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1.
Immunity ; 52(2): 357-373.e9, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32049051

RESUMO

Clearance of apoptotic cells by macrophages prevents excessive inflammation and supports immune tolerance. Here, we examined the effect of blocking apoptotic cell clearance on anti-tumor immune response. We generated an antibody that selectively inhibited efferocytosis by phagocytic receptor MerTK. Blockade of MerTK resulted in accumulation of apoptotic cells within tumors and triggered a type I interferon response. Treatment of tumor-bearing mice with anti-MerTK antibody stimulated T cell activation and synergized with anti-PD-1 or anti-PD-L1 therapy. The anti-tumor effect induced by anti-MerTK treatment was lost in Stinggt/gt mice, but not in Cgas-/- mice. Abolishing cGAMP production in Cgas-/- tumor cells, depletion of extracellular ATP, or inactivation of the ATP-gated P2X7R channel also compromised the effects of MerTK blockade. Mechanistically, extracellular ATP acted via P2X7R to enhance the transport of extracellular cGAMP into macrophages and subsequent STING activation. Thus, MerTK blockade increases tumor immunogenicity and potentiates anti-tumor immunity, which has implications for cancer immunotherapy.


Assuntos
Macrófagos/imunologia , Proteínas de Membrana/metabolismo , Neoplasias/imunologia , Nucleotídeos Cíclicos/metabolismo , Receptores Purinérgicos P2X7/metabolismo , c-Mer Tirosina Quinase/imunologia , Trifosfato de Adenosina/metabolismo , Animais , Apoptose , Antígeno B7-H1/imunologia , Células Cultivadas , Feminino , Imunidade Inata , Imunoterapia , Interferon Tipo I/metabolismo , Macrófagos/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/terapia , Nucleotidiltransferases/deficiência , Nucleotidiltransferases/metabolismo , Fagocitose , Receptor de Morte Celular Programada 1/imunologia , Receptores Purinérgicos P2X7/deficiência , Transdução de Sinais/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto , c-Mer Tirosina Quinase/genética
2.
J Cell Sci ; 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38904097

RESUMO

PTPRK is a receptor tyrosine phosphatase linked to the regulation of growth factor signalling and tumour suppression. It is stabilized at the plasma membrane by trans homophilic interactions upon cell-cell contact. It regulates cell-cell adhesion, but is also reported to regulate numerous cancer-associated signalling pathways. However, its signalling mechanism remains to be determined. Here, we find that PTPRK regulates cell adhesion signalling, suppresses invasion and promotes collective, directed migration in colorectal cancer cells. In vivo, PTPRK supports recovery from inflammation-induced colitis. In addition, we confirm that PTPRK functions as a tumour suppressor in the mouse colon and in colorectal cancer xenografts. PTPRK regulates growth factor and adhesion signalling, and suppresses epithelial to mesenchymal transition (EMT). Contrary to the prevailing notion that PTPRK directly dephosphorylates EGFR, we find that PTPRK regulation of both EGFR and EMT is independent of its catalytic function. This suggests that additional adaptor and scaffold functions are important features of PTPRK signalling.

3.
Ann Surg Oncol ; 31(4): 2727-2736, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38177461

RESUMO

BACKGROUND: Robot-assisted pelvic lymph node dissection (rPLND) has been reported in heterogenous groups of patients with melanoma, including macroscopic or at-high-risk-for microscopic metastasis. With changing indications for surgery in melanoma, and availability of effective systemic therapies, pelvic dissection is now performed for clinically detected bulky lymph node metastasis followed by adjuvant drug therapy. rPLND has not been compared with open pelvic lymph node dissection (oPLND) for modern practice. METHODS: All patients undergoing pelvic node dissection for macroscopic melanoma at a single institution were reviewed as a cohort, observational study. RESULTS: Twenty-two pelvic lymph node dissections were identified (8 oPLND; 14 rPLND). The number of pelvic lymph nodes removed was similar (median oPLND 6.5 (interquartile range [IQR] 6.0-12.5] versus rPLND 6.0 [3.75-9.0]), with frequent matted nodes (11/22, 50.0%). Operative time (median oPLND 130 min [IQR 95.5-182] versus rPLND 126 min [IQR 97.8-160]) and complications (Clavien-Dindo scale) were similar. Length of hospital stay (median 5.34 days (IQR 3.77-6.94) versus 1.98 days (IQR 1.39-3.50) and time to postoperative adjuvant therapy (median 11.6 weeks [IQR 10.6-18.5] versus 7.71 weeks [IQR 6.29-10.4]) were shorter in the rPLND group. No differences in pelvic lymph node recurrence (p = 0.984), distant metastatic recurrence (p = 0.678), or melanoma-specific survival (p = 0.655) were seen (median follow-up 21.1 months [rPLND] and 25.7 months [oPLND]). CONCLUSIONS: rPLND is an effective way to remove bulky pelvic lymph nodes in melanoma, with a shorter recovery and reduced interval to initiating adjuvant therapy compared with oPLND. This group of patients may especially benefit from neoadjuvant systemic approaches to management.


