestinal/psicologia , Adaptação Psicológica , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação das Necessidades , Pesquisa QualitativaRESUMO
Many hospitals, and medical and dental clinics and offices, routinely monitor their procedural-sedation practices-tracking adverse events, outcomes, and efficacy in order to optimize the sedation delivery and practice. Currently, there exist substantial differences between settings in the content, collection, definition, and interpretation of such sedation outcomes, with resulting widespread reporting variation. With the objective of reducing such disparities, the International Committee for the Advancement of Procedural Sedation has herein developed a multidisciplinary, consensus-based, standardized tool intended to be applicable for all types of sedation providers in all locations worldwide. This tool is amenable for inclusion in either a paper or an electronic medical record. An additional, parallel research tool is presented to promote consistency and standardized data collection for procedural-sedation investigations.
Assuntos
Anestesiologia/métodos , Sedação Consciente/normas , Comitês Consultivos , Lista de Checagem , Consenso , Humanos , Assistência Centrada no Paciente , Melhoria de Qualidade , Padrões de Referência , Pesquisa , Terminologia como AssuntoRESUMO
Background: Although pulmonary aspiration complicating operative general anaesthesia has been extensively studied, little is known regarding aspiration during procedural sedation. Methods: We performed a comprehensive, systematic review to identify and catalogue published instances of aspiration involving procedural sedation in patients of all ages. We sought to report descriptively the circumstances, nature, and outcomes of these events. Results: Of 1249 records identified by our search, we found 35 articles describing one or more occurrences of pulmonary aspiration during procedural sedation. Of the 292 occurrences during gastrointestinal endoscopy, there were eight deaths. Of the 34 unique occurrences for procedures other than endoscopy, there was a single death in a moribund patient, full recovery in 31, and unknown recovery status in two. We found no occurrences of aspiration in non-fasted patients receiving procedures other than endoscopy. Conclusions: This first systematic review of pulmonary aspiration during procedural sedation identified few occurrences outside of gastrointestinal endoscopy, with full recovery typical. Although diligent caution remains warranted, our data indicate that aspiration during procedural sedation appears rare, idiosyncratic, and typically benign.
Assuntos
Anestesia Geral , Complicações Intraoperatórias/fisiopatologia , Aspiração Respiratória/fisiopatologia , HumanosRESUMO
OBJECTIVE: Most MRI-based osteoarthritis (OA) studies have focused on a single knee per person and thus, data on bilaterality is sparse. Study aim was to describe symmetricity of MRI-detected OA features in a cohort of subjects with knee pain. DESIGN: Participants were 169 subjects with chronic knee pain who had 3 T MRI of both knees using the same protocol as in the Osteoarthritis Initiative. Knees were read for cartilage damage, bone marrow lesions (BMLs), and meniscal damage according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Chi(2) tests were used to compare the proportion of knees with unilateral tissue pathology to the proportion what would be expected if both knees were independent. We further used percent agreement and linear weighted kappa statistics to describe agreement of cartilage damage and BMLs in the same articular plates. RESULTS: 51.2% of participants were men, mean age was 52.1 (±6.2), mean BMI was 29.0 kg/m(2) (±4.1). All plates showed a significant higher degree of symmetricity for cartilage damage as evidenced by weighted kappas ranging from 0.32 to 0.59. For BMLs the degree of symmetricity was higher for the patella, trochlea, medial tibia, lateral femur, and medial femur; for meniscal damage the degree of unilaterality was lower for all medial meniscal subregions but not all lateral. Kappas ranged between 0.52 and 0.68 for cartilage and 0.30 and 0.55 for BMLs for the four subregions with highest agreement. CONCLUSION: A higher degree of symmetricity of tissue damage than expected by chance was observed in this cohort of subjects with knee pain.
