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The TAM receptors (Tyro3, Axl, and Mer) are a family of homologous receptor-tyrosine kinases that inhibit Toll-like receptor signaling to regulate downstream pathways and restore homeostasis. TAM triple mutant mice (Tyro3-/-, Axl-/-, Mer-/-) have elevated levels of pro-inflammatory cytokines and are prone to developing lymphoproliferative disorders and autoimmunity. Understanding differential expression of TAM receptors among human subjects is critical to harnessing this pathway for therapeutic interventions. We have quantified changes in TAM expression during the ontogeny of human macrophages using paired samples of monocytes and macrophages to take advantage of characteristic expression within an individual. No significant differences in levels of Tyro3 were found between monocytes and macrophages (flow cytometry: p=0.652, immunoblot: p=0.231, qPCR: p=0.389). Protein levels of Axl were reduced (flow cytometry: p=0.049, immunoblot: p<0.001) when monocytes matured to macrophages. No significant differences in the levels of Axl mRNA transcripts were found (qPCR: p=0.082), however, Tyro3 and Axl were proportionate. The most striking difference was upregulation of expression of Mer with both protein and mRNA being significantly increased when monocytes developed into macrophages (flow cytometry: p<0.001, immunoblot: p<0.001, qPCR: p=0.004). A fuller characterization of TAM receptor expression in macrophage ontogeny informs our understanding of their function and potential therapeutic interventions.
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This study examined the relationship between scores on the Hypnotic Induction Profile (HIP) and the trait of absorption in three different clinical groups: Smokers (n = 226), Phobics (n = 95), and patients with Chronic Pain (n = 65). Two hypotheses were investigated. The first predicted that both the Eye-Roll sign (ERS) and Induction Score (IND) of the HIP would correlate similarly (r = .30) with scores on the Tellegen Absorption Scale (TAS), as has been previously reported with other measures of hypnotic responsivity in student samples. The second was that using a combination of both ERS and IND scores to predict TAS scores would result in a significant increase in forecasting accuracy over using either HIP measure alone. Both hypotheses were supported in all three clinical groups. Correlations between HIP and Absorption scores ranged from .33 to .53. Clinical and theoretical implications of the findings are discussed.
Assuntos
Dor Crônica/fisiopatologia , Hipnose , Transtornos Fóbicos/fisiopatologia , Fumar/fisiopatologia , Adulto , HumanosRESUMO
BACKGROUND: In 2010, the Department of Veterans Affairs Healthcare System (VA) implemented policy to provide Comprehensive Primary Care (for acute, chronic, and female-specific care) from designated Women's Health providers (DWHPs) at all VA sites. However, since that time no comparisons of quality measures have been available to assess the level of care for women Veterans assigned to these providers. OBJECTIVES: To evaluate the associations between cervical and breast cancer screening rates among age-appropriate women Veterans and designation of primary-care provider (DWHP vs. non-DWHP). RESEARCH DESIGN: Cross-sectional analyses using the fiscal year 2012 data on VA women's health providers, administrative files, and patient-specific quality measures. SUBJECTS: The sample included 37,128 women Veterans aged 21 through 69 years. MEASURES: Variables included patient demographic and clinical factors (ie, age, race, ethnicity, mental health diagnoses, obesity, and site), and provider factors (ie, DWHP status, sex, and panel size). Screening measures were defined by age-appropriate subgroups using VA national guidelines. RESULTS: Female-specific cancer screening rates were higher among patients assigned to DWHPs (cervical cytology 94.4% vs. 91.9%, P<0.0001; mammography 86.3% vs. 83.3%, P<0.0001). In multivariable models with adjustment for patient and provider characteristics, patients assigned to DWHPs had higher odds of cervical cancer screening (odds ratio, 1.26; 95% confidence interval, 1.07-1.47; P<0.0001) and breast cancer screening (odds ratio, 1.24; 95% CI, 1.10-1.39; P<0.0001). CONCLUSIONS: As the proportion of women Veterans increases, assignment to DWHPs may raise rate of female-specific cancer screening within VA. Separate evaluation of sex neutral measures is needed to determine whether other measures accrue benefits for patients with DWHPs.
Assuntos
Neoplasias da Mama/diagnóstico , Programas de Rastreamento/estatística & dados numéricos , Atenção Primária à Saúde , Neoplasias do Colo do Útero/diagnóstico , Saúde dos Veteranos , Saúde da Mulher , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Política Organizacional , Estudos Retrospectivos , Estados Unidos , United States Department of Veterans AffairsRESUMO
We evaluated in vivo innate immune responses in monocyte populations from 67 young (aged 21-30 years) and older (aged ≥65 years) adults before and after influenza vaccination. CD14(+)CD16(+) inflammatory monocytes were induced after vaccination in both young and older adults. In classical CD14(+)CD16(-) and inflammatory monocytes, production of tumor necrosis factor α and interleukin 6, as measured by intracellular staining, was strongly induced after vaccination. Cytokine production was strongly associated with influenza vaccine antibody response; the highest levels were found as late as day 28 after vaccination in young subjects and were substantially diminished in older subjects. Notably, levels of the anti-inflammatory cytokine interleukin 10 (IL-10) were markedly elevated in monocytes from older subjects before and after vaccination. In purified monocytes, we found age-associated elevation in phosphorylated signal transducer and activator of transcription-3, and decreased serine 359 phosphorylation of the negative IL-10 regulator dual-specificity phosphatase 1. These findings for the first time implicate dysregulated IL-10 production in impaired vaccine responses in older adults.
