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BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) survivors experience significant psychological distress and low levels of positive psychological well-being, which can undermine patient-reported outcomes (PROs), such as quality of life (QoL). Hence, we conducted a pilot randomized clinical trial to assess the feasibility and preliminary efficacy of a telephone-delivered positive psychology intervention (Positive Affect for the Transplantation of Hematopoietic stem cells intervention [PATH]) for improving well-being in HSCT survivors. METHODS: HSCT survivors who were 100 days post-HSCT for hematologic malignancy at an academic institution were randomly assigned to either PATH or usual care. PATH, delivered by a behavioral health expert, entailed 9 weekly phone sessions on gratitude, personal strengths, and meaning. We defined feasibility a priori as >60% of eligible participants enrolling in the study and >75% of PATH participants completing ≥6 of 9 sessions. At baseline and 9 and 18 weeks, patients self-reported gratitude, positive affect, life satisfaction, optimism, anxiety, depression, posttraumatic stress disorder (PTSD), QoL, physical function, and fatigue. We used repeated measures regression models and estimates of effect size (Cohen's d) to explore the preliminary effects of PATH on outcomes. RESULTS: We enrolled 68.6% (72/105) of eligible patients (mean age, 57 years; 50% female). Of those randomized to PATH, 91% completed all sessions and reported positive psychology exercises as easy to complete and subjectively useful. Compared with usual care, PATH participants reported greater improvements in gratitude (ß = 1.38; d = 0.32), anxiety (ß = -1.43; d = -0.40), and physical function (ß = 2.15; d = 0.23) at 9 weeks and gratitude (ß = 0.97; d = 0.22), positive affect (ß = 2.02; d = 0.27), life satisfaction (ß = 1.82; d = 0.24), optimism (ß = 2.70; d = 0.49), anxiety (ß = -1.62; d = -0.46), depression (ß = -1.04; d = -0.33), PTSD (ß = -2.50; d = -0.29), QoL (ß = 7.70; d = 0.41), physical function (ß = 5.21; d = 0.56), and fatigue (ß = -2.54; d = -0.33) at 18 weeks. CONCLUSIONS: PATH is feasible, with promising signals for improving psychological well-being, QoL, physical function, and fatigue in HSCT survivors. Future multisite trials that investigate PATH's efficacy are needed to establish its effects on PROs in this population.
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Transplante de Células-Tronco Hematopoéticas , Psicologia Positiva , Qualidade de Vida , Humanos , Transplante de Células-Tronco Hematopoéticas/psicologia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Adulto , Psicologia Positiva/métodos , Transplante Homólogo , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/psicologia , Idoso , Sobreviventes/psicologia , Sobreviventes de Câncer/psicologiaRESUMO
OBJECTIVE: Associations between positive psychological well-being (PPWB) and patient-reported outcomes (PROs, e.g., quality of life [QOL]) have yet to be studied extensively in patients with hematologic malignancies who are allogeneic hematopoietic stem cell transplant (HSCT) survivors, despite substantial evidence that PPWB impacts PROs of other medical populations. METHODS: We conducted a secondary analysis of cross-sectional data examining the association of PPWB and PROs at day 100 post-transplant among 158 allogeneic HSCT recipients. Optimism, gratitude, life satisfaction, and PROs (i.e., QOL, anxiety, depression, and PTSD symptoms) were assessed using the Life Orientation Test-Revised, Gratitude Questionnaire, Satisfaction with Life Scale, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Hospital Anxiety and Depression Scale, and Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, respectively. We used linear and multivariate regressions for all analyses and controlled for patient factors. RESULTS: Optimism was associated with better QOL (ß = 1.46; p < 0.001) and lower levels of anxiety (ß = -0.28; p < 0.001), depression (ß = -0.31; p < 0.001), and PTSD (ß = -0.58; p < 0.001). Gratitude was associated with better QOL (ß = 1.11; p < 0.001) and lower levels of anxiety (ß = -0.21; p = 0.001), depression (ß = -0.14; p = 0.021), and PTSD (ß = -0.32; p = 0.032). Finally, satisfaction with life was associated with better QOL (ß = 1.26; p < 0.001) and lower levels of anxiety (ß = -0.18; p < 0.001), depression (ß = -0.21; p < 0.001), and PTSD (ß = -0.49; p < 0.001). CONCLUSION: Optimism, gratitude, and satisfaction with life were all associated with better QOL and lower levels of psychological distress in allogeneic HSCT survivors. These data support studies to harness PPWB as a therapeutic intervention for this population throughout HSCT recovery.