Assuntos
Linfadenopatia , Melanoma , Robótica , Humanos , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Melanoma/patologia , Linfonodos/cirurgia , Linfonodos/patologia , Excisão de Linfonodo , Pelve/cirurgia , Linfadenopatia/cirurgia , Estudos Retrospectivos , Espaço Retroperitoneal/cirurgia , Resultado do Tratamento
4.
Artif Organs ; 48(4): 386-391, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37990598

RESUMO

BACKGROUND: Patients with left ventricular assist devices (LVADs) require systemic anticoagulation. The use of enoxaparin for bridging to warfarin remains understudied in this population. METHODS: This single-center retrospective study was performed to characterize enoxaparin use and associated thrombotic and bleeding outcomes in adult outpatients with LVADs from January 2018 to July 2021. RESULTS: Fifty-four enoxaparin bridging events were evaluated in 49 patients. Most patients with HeartMate II (HM2) and HeartWare (HVAD) devices received enoxaparin dosed 1 mg/kg every 12 h. In patients with HeartMate 3 (HM3) devices, an equal number of patients received 0.5 mg/kg every 12 h and 1 mg/kg every 12 h, with a smaller subset receiving intermediate doses. The median duration of bridging was 6 days (4-8 [IQR]). One major bleeding event required discontinuation of enoxaparin and hospitalization in a patient with an HM3 device. Thrombotic events occurred in four patients with two incidents of pump thrombosis requiring pump exchange and two ischemic strokes. All thrombotic events occurred in patients with HVAD or HM2 devices. CONCLUSION: These results suggest that enoxaparin bridging in LVAD patients was well-tolerated with low bleeding and thrombotic rates, particularly with the HM3 device.


Assuntos
Insuficiência Cardíaca , Coração Auxiliar , Trombose , Adulto , Humanos , Enoxaparina/efeitos adversos , Varfarina/efeitos adversos , Estudos Retrospectivos , Pacientes Ambulatoriais , Coração Auxiliar/efeitos adversos , Insuficiência Cardíaca/cirurgia , Insuficiência Cardíaca/complicações , Hemorragia/induzido quimicamente , Hemorragia/prevenção & controle , Trombose/prevenção & controle , Trombose/complicações
5.
Fam Community Health ; 47(3): 209-218, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38713756

RESUMO

BACKGROUND: Adult day services (ADS) are therapeutic, social, and health-related activities that keep people in their homes, rather than institutional settings. While there is a growing body of literature on ADS for older adults, there is far less information available about ADS for younger adults with intellectual and/or developmental disabilities (IDDs). METHOD: Researchers conducted a scoping review of 6 databases (892 total articles). RESULTS: After applying inclusion and exclusion criteria, 74 full articles were reviewed, with 10 articles meeting study requirements. The research team found the literature is limited to simple descriptive reports or interventions that use ADS as a platform. CONCLUSIONS: Simply put, we know very little about the services provided to younger adults with IDD in ADS. Implications for future research are discussed, including the need to catalog the services offered in ADS for younger adults with IDD and to evaluate their impact on participant well-being.