Assuntos
Citocinas/metabolismo , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Interleucina-10/metabolismo , Monócitos/metabolismo , Adulto , Fatores Etários , Idoso , Citocinas/imunologia , Fosfatase 1 de Especificidade Dupla/imunologia , Fosfatase 1 de Especificidade Dupla/metabolismo , Feminino , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Regulação da Expressão Gênica/imunologia , Humanos , Imunidade Inata , Influenza Humana/imunologia , Influenza Humana/virologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Interleucina-6/metabolismo , Receptores de Lipopolissacarídeos/imunologia , Receptores de Lipopolissacarídeos/metabolismo , Masculino , Monócitos/imunologia , Fosforilação , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/imunologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Vacinação , Adulto JovemRESUMO
OBJECTIVES: To summarize evidence regarding the health outcomes associated with polypharmacy, defined as number of prescribed medications, in older community-dwelling persons. DESIGN: Systematic review of MEDLINE (OvidSP 1946 to May, Week 3, 2014). SETTING: Community. PARTICIPANTS: Observational studies examining health outcomes according to number of prescription medications taken. MEASUREMENTS: Association between number of medications and health outcomes. Because of the importance of comorbidity as a potential confounder of the relationship between polypharmacy and health outcomes, articles were assessed regarding the quality of their adjustment for confounding. RESULTS: Of the 50 studies identified, the majority that were rated good in terms of their adjustment for comorbidity demonstrated relationships between polypharmacy and a range of outcomes, including falls, fall outcomes, fall risk factors, adverse drug events, hospitalization, mortality, and measures of function and cognition. However, a number of these studies failed to demonstrate associations, as did a substantial proportion of studies rated fair or poor. CONCLUSION: Data are mixed regarding the relationship between polypharmacy, considered in terms of number of medications, and adverse outcomes in community-dwelling older persons. Because of the challenge of confounding, randomized controlled trials of medication discontinuation may provide more-definitive evidence regarding this relationship than observational studies can provide.
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Doença Crônica/tratamento farmacológico , Polimedicação , Medicamentos sob Prescrição/administração & dosagem , Medicamentos sob Prescrição/efeitos adversos , Acidentes por Quedas , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Avaliação Geriátrica , Humanos , Fatores de RiscoRESUMO
Surgery is common in older adults, so geriatric and surgical providers need to develop expertise in the care of older adults undergoing surgery. The Co-management of Older Operative Patients En Route Across Treatment Environments (CO-OPERATE) program is a clinical and educational collaboration between geriatrics and several surgical specialties at Veterans Affairs Health Care Connecticut. Individuals in CO-OPERATE are co-managed during the pre-, peri-, and postoperative periods. General surgery, urology, vascular surgery, orthopedics, cardiothoracic surgery and neurosurgery all participate in the program, with geriatrics expertise provided by a geriatrician, geriatric nurse practitioner and a geriatric clinical pharmacist. In the initial 3 years, there were 211 CO-OPERATE participants; 31% were evaluated preoperatively, and 62% of the individuals seen preoperatively were seen in clinic. There was a median of three recommendations per consultation. At discharge, 56% returned to the community. Individuals seen preoperatively were more likely to return to the community (63%) than those seen after surgery (50%, P = .10). Geriatrics co-management with a variety of surgical specialties is feasible and may be associated with higher rates of discharge back to the community.
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Comportamento Cooperativo , Idoso Fragilizado , Comunicação Interdisciplinar , Equipe de Assistência ao Paciente/organização & administração , Assistência Perioperatória/métodos , Atividades Cotidianas/classificação , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Connecticut , Avaliação da Deficiência , Feminino , Geriatria/organização & administração , Hospitais Universitários , Hospitais de Veteranos , Humanos , Tempo de Internação , Masculino , Alta do Paciente , Especialidades Cirúrgicas/organização & administraçãoRESUMO
Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis.
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Lesão Pulmonar/etiologia , MAP Quinase Quinase 3/sangue , MAP Quinase Quinase 3/deficiência , Mitocôndrias/fisiologia , Mitofagia , Sepse/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Animais , Células Endoteliais/metabolismo , Feminino , Humanos , Lipopolissacarídeos , Pulmão/metabolismo , MAP Quinase Quinase 3/fisiologia , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitofagia/efeitos dos fármacos , Proteínas Quinases/metabolismo , Sepse/complicações , Sirtuína 1/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismoRESUMO
The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF (Mif(-/-)) or the MIF receptor CD74 (Cd74(-/-)) and wild-type (WT) controls were aged for 6 mo. Both Mif(-/-) and Cd74(-/-) mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif(-/-) mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers (n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7-11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6-14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.