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Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Humanos , Qualidade de Vida/psicologia , Estudos Transversais , Satisfação do Paciente , Transplante de Células-Tronco Hematopoéticas/psicologia , Satisfação Pessoal , Medidas de Resultados Relatados pelo PacienteRESUMO
BACKGROUND: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD). METHODS: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) (mitochondrial biogenesis), and electron transport chain complexes I-V were measured with Western blot. RESULTS: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO2/s/mg, respectively [p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1α (p < 0.01), VDAC (p = 0.022), complex I (p = 0.021), and complex III (p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking (n = 5) and those not currently smoking (n = 63). CONCLUSIONS: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed.
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Fumar Cigarros , Doença Arterial Periférica , Humanos , Idoso , Fumar Cigarros/efeitos adversos , Mitocôndrias/metabolismo , Músculo Esquelético/irrigação sanguíneaRESUMO
PURPOSE: The surgical management of congenital dacryocystoceles has evolved in recent decades. The aim of this study was to explore the effectiveness of endoscopic examination and powered microdebridement in the management of nasal cysts associated with congenital dacryocystoceles. METHODS: In this retrospective case series, all patients with congenital dacryocystoceles who underwent surgical intervention under general anesthesia at a single institution over a 12-year period (2009-2020) were included. RESULTS: Thirty-seven lacrimal drainage systems from 29 patients were included, 8 patients (28%) had bilateral dacryocystoceles. Twenty-two (76%) were females, and 5 (17%) patients had a history of prematurity. Mean (±SD) age at diagnosis was 15 ± 28 days, and 1.4 ± 1.7 months at surgical intervention. Mean follow-up was 7.5 months. The right side was more commonly involved (20 [69%] OD vs. 17 [59%] OS). Dacryocystitis was diagnosed at presentation in 23 lacrimal drainage systems (62%). Intraoperatively, intranasal cysts were observed in 32 lacrimal drainage systems (86%), and a powered microdebrider was used to excise each cyst. In 6 of the 21 supposed unilateral cases (29%), a contralateral cyst was identified and treated. The average birth age of patients with intranasal cysts was 39 weeks versus 36 weeks of patients without ( p = 0.03). Surgical success was found in 36 of 37 sides treated (97%); one case (3%) underwent unilateral endoscopic dacryocystorhinostomy during the follow-up period due to persistent symptoms. CONCLUSIONS: Congenital dacryocystoceles are associated with intranasal cysts in most cases. Surgical intervention with microdebrider is associated with a favorable outcome. Bilateral endonasal examination is ideal in all cases.
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Canaliculite , Cistos , Dacriocistite , Dacriocistorinostomia , Obstrução dos Ductos Lacrimais , Ducto Nasolacrimal , Doença Crônica , Cistos/complicações , Cistos/diagnóstico , Cistos/cirurgia , Dacriocistite/cirurgia , Endoscopia , Feminino , Humanos , Lactente , Obstrução dos Ductos Lacrimais/congênito , Obstrução dos Ductos Lacrimais/diagnóstico , Masculino , Ducto Nasolacrimal/cirurgia , Estudos RetrospectivosRESUMO
BACKGROUND: The survival of patients with high-risk neuroblastoma has increased with multimodal therapy, but most survivors demonstrate growth failure. OBJECTIVE: To assess physeal abnormalities in children with high-risk neuroblastoma in comparison to normal controls by using diffusion tensor imaging (DTI) of the distal femoral physis and adjacent metaphysis. MATERIALS AND METHODS: We prospectively obtained physeal DTI at 3.0 T in 20 subjects (mean age: 12.4 years, 7 females) with high-risk neuroblastoma treated with high-dose cis-retinoic acid, and 20 age- and gender-matched controls. We compared fractional anisotropy (FA), normalized tract volume (cm3/cm2) and tract concentration (tracts/cm2) between the groups, in relation to height Z-score and response to growth hormone therapy. Tractography images were evaluated qualitatively. RESULTS: DTI parameters were significantly lower in high-risk neuroblastoma survivors compared to controls (P<0.01), particularly if the patients were exposed to both cis-retinoic acid and total body irradiation (P<0.05). For survivors and controls, DTI values were respectively [mean ± standard deviation]: tract concentration (tracts/cm2), 23.2±14.7 and 36.7±10.5; normalized tract volume (cm3/cm2), 0.44±0.27 and 0.70±0.21, and FA, 0.22±0.05 and 0.26±0.02. High-risk neuroblastoma survivors responding to growth hormone compared to non-responders had higher FA (0.25±0.04 and 0.18±0.03, respectively, P=0.02), and tract concentration (tracts/cm2) (31.4±13.7 and 14.8±7.9, respectively, P<0.05). FA, normalized tract volume and tract concentration were linearly related to height Z-score (R2>0.31; P<0.001). Qualitatively, tracts were nearly absent in all non-responders to growth hormone and abundant in all responders (P=0.02). CONCLUSION: DTI shows physeal abnormalities that correlate with short stature in high-risk neuroblastoma survivors and demonstrates response to growth hormone treatment.