Assuntos
Cartilagem Articular/diagnóstico por imagem , Cartilagem Articular/patologia , Articulação do Joelho/diagnóstico por imagem , Articulação do Joelho/patologia , Osteoartrite do Joelho/diagnóstico por imagem , Osteoartrite do Joelho/patologia , Adulto , Idoso , Artralgia/etiologia , Feminino , Humanos , Imageamento Tridimensional , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , RadiografiaRESUMO
OBJECTIVE: To determine the prevalence of intraarticular susceptibility artifacts and to detect longitudinal changes in the artifacts, on 3T magnetic resonance imaging (MRI) of the knee in a cohort of patients with knee pain, and to assess the association of susceptibility artifacts with radiographic intraarticular calcifications. DESIGN: Three hundred and forty-six knees of 177 subjects aged 35-65 were included. 3T MRI was performed at baseline and at 6 months. Baseline radiographs were assessed for presence/absence of linear/punctate calcifications within the tibiofemoral joint (TFJ) space. Corresponding MRIs were assessed for susceptibility artifacts (i.e., linear/punctate hypointensities) in the TFJ space on coronal dual-echo steady-state (DESS) sequences. Kappa statistics were applied to determine agreement between findings on baseline DESS and radiography. Changes in artifacts over time were recorded. RESULTS: In the medial compartment, 13 (4%) of the knees showed susceptibility artifacts at baseline. Six knees had persistent artifacts and six knees had incident artifacts at follow-up. Agreement between DESS and radiography was κ = 0.18 (-0.15, 0.51) in the medial compartment. Frequency of artifacts in the lateral compartment was low (2%). CONCLUSION: Susceptibility artifacts detected on knee MRI are not frequent, and likely correspond to vacuum phenomena as they commonly change over time and are not associated with intraarticular calcifications. Radiologists should be aware of these artifacts as they can interfere with cartilage segmentation.
Assuntos
Artefatos , Calcinose/patologia , Doenças das Cartilagens/patologia , Cartilagem Articular/patologia , Articulação do Joelho/patologia , Osteoartrite do Joelho/patologia , Adulto , Idoso , Calcinose/diagnóstico por imagem , Doenças das Cartilagens/diagnóstico por imagem , Cartilagem Articular/diagnóstico por imagem , Suscetibilidade a Doenças , Feminino , Humanos , Articulação do Joelho/diagnóstico por imagem , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osteoartrite do Joelho/diagnóstico por imagem , RadiografiaRESUMO
BACKGROUND: A substantial proportion of individuals who live in community settings in the UK experience malnutrition. Routine screening for malnutrition by healthcare practitioners has been recommended in many regions. The present study aimed to understand community nurses' perceptions of barriers and facilitators to undertaking nutritional screening. METHODS: A qualitative study was undertaken with a purposive sample of community nurses working in one UK healthcare organisation. Semi-structured interviews were used to elicit perceptions of barriers and facilitators. Interviews were digitally recorded, anonymised and transcribed. Initial codes were assigned for salient constructs identified in the transcripts, refined by grouping, and a thematic list was developed. RESULTS: Twenty district nurses and community matrons were interviewed at which time saturation of the data was achieved. Six themes emerged: supportive organisational culture, time and resource to screen and intervene, ease and acceptability of the screening tool, professional judgement as good as screening, the need for training and sharing good practice, and enhancing communication between care settings. CONCLUSIONS: The findings of the present study suggest that screening is more likely to be completed where an organisation is perceived to have a clear expectation that it is undertaken and also demonstrates this through training and availability of resources. The need for a process or tool that nurses find easy to use and relevant to their practice area was highlighted. Further research should examine the effect of the use of a nutritional screening tool by community nurses on nutritional care planning and intervention.
Assuntos
Desnutrição/diagnóstico , Programas de Rastreamento/métodos , Programas de Rastreamento/enfermagem , Enfermeiras e Enfermeiros , Atitude do Pessoal de Saúde , Comunicação , Estudos de Avaliação como Assunto , Feminino , Humanos , Reino UnidoRESUMO
BACKGROUND: Recent reports have suggested that registered nurses may not screen patients admitted to their care for malnutrition. The objective of this integrative review was to locate and review published research investigating barriers and facilitators to nutritional screening by nurses. METHODS: A systematic search for relevant English language publications was conducted through CINAHL®, Web of Science, MEDLINE® and EMBASE and an Internet search engine (completed November 2011). Reference lists of relevant publications were also searched. Search terms included nursing, dietetics, nutrition disorders and screening, as well as associated MeSH® terms and Subject Headings. Six hundred and sixteen publications were identified and 605 were excluded. Publications reporting research concerning barriers and facilitators to nutritional screening by nurses were selected using exclusion and inclusion criteria. These were reviewed and the key findings described, categorised, combined, reviewed and refined to create themes. RESULTS: Eleven publications were reviewed. Publications primarily reported hospital-based studies undertaken in three continents and considered barriers rather than facilitators. Five themes emerged: organisational culture, competing priorities, the value of clinical judgement, training and education, and discrepancy between attitudes and practice. CONCLUSIONS: Studies primarily involved acute care and indicated that routine screening for malnutrition will not take place unless it is considered an integral part of nursing assessment that is required by policy and resourced appropriately. Qualitative studies investigating barriers and facilitators to screening for malnutrition in community settings are needed and research is required to test interventions designed to modify or remove barriers and facilitate screening.