Assuntos
Deficiências do Desenvolvimento , Deficiência Intelectual , Humanos , Deficiências do Desenvolvimento/terapia , Deficiência Intelectual/terapia , Adulto , Centros-Dia de Assistência à Saúde para Adultos , Hospital Dia
6.
J Cardiovasc Pharmacol ; 80(6): 820-825, 2022 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-35976119

RESUMO

ABSTRACT: Dofetilide is an antiarrhythmic agent and primarily eliminated renally. Initial dosing is determined by creatinine clearance, calculated by total body weight in the Cockcroft-Gault equation. To date, there is no evidence comparing the dosing of dofetilide in obese versus nonobese patients. We conducted a retrospective review of 217 adults admitted for dofetilide loading to evaluate the tolerability of dofetilide in obese versus nonobese patients. The rate of dose adjustments, including dose reductions and discontinuations, was compared between obese versus nonobese patients in unadjusted and adjusted analyses. Electrocardiograms were collected throughout the loading period, and calculation of QT intervals was performed. Obese patients did not have a significantly higher frequency of dose adjustments compared with nonobese patients (51.5% vs. 44.8%, P = 0.33). Using total body weight to determine starting doses was associated with great odds of dose adjustments compared with ideal body weight (OR 3.69, P = 0.002) and adjusted body weight (OR 4.46, P = 0.02). Men required significantly fewer dose adjustments compared with women on multivariate analysis (OR 0.53, P = 0.03). Obesity is not associated with an increase in the rate of dose adjustments. Total body weight should be used with caution to calculate initial doses of dofetilide in women because it may lead to a higher rate of dose adjustments compared with ideal body weight. Additional studies are needed to confirm the optimal method for selecting starting doses of dofetilide in women, particularly those with a body mass index of ≥30.


Assuntos
Redução da Medicação , Obesidade , Humanos , Feminino , Obesidade/diagnóstico , Peso Corporal
7.
J Gerontol Soc Work ; 65(4): 450-464, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34511052

RESUMO

Nursing home social workers are on the frontlines during COVID-19 responding to individual resident needs, the needs of staff, and larger health needs of the nursing home. However, it is unclear whether nursing home social workers feel adequately trained and prepared in responding to disasters, such as COVID-19. To explore this, we used a study cross-sectional survey distributed via social media focusing on 1) prior training on disaster preparedness, 2) any content social workers wish had been a part of their education, and 3) suggestions for educators/academics to serve social workers on the frontlines. Data in this study are based on a sample of 63 (N=63) nursing home social workers. Demographic data were analyzed using SPSS and qualitative data were analyzed using the RaDar (rigorous and accelerated data reduction) technique. Findings revealed that most social workers had little to no training in disaster preparedness, and shared areas of future education initiatives. Participants also shared the need for bridging the research to practice gap through open access articles and support from academics. Findings from the present study reveal areas social work programs can expand gerontology-focused course offerings. Additionally, developments promoting practitioner support from academics is worth consideration.


Assuntos
COVID-19 , Desastres , COVID-19/epidemiologia , Estudos Transversais , Humanos , Casas de Saúde , Serviço Social
8.
Eur J Immunol ; 50(6): 891-902, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32043568

RESUMO

CD96 is a member of the poliovirus receptor (PVR, CD155)-nectin family that includes T cell Ig and ITIM domain (TIGIT) and CD226. While CD96, TIGIT, and CD226 have important roles in regulating NK cell activity, and TIGIT and CD226 have also been shown to regulate T cell responses, it is unclear whether CD96 has inhibitory or stimulatory function in CD8+ T cells. Here, we demonstrate that CD96 has co-stimulatory function on CD8+ T cells. Crosslinking of CD96 on human or mouse CD8+ T cells induced activation, effector cytokine production, and proliferation. CD96 was found to transduce its activating signal through the MEK-ERK pathway. CD96-mediated signaling led to increased frequencies of NUR77- and T-bet-expressing CD8+ T cells and enhanced cytotoxic effector activity, indicating that CD96 can modulate effector T cell differentiation. Antibody blockade of CD96 or genetic ablation of CD96 expression on CD8+ T cells impaired expression of transcription factors and proinflammatory cytokines associated with CD8+ T cell activation in in vivo models. Taken together, CD96 has a co-stimulatory role in CD8+ T cell activation and effector function.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Ativação Linfocitária , Sistema de Sinalização das MAP Quinases/imunologia , Modelos Imunológicos , Animais , Antígenos CD/genética , Diferenciação Celular/genética , Linhagem Celular Tumoral , Humanos , Sistema de Sinalização das MAP Quinases/genética , Camundongos , Camundongos Knockout
9.
Nat Methods ; 15(7): 512-514, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29786090

RESUMO

Despite widespread use of CRISPR, comprehensive data on the frequency and impact of Cas9-mediated off-targets in modified rodents are limited. Here we present deep-sequencing data from 81 genome-editing projects on mouse and rat genomes at 1,423 predicted off-target sites, 32 of which were confirmed, and show that high-fidelity Cas9 versions reduced off-target mutation rates in vivo. Using whole-genome sequencing data from ten mouse embryos, treated with a single guide RNA (sgRNA), and from their genetic parents, we found 43 off-targets, 30 of which were predicted by an adapted version of GUIDE-seq.


Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Engenharia Genética , Genômica/métodos , Animais , Linhagem Celular , Feminino , Masculino , Camundongos , Reação em Cadeia da Polimerase Multiplex/métodos , RNA/genética , Ratos , Sequenciamento Completo do Genoma/métodos
10.
Nature ; 526(7575): 666-71, 2015 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-26375259

RESUMO

Intracellular lipopolysaccharide from Gram-negative bacteria including Escherichia coli, Salmonella typhimurium, Shigella flexneri, and Burkholderia thailandensis activates mouse caspase-11, causing pyroptotic cell death, interleukin-1ß processing, and lethal septic shock. How caspase-11 executes these downstream signalling events is largely unknown. Here we show that gasdermin D is essential for caspase-11-dependent pyroptosis and interleukin-1ß maturation. A forward genetic screen with ethyl-N-nitrosourea-mutagenized mice links Gsdmd to the intracellular lipopolysaccharide response. Macrophages from Gsdmd(-/-) mice generated by gene targeting also exhibit defective pyroptosis and interleukin-1ß secretion induced by cytoplasmic lipopolysaccharide or Gram-negative bacteria. In addition, Gsdmd(-/-) mice are protected from a lethal dose of lipopolysaccharide. Mechanistically, caspase-11 cleaves gasdermin D, and the resulting amino-terminal fragment promotes both pyroptosis and NLRP3-dependent activation of caspase-1 in a cell-intrinsic manner. Our data identify gasdermin D as a critical target of caspase-11 and a key mediator of the host response against Gram-negative bacteria.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Inflamassomos/metabolismo , Transdução de Sinais , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/química , Proteínas Reguladoras de Apoptose/deficiência , Proteínas Reguladoras de Apoptose/genética , Caspases Iniciadoras , Linhagem Celular , Feminino , Bactérias Gram-Negativas/imunologia , Humanos , Inflamassomos/efeitos dos fármacos , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Lipopolissacarídeos/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Macrófagos Peritoneais/metabolismo , Masculino , Camundongos , Mutação/genética , Necrose , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas de Ligação a Fosfato , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Sepse/microbiologia , Transdução de Sinais/genética , Análise de Sobrevida
11.
Proc Natl Acad Sci U S A ; 115(50): E11731-E11740, 2018 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-30504141

RESUMO

Natural killer (NK) cell recognition of tumor cells is mediated through activating receptors such as CD226, with suppression of effector functions often controlled by negative regulatory transcription factors such as FOXO1. Here we show that CD226 regulation of NK cell cytotoxicity is facilitated through inactivation of FOXO1. Gene-expression analysis of NK cells isolated from syngeneic tumors grown in wild-type or CD226-deficient mice revealed dysregulated expression of FOXO1-regulated genes in the absence of CD226. In vitro cytotoxicity and stimulation assays demonstrated that CD226 is required for optimal killing of tumor target cells, with engagement of its ligand CD155 resulting in phosphorylation of FOXO1. CD226 deficiency or anti-CD226 antibody blockade impaired cytotoxicity with concomitant compromised inactivation of FOXO1. Furthermore, inhibitors of FOXO1 phosphorylation abrogated CD226-mediated signaling and effector responses. These results define a pathway by which CD226 exerts control of NK cell responses against tumors.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Proteína Forkhead Box O1/antagonistas & inibidores , Proteína Forkhead Box O1/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Animais , Antígenos de Diferenciação de Linfócitos T/genética , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Humanos , Ligantes , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos , Camundongos Knockout , Nectinas/metabolismo , Fosforilação , Receptores Virais/metabolismo , Transdução de Sinais/imunologia
12.
Home Health Care Serv Q ; 40(1): 16-26, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32865476