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Imagem de Tensor de Difusão/métodos , Transtornos do Crescimento/tratamento farmacológico , Neuroblastoma/diagnóstico por imagem , Neuroblastoma/tratamento farmacológico , Tretinoína/uso terapêutico , Adolescente , Fatores Etários , Anisotropia , Estatura/efeitos dos fármacos , Estudos de Casos e Controles , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Fêmur/diagnóstico por imagem , Fêmur/patologia , Transtornos do Crescimento/etiologia , Humanos , Modelos Lineares , Masculino , Análise Multivariada , Neuroblastoma/mortalidade , Estudos Retrospectivos , Medição de Risco , Fatores Sexuais , Sobreviventes , Tretinoína/efeitos adversosRESUMO
OBJECTIVE: Hospital arrival via Emergency Medical Services (EMS) and EMS prenotification are associated with faster evaluation and treatment of stroke. We sought to determine the impact of diagnostic accuracy by prehospital providers on emergency department quality measures. METHODS: A retrospective study was performed of patients presenting via EMS between September 2009 and December 2012 with a discharge diagnosis of transient ischemic attack (TIA), ischemic stroke (IS), or intracerebral hemorrhage (ICH). Hospital and EMS databases were used to determine EMS impression, prehospital and in-hospital time intervals, EMS prenotification, NIH stroke scale (NIHSS), symptom duration, and thrombolysis rate. RESULTS: 399 cases were identified: 14.5% TIA, 67.2% IS, and 18.3% ICH. EMS providers correctly recognized 57.6% of cases. Compared to cases missed by EMS, correctly recognized cases had longer median on-scene time (17 vs. 15 min, p = 0.01) but shorter transport times (12 vs. 15 min, p = 0.001). Cases correctly recognized by EMS were associated with shorter door-to-physician time (4 vs. 11 min, p < 0.001) and shorter door-to-CT time (23 vs. 48 min, p < 0.001). These findings were independent of age, NIHSS, symptom duration, and EMS prenotification. Patients with ischemic stroke correctly recognized by EMS were more likely to receive thrombolytic therapy, independent of age, NIHSS, symptom duration both with and without prenotification. CONCLUSION: Recognition of stroke by EMS providers was independently associated with faster door-to-physician time, faster door-to-CT time, and greater odds of receiving thrombolysis. Quality initiatives to improve EMS recognition of stroke have the potential to improve hospital-based quality of stroke care.
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Serviços Médicos de Emergência/estatística & dados numéricos , Serviço Hospitalar de Emergência/normas , Acidente Vascular Cerebral/diagnóstico , Idoso , Estudos de Coortes , Bases de Dados Factuais , Serviços Médicos de Emergência/normas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/tratamento farmacológico , Terapia Trombolítica/estatística & dados numéricosRESUMO
PURPOSE: The purpose of this study was to evaluate the progression of dry eye disease (DED) symptoms and signs over 2 years through a secondary analysis of data collected from the Dry Eye Assessment and Management study. METHODS: Participants who were assigned to omega-3 fatty acid in the first year were rerandomized in the second year to either continue with omega-3 fatty acid or switch to placebo. At baseline, 3, 6, 12, 18, and 24 months, DED symptoms were evaluated by using the Ocular Surface Disease Index and the Brief Ocular Discomfort Index (BODI). DED signs were assessed using conjunctival staining, corneal staining, tear break-up time, Schirmer testing, and keratography measures. Medication usage was documented at each visit. Because the treatment and placebo groups displayed no statistical differences in both signs and symptoms, data from the 43 participants were combined to assess longitudinal changes in symptoms and signs. RESULTS: At 3 months after omega-3 fatty acid treatment, there were significant improvements from baseline in Ocular Surface Disease Index and Brief Ocular Discomfort Index scores (all P ≤ 0.002) and less use of artificial tears or gel (P = 0.02), but between 3 and 24 months, no significant changes in symptoms and treatments were observed (P ≥ 0.06). Except for a significant improvement in conjunctival staining score over 2 years (P = 0.001), there were no significant sign changes in corneal staining (P = 0.32), tear break-up time (P = 0.43), Schirmer test (P = 0.09), and additional measures (all P ≥ 0.07). CONCLUSIONS: We did not observe a progression of DED signs or symptoms over a 2-year period, except for a probable placebo response in symptoms in the first 3 months and an improvement in conjunctival staining score.