Assuntos
Desnutrição/diagnóstico , Programas de Rastreamento/métodos , Prática Privada de Enfermagem , Bases de Dados Factuais , Prática Clínica Baseada em Evidências , Humanos , Programas de Rastreamento/enfermagemRESUMO
BACKGROUND: Marked increases in Clostridium difficile infection (CDI) incidence, driven by epidemic strain spread, is a global phenomenon. METHODS: The Clostridium difficile Ribotyping Network (CDRN) was established in 2007 as part of enhanced CDI surveillance in England, to facilitate the recognition and control of epidemic strains. We report on changes in CDI epidemiology in England in the first 3 years of CDRN. RESULTS: CDRN received 12,603 fecal specimens, comprising significantly (P < .05) increasing numbers and proportions of national CDI cases in 2007-2008 (n = 2109, 3.8%), 2008-2009 (n = 4774, 13.2%), and 2009-2010 (n = 5720, 22.3%). The C. difficile recovery rate was 90%, yielding 11,294 isolates for ribotyping. Rates of 9 of the 10 most common ribotypes changed significantly (P < .05) during 2007-2010. Clostridium difficile ribotype 027 predominated, but decreased markedly from 55% to 36% and 21% in 2007-2008, 2008-2009, and 2009-2010, respectively. The largest regional variations in prevalence occurred for ribotypes 027, 002, 015, and 078. Cephalosporin and fluoroquinolone use in CDI cases was reported significantly (P < .05) less frequently during 2007-2010. Mortality data were subject to potential reporting bias, but there was a significant decrease in CDI-associated deaths during 2007-2010, which may have been due to multiple factors, including reduced prevalence of ribotype 027. CONCLUSIONS: Access to C. difficile ribotyping was associated with significant changes in the prevalence of epidemic strains, especially ribotype 027. These changes coincided with markedly reduced CDI incidence and related mortality in England. CDI control programs should include prospective access to C. difficile typing and analysis of risk factors for CDI and outcomes.
Assuntos
Clostridioides difficile/isolamento & purificação , Infecções por Clostridium/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Clostridioides difficile/classificação , Clostridioides difficile/genética , Infecções por Clostridium/tratamento farmacológico , Infecções por Clostridium/microbiologia , Inglaterra/epidemiologia , Fezes/microbiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Prevalência , Vigilância em Saúde Pública , RibotipagemRESUMO
Currently, there are no established definitions or terminology for sedation-related adverse events (AEs). With clear terminology and definitions, sedation events may be accurately identified and tracked, providing a benchmark for defining the occurrence of AEs, ranging from minimal to severe. This terminology could apply to sedation performed in any location and by any provider. We present a consensus document from the International Sedation Task Force (ISTF) of the World Society of Intravenous Anaesthesia (World SIVA). The ISTF is composed of adult and paediatric sedation practitioners from multiple disciplines throughout the world.