RESUMO

Community advisory boards (CABs) have become increasingly common and important in translational research in health care including studies focusing on home and community-based services. CABs are composed of stakeholders who share interest in research projects and typically include patients/clients, practitioners, community members, policymakers, and researchers. CABs advise researchers on issues ranging from research design and recruitment to implementation and dissemination. In this article, the researchers detail their experiences with the CAB for a pragmatic clinical trail of Adult Day Services (ADS) Plus, an education and support intervention for family caregivers of older adults with dementia using adult day services. Lessons learned, guidelines, and best practices are then presented for developing and working with a CAB in healthcare research.


Assuntos
Participação da Comunidade/métodos , Ensaios Clínicos Pragmáticos como Assunto/métodos , Centros-Dia de Assistência à Saúde para Adultos/organização & administração , Centros-Dia de Assistência à Saúde para Adultos/tendências , Cuidadores/psicologia , Participação da Comunidade/tendências , Humanos , Desenvolvimento de Programas/métodos
13.
J Bus Res ; 128: 31-44, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-36540352

RESUMO

Stock markets across the world have exhibited varying degrees of volatility following the recent COVID-19 pandemic. We have examined the effect of this pandemic on stock market volatility and whether economic strength, measured by a set of selected country-level economic characteristics and factors such as economic resilience, intensity of capitalism, level of corporate governance, financial development, monetary policy rate and quality of health system, can potentially mitigate the possible detrimental effect of the global pandemic on stock market volatility. Using data from 34 developed and emerging markets, we have found that these country-level economic characteristics and factors do help to reduce the volatility arising due to the virus pandemic. The results of this paper are important as policymakers can use these economic factors to set policy responses to tackle extraordinary heat in the global stock market in order to avoid any possible future financial crisis.

14.
J Soc Work End Life Palliat Care ; 16(2): 99-115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32223368

RESUMO

The loss of a family member or friend can have profound psychological and physical implications, particularly for individuals without bereavement support services. Online support groups can be an effective means of extending services beyond the traditional modes of delivery. This is especially true for populations that include isolated individuals and those with limited support networks, limited transportation, challenging time commitments, or reside in communities with limited services available. The literature over the last 10 years was reviewed to discern the potential opportunities and challenges of providing online bereavement support group services. Discussed are challenges for recruitment of participants, availability of technology resources, addressing privacy and confidentiality issues, participants' knowledge of technical equipment, legal considerations, ethical considerations, accessibility, and other best practices. Diverse populations such as adolescents, older adults, and rural communities must be uniquely considered when using online support groups.


Assuntos
Luto , Internet , Grupos de Autoajuda/organização & administração , Assistência Terminal/organização & administração , Confidencialidade , Cultura , Acessibilidade aos Serviços de Saúde/organização & administração , Humanos , Qualidade da Assistência à Saúde/normas , Apoio Social
16.
Soc Work Health Care ; 57(5): 355-375, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29522384

RESUMO

Traumatic events are widely acknowledged to have long-term impacts on individuals, yet only recently have health-care professionals begun to assess for and gain an understanding of trauma in the lives of older adults. For many older adults, trauma is often disenfranchised and overlooked as being either a distant past event (e.g., child abuse) or a normal part of aging (e.g., widowhood). Trauma-informed care, on the other hand, calls for health-care professionals to acknowledge that past and recent events may have been traumatic for older adults and to assess and care plan to reduce or prevent re-traumatization. In this article, we explore the impacts of trauma in later life through a case study of a patient admitted to a long-term care facility. Analysis of this case study suggests several important implications for social work practice in long-term care and the use of person-centered care practices in the care of older adults in general.