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Although allogeneic hematopoietic cell transplantation (HCT) offers a potential for cure for many patients with advanced hematologic malignancies and bone marrow failure or immunodeficiency syndromes, it is an intensive treatment and accompanied by short- and long-term physical and psychological symptoms requiring specialized care. With substantial advances in therapeutic approaches for HCT and supportive care, HCT survivors experience less morbidity and mortality. However, disparities in both HCT access and outcomes persist, and HCT survivors and their caregivers often lack access to much-needed psychosocial care. Additionally, more medical and psychosocial resources are needed to holistically care for HCT survivors with chronic graft-versus-host disease (GVHD). Hence, this chapter focuses on three areas pertaining to advances and gaps in HCT care: disparities in access to and outcomes of HCT, psychosocial and physical symptom management with supportive care interventions, and GVHD prevention and management.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/terapia , Doença Crônica , Disparidades em Assistência à Saúde , Gerenciamento Clínico , Síndrome de Bronquiolite ObliteranteRESUMO
PURPOSE: Some systemic medications are reported to be associated with dry eye disease (DED), yet their associations with the severity of DED signs and symptoms are not well studied. To evaluate these associations, we performed a secondary analysis of data from the DRy Eye Assessment and Management (DREAM) Study. METHODS: Participants (N = 535) were assessed for DED signs using tear break-up time (TBUT), Schirmer testing, corneal fluorescein staining, conjunctival lissamine green staining, meibomian gland dysfunction (MGD), and tear osmolarity and DED symptoms using the Ocular Surface Disease Index (OSDI). We derived a composite signs severity score from the 6 DED signs and categorized participant-reported systemic medications into antidepressants, antihistamines, aspirin, corticosteroids, diuretics, nonsteroidal anti-inflammatory drugs, proton pump inhibitors, statins, vitamin D3, and medications for diabetes mellitus, hypertension, hypothyroidism, migraine, and seizure. Generalized linear models were used to compare DED symptom and sign scores between medication users and non-users, with adjustment for factors associated with DED severity. RESULTS: Compared to non-users, antihistamine users had lower TBUT (p = 0.01) and higher OSDI score (p = 0.02); aspirin users had lower TBUT (p = 0.02); corticosteroid users had lower TBUT (p = 0.02), lower Schirmer test scores (p = 0.03), higher cornea fluorescein staining (p = 0.01), higher composite severity score (p = 0.01), and higher OSDI score (p = 0.03); seizure medication users had higher composite severity score (p = 0.02); vitamin D3 users had lower TBUT (p = 0.001) and greater MGD (p = 0.03); and diuretic users had less MGD (p = 0.03). CONCLUSIONS: Certain systemic medications may be associated with more severe DED. This may guide prescription practices in patients with DED.