Assuntos
Sistemas de Notificação de Reações Adversas a Medicamentos , Sedação Consciente/efeitos adversos , Adulto , Anestesia Intravenosa , Criança , Sedação Consciente/métodos , Consenso , Guias como Assunto , Humanos , Análise de Intenção de Tratamento , Pediatria , Terminologia como Assunto , Resultado do Tratamento , Estados Unidos , United States Food and Drug Administration , Organização Mundial da SaúdeRESUMO
The increasing incidence of nosocomial infections caused by glycopeptide-resistant enterococci is a global concern. Enterococcal species are also difficult to eradicate with existing cleaning regimens; they can survive for long periods on surfaces, thus contributing to cases of reinfection and spread of antibiotic-resistant strains. We have investigated the potential use of copper alloys as bactericidal surfaces. Clinical isolates of vancomycin-resistant Enterococcus faecalis and Enterococcus faecium were inoculated onto copper alloy and stainless steel surfaces. Samples were assessed for the presence of viable cells by conventional culture, detection of actively respiring cells, and assessment of cell membrane integrity. Both species survived for up to several weeks on stainless steel. However, no viable cells were detected on any alloys following exposure for 1 h at an inoculum concentration of Assuntos
Ligas/farmacologia
, Cobre/farmacologia
, DNA Bacteriano/metabolismo
, Desinfetantes/farmacologia
, Enterococcus faecalis/efeitos dos fármacos
, Enterococcus faecium/efeitos dos fármacos
, Membrana Celular/fisiologia
, Fragmentação do DNA
, DNA Bacteriano/genética
, Enterococcus faecalis/crescimento & desenvolvimento
, Enterococcus faecalis/isolamento & purificação
, Enterococcus faecalis/metabolismo
, Enterococcus faecium/crescimento & desenvolvimento
, Enterococcus faecium/isolamento & purificação
, Enterococcus faecium/metabolismo
, Genoma Bacteriano
, Infecções por Bactérias Gram-Positivas/microbiologia
, Viabilidade Microbiana/efeitos dos fármacos
, Oxirredução
, Plasmídeos
, Resistência a Vancomicina
RESUMO
In the insect Oncopeltus (Hemiptera, Lygaeidae), after blastoderm formation, labeled cells in one segment never give rise to cells in another; clones always respect a sharply defined line, the segmental boundary. Similarly, demarcation lines defining "compartments" have been recently found within the imaginal disks of Drosophila and promise to be of first importance in developmental genetics. In Oncopeltus the segmental border is a straight line in a smiple epithelial monolayer and is marked by a change in pigmentation that is visible in the electron microscope. Reconstructions from serial sections show that there is a change of cell shape at the boundary, but attachment desmosomes, septate junctions, and gap junctions link cells of different segments as well as cells of the same segment. The form of the epithelium at different stages of the molt cycle is described, and the possibility that there may be an abrupt change of cell adhesiveness at the segment boundary is discussed.
Assuntos
Hemípteros/anatomia & histologia , Animais , Membrana Celular/ultraestrutura , Grânulos Citoplasmáticos/ultraestrutura , Desmossomos/ultraestrutura , Células Epiteliais , Epitélio/ultraestrutura , Junções Intercelulares/ultraestrutura , Larva/anatomia & histologia , Microscopia Eletrônica , Modelos Anatômicos , Pigmentos BiológicosRESUMO
Male F-344 rats were administered corn oil (vehicle control), d-limonene (positive control, 300mg/kg), or MIBK (1000mg/kg) and female F-344 rats corn oil (vehicle control) or MIBK for 10 consecutive days by oral gavage. Approximately 24h after the final dose the kidneys were excised and the left kidney prepared and evaluated for histological changes including protein (hyaline) droplet accumulation, immunohistochemical staining for alpha2u-globulin (alpha2u), and proliferating cell nuclear antigen (PCNA) to quantitate renal cell proliferation. The right kidney was prepared for quantitation of total protein and alpha2u using an ELISA. MIBK elicited an increase in protein droplets, accumulation of alpha2u, and renal cell proliferation in male, but not female rats, responses characteristic of alpha2u-mediated nephropathy. MIBK produced identical histopathological changes in the male rat kidney when compared to d-limonene, an acknowledged inducer of alpha2u-nephropathy except that the grade of severity tended to be slightly lower with MIBK. MIBK did not induce any effects in female rats. Therefore, renal histopathology, along with the other measures of alpha2u accumulation, provides additional weight of evidence to support the inclusion of MIBK in the category of chemicals exerting renal effects through a alpha2u-nephropathy-mediated mode-of-action.