Assuntos
Casas de Saúde , Trauma Psicológico , Idoso , Envelhecimento , Feminino , Humanos , Assistência de Longa Duração , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Serviço Social
17.
S D Med ; 71(5): 222-223, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29999609

RESUMO

BACKGROUND: Kpa (KEL3, Penney) is a red blood cell antigen within the Kell system, first described in 1957, that occurs in less than 2 percent of the population. Although anti-Kpa antibodies were identified in 2-5 percent of those with alloantibodies among patients requiring chronic transfusion, only five previously published case reports of anti-Kpa reactions were identified. CASE REPORT: Reported here is a case of an elderly female who experienced an acute hemolytic transfusion reaction due to this antigen. Following initiation of blood transfusion, she experienced a sudden onset of rigorous chills, accompanied by elevated temperature, tachycardia, and hypertension. Laboratory studies showed uremia, elevated creatinine, positive direct Coomb's, and low haptoglobin. Serology revealed anti-Kpa antibody. CONCLUSION: This report is only the sixth, to our knowledge, of a significant reaction attributable to anti-Kpa and only the second of an acute hemolytic reaction associated with it. It serves as a reminder of the potential of low incidence antigens causing severe reactions; this potential should be considered when evaluating acute hemolytic reaction.


Assuntos
Incompatibilidade de Grupos Sanguíneos , Hemólise/imunologia , Reação Transfusional/imunologia , Idoso , Feminino , Humanos , Isoanticorpos
18.
JAMA ; 318(2): 132-145, 2017 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-28697253

RESUMO

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.


Assuntos
Antidepressivos/administração & dosagem , Antipsicóticos/uso terapêutico , Aripiprazol/uso terapêutico , Bupropiona/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Substituição de Medicamentos , Adulto , Antidepressivos/uso terapêutico , Resistência a Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estados Unidos , Veteranos
19.
Home Health Care Serv Q ; 36(1): 1-15, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28318409

RESUMO

Green care farms (GCF) provide unique opportunities to persons with disabilities to engage in meaningful and therapeutic activities in farm settings. In this pilot study, the researchers examined the feasibility and impact of the first GCF in the United States. Qualitative interviews (N = 19) and thematic analysis were conducted. GCF participants and family members were enthusiastic about participation and identified benefits such as respite and improved mood. Administrators and farmers indicated that GCF challenged the status quo of funding, programming, and farming. Administrators speculated that the future success of GCF relies upon administrative expertise, local relationships, and managing risk and liability.


Assuntos
Agricultura , Pessoas com Deficiência/estatística & dados numéricos , Avaliação de Programas e Projetos de Saúde/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Agricultura/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pesquisa Qualitativa , Inquéritos e Questionários , Estados Unidos , Recursos Humanos
20.
PLoS Genet ; 9(2): e1003278, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23408910

RESUMO

During pancreatic development, transcription factor cascades gradually commit precursor populations to the different endocrine cell fate pathways. Although mutational analyses have defined the functions of many individual pancreatic transcription factors, the integrative transcription factor networks required to regulate lineage specification, as well as their sites of action, are poorly understood. In this study, we investigated where and how the transcription factors Nkx2.2 and Neurod1 genetically interact to differentially regulate endocrine cell specification. In an Nkx2.2 null background, we conditionally deleted Neurod1 in the Pdx1+ pancreatic progenitor cells, the Neurog3+ endocrine progenitor cells, or the glucagon+ alpha cells. These studies determined that, in the absence of Nkx2.2 activity, removal of Neurod1 from the Pdx1+ or Neurog3+ progenitor populations is sufficient to reestablish the specification of the PP and epsilon cell lineages. Alternatively, in the absence of Nkx2.2, removal of Neurod1 from the Pdx1+ pancreatic progenitor population, but not the Neurog3+ endocrine progenitor cells, restores alpha cell specification. Subsequent in vitro reporter assays demonstrated that Nkx2.2 represses Neurod1 in alpha cells. Based on these findings, we conclude that, although Nkx2.2 and Neurod1 are both necessary to promote beta cell differentiation, Nkx2.2 must repress Neurod1 in a Pdx1+ pancreatic progenitor population to appropriately commit a subset of Neurog3+ endocrine progenitor cells to the alpha cell lineage. These results are consistent with the proposed idea that Neurog3+ endocrine progenitor cells represent a heterogeneous population of unipotent cells, each restricted to a particular endocrine lineage.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Diferenciação Celular , Proteínas de Homeodomínio , Pâncreas , Fatores de Transcrição , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem da Célula , Regulação da Expressão Gênica no Desenvolvimento , Células Secretoras de Glucagon/metabolismo , Proteína Homeobox Nkx-2.2 , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/metabolismo , Camundongos , Proteínas Nucleares , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Pâncreas/metabolismo , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Peixe-Zebra
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