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Síndromes do Olho Seco , Índice de Gravidade de Doença , Lágrimas , Humanos , Síndromes do Olho Seco/diagnóstico , Síndromes do Olho Seco/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Lágrimas/metabolismo , Idoso , AdultoRESUMO
Background: The factors associated with unplanned higher-level re-amputation (UHRA) and one-year mortality among patients with chronic limb-threatening ischemia (CLTI) after lower extremity amputation are poorly understood. Methods: This was a single-center retrospective study of patients who underwent amputations for CLTI between 2014 and 2017. Unadjusted bivariate analyses and adjusted odds ratios (AOR) from logistic regression models were used to assess associations between pre-amputation risk factors and outcomes (UHRA and one-year mortality). Results: We obtained data on 203 amputations from 182 patients (median age 65 years [interquartile range (IQR) 57, 75]; 70.7% males), including 118 (58.1%) toe, 20 (9.9%) transmetatarsal (TMA), 37 (18.2%) below-knee (BKA), and 28 (13.8%) amputations at or above the knee. Median follow-up was 285 days (IQR 62, 1348). Thirty-six limbs (17.7%) had a UHRA, and the majority of these (72.2%) were following index forefoot amputations. Risk factors for UHRA included non-ambulatory status (AOR 6.74, 95% confidence interval (CI) 1.74-26.18; p < 0.10) and toe pressure < 30 mm Hg (AOR 4.89, 95% CI 1.52-15.78; p < 0.01). One-year mortality was 17.2% (n = 32), and risk factors included coronary artery disease (AOR 3.93, 95% CI 1.56-9.87; p < 0.05), congestive heart failure (AOR 4.90, 95% CI 1.96-12.29; p = 0.001), end-stage renal disease (AOR 7.54, 95% CI 3.10-18.34; p < 0.001), and non-independent ambulation (AOR 4.31, 95% CI 1.20-15.49; p = 0.03). Male sex was associated with a reduced odds of death at 1 year (AOR 0.37, 95% CI 0.15-0.89; p < 0.05). UHRA was not associated with one-year mortality. Conclusions: Rates of UHRA after toe amputations and TMA are high despite revascularization and one-year mortality is high among patients with CLTI requiring amputation.
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Caregivers of patients with hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT) play a crucial role in supporting their loved ones through physical, emotional, and practical challenges. This role has been associated with high levels of psychological distress and low levels of positive psychological well-being (PPWB). Positive psychology interventions for caregivers in other disease groups (eg, breast cancer) have been associated with improved outcomes. However, positive psychology interventions that specifically address HSCT caregivers' psychological needs are currently lacking. The goal of this single-arm open-pilot trial was to determine the feasibility and acceptability of the Positive Affect in the Transplantation of Hematopoietic Stem Cells (PATH) intervention for HSCT Caregivers to identify caregiver preferences to tailor PATH for HSCT caregivers. Adult caregivers of HSCT recipients were eligible for PATH during the HSCT recipient's first 100 d post-transplant. We defined, a priori, feasibility as >60% of participants who start the intervention completing ≥6/9 intervention sessions and acceptability as weekly ratings of ease and utility of the PP exercises ≥7/10 on a 10-point Likert Scale (0 = very difficult/not helpful; 10 = very easy/very helpful). We conducted semistructured qualitative exit interviews (n = 15) to explore HSCT caregivers' perception of PATH's content, benefits of PATH, as well as facilitators and barriers to engaging with the intervention. Transcribed interviews were analyzed using framework-guided rapid analysis by 2 coders. The intervention was feasible with 83% (15/18) of caregivers who started the intervention completing ≥6/9 intervention sessions. Among caregivers who completed ≥6/9 intervention sessions, ratings of ease (mean = 8.1; 95% CI: 7.4, 8.7) and utility (mean = 8.3; 95% CI: 7.8, 8.9) also exceeded our a priori threshold of ≥7/10. Caregivers identified benefits of PATH, including identifying and responding to emotions, dedicating time to self-care, and cultivating important relationships. Sociodemographic factors (eg, being retired) and the manualized structure of PATH were cited as facilitators to intervention engagement. Barriers to PATH engagement included lack of time and competing caregiving responsibilities. Caregivers preferred remote intervention delivery within the first 100 d post HSCT. This is the first study to show a 9-wk, phone-delivered positive psychology intervention is feasible in caregivers of allogeneic HSCT recipients. Our findings also underscore the specific preferences of this population for positive psychology interventions. Larger studies are warranted to establish the efficacy of these interventions in addressing persistent unmet psychological needs for HSCT caregivers.
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Cuidadores , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Cuidadores/psicologia , Projetos Piloto , Psicologia Positiva , Estresse Psicológico/terapia , Estresse Psicológico/psicologiaRESUMO
Background: Social support is associated with improved clinical outcomes but is understudied among US immigrants. We examined two types of social support, perceived health provider support and community support, and characterized perceptions of social support among US immigrants compared with nonimmigrants. Methods: We conducted cross-sectional data analysis on self-reported data from Health Information National Trends Survey 5, Cycle 2. Population-level estimates were obtained using jack-knife replicate weights. Results: Immigrant status was not associated with perceived health care provider support or community support. However, compared with nonimmigrants, US immigrants were more likely to report rarely (adjusted odds ratio [aOR]=3.07) or never (aOR=3.18) having access to emotional support. Conclusions: Further research that incorporates nuanced factors (eg, time since arrival) that may influence social support in diverse US immigrant groups is needed to determine the impact of social support on health outcomes in an underserved and often overlooked population.