Assuntos
alfa-Globulinas/metabolismo , Nefropatias/induzido quimicamente , Metil n-Butil Cetona/farmacologia , Administração Oral , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Metil n-Butil Cetona/administração & dosagem , Tamanho do Órgão/efeitos dos fármacos , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Endogâmicos F344RESUMO
There are many methods for analysing wear volume in failed polyethylene acetabular components. We compared a radiological technique with three recognised ex vivo methods of measurement. We tested 18 ultra-high-molecular-weight polyethylene acetabular components revised for wear and aseptic loosening, of which 13 had pre-revision radiographs, from which the wear volume was calculated based upon the linear wear. We used a shadowgraph technique on silicone casts of all of the retrievals and a coordinate measuring method on the components directly. For these techniques, the wear vector was calculated for each component and the wear volume extrapolated using mathematical equations. The volumetric wear was also measured directly using a fluid-displacement method. The results of each technique were compared. The series had high wear volumes (mean 1385 mm(3); 730 to 1850) and high wear rates (mean 205 mm(3)/year; 92 to 363). There were wide variations in the measurements of wear volume between the radiological and the other techniques. Radiograph-derived wear volume correlated poorly with that of the fluid-displacement method, co-ordinate measuring method and shadowgraph methods, becoming less accurate as the wear increased. The mean overestimation in radiological wear volume was 47.7% of the fluid-displacement method wear volume. Fluid-displacement method, coordinate measuring method and shadowgraph determinations of wear volume were all better than that of the radiograph-derived linear measurements since they took into account the direction of wear. However, only radiological techniques can be used in vivo and remain useful for monitoring linear wear in the clinical setting. Interpretation of radiological measurements of acetabular wear must be done judiciously in the clinical setting. In vitro laboratory techniques, in particular the fluid-displacement method, remain the most accurate and reliable methods of assessing the wear of acetabular polyethylene.
Assuntos
Prótese de Quadril , Polietileno , Falha de Prótese , Acetábulo/diagnóstico por imagem , Acetábulo/cirurgia , Artroplastia de Quadril , Análise de Falha de Equipamento/métodos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Desenho de Prótese , RadiografiaRESUMO
Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. Accordingly, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist) or a green fluorescence protein (GFP) (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin, whereas males rapidly lost physiological effects and developed leptin resistance as confirmed by lower acute leptin-mediated phosphorylation of signal transducer and activator of transcription 3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist-females gained lean body mass. Consequently, the lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, the present study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether such physiological responses are mediated by female or male sex hormones.
Assuntos
Leptina/fisiologia , Caracteres Sexuais , Animais , Composição Corporal , Peso Corporal , Ingestão de Alimentos , Feminino , Leptina/sangue , Masculino , Tamanho do Órgão , Fosforilação , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismoRESUMO
BACKGROUND: Epidemiologic and in vitro studies suggest that SLCO-encoded organic anion transporting polypeptide (OATP) transporters influence the response of prostate cancer (PCa) to androgen deprivation by altering intratumor androgens. We have previously shown that castration-resistant metastases express multiple SLCO transporters at significantly higher levels than primary PCa, suggesting that OATP-mediated steroid transport is biologically relevant in advanced disease. However, whether OATP-mediated steroid transport can actually modify prostate tumor androgen levels in vivo has never been demonstrated. METHODS: We sought to determine whether OATP-mediated steroid transport can measurably alter PCa androgen levels in vivo. We evaluated the uptake of dehydroepiandrosterone (DHEAS), E1S and testosterone in LNCaP cells engineered to express OATP1B1, 1B3, 2B1 or 4A1. We measured the uptake via administration of tritiated steroids to castrate mice bearing vector control or OATP1B1-, 2B1- or 4A1-expressing xenografts. We treated tumor-bearing mice with DHEAS and testosterone at physiologically relevant levels and measured intratumor accumulation of administered steroids by mass spectrometry. RESULTS: OATP1B1- and 2B-expressing xenografts each showed a threefold increase in tritiated-DHEAS uptake vs vector controls (P=0.002 and P=0.036, respectively). At circulating DHEAS levels similar to those in abiraterone-treated men (~15 µg dl-1), OATP1B1- and 2B1-expressing xenografts showed a 3.9-fold (P=0.057) and 1.9-fold (P=0.048) increase in tumor accumulation of DHEAS and a 1.6-fold (P=0.057) and 2.7-fold (P=0.095) increase in DHEA, respectively. At the substantial circulating testosterone levels found in eugonadal men, a consistent effect of OATP1B1, 2B1 or 4A1 on testosterone uptake in vivo was not detected. CONCLUSIONS: OATP transporters measurably alter DHEAS uptake and intratumor androgen levels in prostate tumors in vivo, even at circulating androgen levels achieved in abiraterone-treated patients. These novel data emphasize the continued need to inhibit ligand-mediated androgen receptor signaling in PCa tumors, and support prospective evaluation of studies designed to test inhibition of OATP-mediated DHEAS uptake and utilization.