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Emigrantes e Imigrantes , Apoio Social , Humanos , Emigrantes e Imigrantes/psicologia , Emigrantes e Imigrantes/estatística & dados numéricos , Feminino , Masculino , Estudos Transversais , Adulto , Estados Unidos , Pessoa de Meia-Idade , Área Carente de Assistência Médica , Idoso , Adulto Jovem , Adolescente , Acessibilidade aos Serviços de SaúdeRESUMO
Glaucomatous neurodegeneration, a blinding disease affecting millions worldwide, has a need for the exploration of new and effective therapies. Previously, the glucagon-like peptide-1 receptor (GLP-1R) agonist NLY01 was shown to reduce microglia/macrophage activation, rescuing retinal ganglion cells after IOP elevation in an animal model of glaucoma. GLP-1R agonist use is also associated with a reduced risk for glaucoma in patients with diabetes. In this study, we demonstrate that several commercially available GLP-1R agonists, administered either systemically or topically, hold protective potential in a mouse model of hypertensive glaucoma. Further, the resulting neuroprotection likely occurs through the same pathways previously shown for NLY01. This work contributes to a growing body of evidence suggesting that GLP-1R agonists represent a viable therapeutic option for glaucoma.
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Retinal inflammation underlies multiple prevalent ocular and neurological diseases. Similar inflammatory processes are observed in glaucomatous optic neuropathy, age-related macular degeneration, retinitis pigmentosa, posterior uveitis, Alzheimer's disease, and Parkinson's disease. In particular, human and animal studies have demonstrated the important role microglia/macrophages play in initiating and maintaining a pro-inflammatory environment in degenerative processes impacting vision. On the other hand, microglia have also been shown to have a protective role in multiple central nervous system diseases. Identifying the mechanisms underlying cell dysfunction and death is the first step toward developing novel therapeutics for these diseases impacting the central nervous system. In addition to reviewing recent key studies defining important mediators of retinal inflammation, with an emphasis on translational studies that bridge this research from bench to bedside, we also highlight a promising therapeutic class of medications, the glucagon-like peptide-1 receptor agonists. Finally, we propose areas where additional research is necessary to identify mechanisms that can be modulated to shift the balance from a neurotoxic to a neuroprotective retinal environment.
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Doenças Neurodegenerativas , Retinose Pigmentar , Animais , Encéfalo/metabolismo , Inflamação/metabolismo , Microglia/metabolismo , Células Mieloides/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Retina/metabolismo , Retinose Pigmentar/metabolismoRESUMO
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a common therapy for pediatric hematologic malignancies. With improved supportive care, addressing treatment-related late effects is at the forefront of survivor long-term health and quality of life. We previously demonstrated that alloHSCT survivors had increased adiposity, decreased lean mass, and lower bone density and strength, 7 years (median) from alloHSCT compared to their healthy peers. Yet it is unknown whether these deficits persist. Our longitudinal study characterized changes in muscle and bone over a period of 3.4 (range, 2.0 to 4.9) years in 47 childhood alloHSCT survivors, age 5-26 years at baseline (34% female). Tibia cortical bone geometry and volumetric density and lower leg muscle cross-sectional area (MCSA) were assessed via peripheral quantitative computed tomography (pQCT). Anthropometric and pQCT measurements were converted to age, sex, and ancestry-specific standard deviation scores, adjusted for leg length. Muscle-specific force was assessed as strength relative to MCSA adjusted for leg length (strength Z-score). Measurements were compared to a healthy reference cohort (n = 921), age 5-30 years (52% female). At baseline and follow-up, alloHSCT survivors demonstrated lower height Z-scores, weight Z-scores, and leg length Z-scores compared to the healthy reference cohort. Deficits in MCSA, trabecular volumetric bone density, and cortical bone size and estimated strength (section modulus) were evident in survivors (all p < 0.05). Between the two study time points, anthropometric, muscle, and bone Z-scores did not change significantly in alloHSCT survivors. Approximately 15% and 17% of alloHSCT survivors had MCSA and section modulus Z-score < -2.0, at baseline and follow-up, respectively. Furthermore, those with a history of total body irradiation compared to those without demonstrated lower MCSA at follow-up. The persistent muscle and bone deficits in pediatric alloHSCT survivors support the need for strategies to improve bone and muscle health in this at-risk population. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Adolescente , Adulto , Densidade Óssea/fisiologia , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Estudos Longitudinais , Masculino , Músculo Esquelético , Sobreviventes , Tíbia/patologia , Adulto JovemRESUMO
Plant steroid hormones, brassinosteroids (BRs), are of great importance for plant growth and development. BRs signal through a cell surface receptor kinase, BRI1, and a GSK3-like kinase, BIN2, to regulate the BES1/BZR1 family of transcription factors, which directly bind to target gene promoters to activate or repress gene expression and mediate BR responses. To understand how BES1 regulates target gene expression, we identified two BES1-interacting proteins, ELF6 (early flowering 6) and its homolog REF6 (relative of early flowering 6), both of which are Jumonji N/C (JmjN/C) domain-containing proteins and were previously found to regulate flowering time. The interactions between BES1 and ELF6/REF6 were confirmed by GST pull-down and BiFC (bimolecular fluorescence complementation) experiments. Mutations in ELF6 or REF6 genes in Arabidopsis lead to BR-related phenotypes, including impaired cell elongation and reduced expression of BR target genes. Chromatin immunoprecipitation (ChIP) experiments indicated that histone 3 lysine 9 (H3K9) methylation status was changed in elf6 and ref6 mutants, consistent with recent findings that many Jmj proteins are histone demethylases. Our results demonstrate that BES1 recruits other transcriptional regulators such as ELF6 and REF6 to regulate target gene expression and coordinate BR responses with other developmental processes such as control of flowering time. Jmj domain-containing histone demethylases are involved in gene expression in many developmental processes and diseases, but how these proteins affect specific pathways is not well understood. Thus, our study establishes an important mechanism by which Jmj domain proteins modulate specific gene expression by interacting with pathway-specific transcription factors such as BES1.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , Proteínas Nucleares/metabolismo , Reguladores de Crescimento de Plantas/fisiologia , Fatores de Transcrição/metabolismo , Sequência de Aminoácidos , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Imunoprecipitação da Cromatina , Proteínas de Ligação a DNA , Histonas/metabolismo , Dados de Sequência Molecular , Mutação , Proteínas Nucleares/genética , Fenótipo , Estrutura Terciária de Proteína , Fatores de Transcrição/genética , Técnicas do Sistema de Duplo-HíbridoRESUMO
BACKGROUND: Survival from paediatric high-risk neuroblastoma (HR-NBL) has increased, but cis-retinoic acid (cis-RA), the cornerstone of HR-NBL therapy, can cause osteoporosis and premature physeal closure and is a potential threat to skeletal structure in HR-NBL survivors. Sarcopenia is associated with increased morbidity in survivors of paediatric malignancies. Low muscle mass may be associated with poor prognosis in HR-NBL patients but has not been studied in these survivors. The study objective was to assess bone density, body composition and muscle strength in HR-NBL survivors compared with controls. METHODS: This prospective cross-sectional study assessed areal bone mineral density (aBMD) of the whole body, lumbar spine, total hip, femoral neck, distal 1/3 and ultradistal radius and body composition (muscle and fat mass) using dual-energy X-ray absorptiometry (DXA) and lower leg muscle strength using a dynamometer. Measures expressed as sex-specific standard deviation scores (Z-scores) included aBMD (adjusted for height Z-score), bone mineral apparent density (BMAD), leg lean mass (adjusted for leg length), whole-body fat mass index (FMI) and ankle dorsiflexion peak torque adjusted for leg length (strength-Z). Muscle-specific force was assessed as strength relative to leg lean mass. Outcomes were compared between HR-NBL survivors and controls using Student's t-test or Mann-Whitney U test. Linear regression models examined correlations between DXA and dynamometer outcomes. RESULTS: We enrolled 20 survivors of HR-NBL treated with cis-RA [13 male; mean age: 12.4 ± 1.6 years; median (range) age at therapy initiation: 2.6 (0.3-9.1) years] and 20 age-, sex- and race-matched controls. Height-Z was significantly lower in HR-NBL survivors compared with controls (-1.73 ± 1.38 vs. 0.34 ± 1.12, P < 0.001). Areal BMD-Z, BMAD-Z, FMI-Z, visceral adipose tissue and subcutaneous adipose tissue were not significantly different in HR-NBL survivors compared with controls. Compared with controls, HR-NBL survivors had lower leg lean mass-Z (-1.46 ± 1.35 vs. - 0.17 ± 0.84, P < 0.001) and strength-Z (-1.13 ± 0.86 vs. - 0.15 ± 0.71, P < 0.001). Muscle-specific force was lower in HR-NBL survivors compared with controls (P < 0.05). CONCLUSIONS: Bone mineral density and adiposity are not severely impacted in HR-NBL survivors with growth failure, but significant sarcopenia persists years after treatment. Future studies are needed to determine if sarcopenia improves with muscle-specific interventions in this population of cancer survivors.
Assuntos
Neuroblastoma , Sarcopenia , Adolescente , Densidade Óssea , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Estudos Prospectivos , SobreviventesRESUMO
Iron has been implicated in the pathogenesis of age-related retinal diseases, including age-related macular degeneration (AMD). Previous work showed that intravitreal (IVT) injection of iron induces acute photoreceptor death, lipid peroxidation, and autofluorescence (AF). Herein, we extend this work, finding surprising chronic features of the model: geographic atrophy and sympathetic ophthalmia. We provide new mechanistic insights derived from focal AF in the photoreceptors, quantification of bisretinoids, and localization of carboxyethyl pyrrole, an oxidized adduct of docosahexaenoic acid associated with AMD. In mice given IVT ferric ammonium citrate (FAC), RPE died in patches that slowly expanded at their borders, like human geographic atrophy. There was green AF in the photoreceptor ellipsoid, a mitochondria-rich region, 4 h after injection, followed later by gold AF in rod outer segments, RPE and subretinal myeloid cells. The green AF signature is consistent with flavin adenine dinucleotide, while measured increases in the bisretinoid all-trans-retinal dimer are consistent with the gold AF. FAC induced formation carboxyethyl pyrrole accumulation first in photoreceptors, then in RPE and myeloid cells. Quantitative PCR on neural retina and RPE indicated antioxidant upregulation and inflammation. Unexpectedly, reminiscent of sympathetic ophthalmia, autofluorescent myeloid cells containing abundant iron infiltrated the saline-injected fellow eyes only if the contralateral eye had received IVT FAC. These findings provide mechanistic insights into the potential toxicity caused by AMD-associated retinal iron accumulation. The mouse model will be useful for testing antioxidants, iron chelators, ferroptosis inhibitors, anti-inflammatory medications, and choroidal neovascularization inhibitors.
Assuntos
Compostos Férricos/administração & dosagem , Atrofia Geográfica/induzido quimicamente , Atrofia Geográfica/complicações , Injeções Intraoculares/métodos , Oftalmia Simpática/induzido quimicamente , Oftalmia Simpática/complicações , Estresse Oxidativo/efeitos dos fármacos , Compostos de Amônio Quaternário/administração & dosagem , Animais , Modelos Animais de Doenças , Atrofia Geográfica/diagnóstico por imagem , Atrofia Geográfica/metabolismo , Ferro/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oftalmia Simpática/diagnóstico por imagem , Oftalmia Simpática/metabolismo , Imagem Óptica/métodos , Epitélio Pigmentado da Retina/diagnóstico por imagem , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologiaRESUMO
A paradox of plant hormone biology is how a single small molecule can affect a diverse array of growth and developmental processes. For instance, brassinosteroids (BRs) regulate cell elongation, vascular differentiation, senescence and stress responses. BRs signal through the BES1/BZR1 (bri1-Ethylmethane Sulphonate suppressor 1/brassinazole-resistant 1) family of transcription factors, which regulate hundreds of target genes involved in this pathway, yet little is known of this transcriptional network. Through microarray and chromatin immunoprecipitation (ChIP) experiments, we identified a direct target gene of BES1, AtMYB30, which encodes an MYB family transcription factor. AtMYB30 null mutants display decreased BR responses and enhance the dwarf phenotype of a weak allele of the BR receptor mutant bri1. Many BR-regulated genes have reduced expression and/or hormone-induction in AtMYB30 mutants, indicating that AtMYB30 functions to promote expression of a subset of BR target genes. AtMYB30 and BES1 bind to a conserved MYB-binding site and E-box sequences, respectively, in the promoters of genes that are regulated by both BRs and AtMYB30. Finally, AtMYB30 and BES1 interact with each other both in vitro and in vivo. These results demonstrate that BES1 and AtMYB30 function cooperatively to promote BR target gene expression. Our results therefore establish a new mechanism by which AtMYB30, a direct target of BES1, functions to amplify BR signaling by helping BES1 activate downstream target genes.