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OBJECTIVE: The objective was to review the pharmacology, efficacy, and safety of atezolizumab (Tecentriq) for the treatment of adult and pediatric patients aged 2 years and older with unresectable or metastatic alveolar soft part sarcoma (ASPS). DATA SOURCES: A literature search was conducted using PubMed and MEDLINE databases, published abstracts, and ongoing studies from ClinicalTrials.gov between January 1, 1981, and May 31, 2023. Keywords included atezolizumab, Tecentriq, MPDL3280, immunotherapy, PD-L1, PD-1, pediatrics, sarcoma, and ASPS. STUDY SELECTION AND DATA EXTRACTION: All English-language studies involving atezolizumab for ASPS were included and discussed. DATA SYNTHESIS: Atezolizumab is an anti-programmed death-ligand 1 (PD-L1) monoclonal antibody designed to block the interaction between PD-L1 and the programmed cell death protein 1 (PD-1) receptor. Atezolizumab was granted approval by the FDA specifically for ASPS based on a phase II clinical trial in adult and pediatric patients (n = 49), which reported an overall response rate of 24% and a durable response rate at 6 and 12 months of 67% and 42%, respectively. Common grade 3/4 adverse reactions include musculoskeletal pain (8%), followed by hypertension (6%), weight gain (6%), headache (4%), and dizziness (4%). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Advanced ASPS is a high-risk disease with limited treatment options. Atezolizumab appears to be a viable treatment option in ASPS demonstrating clinical efficacy and a manageable toxicity profile. CONCLUSIONS: With no other treatments that are FDA approved specifically for ASPS, and few demonstrating efficacy in the advanced setting, the approval of atezolizumab, including the first approval for pediatric patients, represents a landmark improvement to the therapeutic arsenal against this rare disease.
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Antígeno B7-H1 , Sarcoma de Parte Blanda Alveolar , Adulto , Humanos , Niño , Receptor de Muerte Celular Programada 1 , Sarcoma de Parte Blanda Alveolar/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversosRESUMEN
Calcium-independent phospholipase A2γ (iPLA2γ) is a mitochondrial enzyme that produces lipid second messengers that facilitate opening of the mitochondrial permeability transition pore (mPTP) and contribute to the production of oxidized fatty acids in myocardium. To specifically identify the roles of iPLA2γ in cardiac myocytes, we generated cardiac myocyte-specific iPLA2γ knock-out (CMiPLA2γKO) mice by removing the exon encoding the active site serine (Ser-477). Hearts of CMiPLA2γKO mice exhibited normal hemodynamic function, glycerophospholipid molecular species composition, and normal rates of mitochondrial respiration and ATP production. In contrast, CMiPLA2γKO mice demonstrated attenuated Ca(2+)-induced mPTP opening that could be rapidly restored by the addition of palmitate and substantially reduced production of oxidized polyunsaturated fatty acids (PUFAs). Furthermore, myocardial ischemia/reperfusion (I/R) in CMiPLA2γKO mice (30 min of ischemia followed by 30 min of reperfusion in vivo) dramatically decreased oxidized fatty acid production in the ischemic border zones. Moreover, CMiPLA2γKO mice subjected to 30 min of ischemia followed by 24 h of reperfusion in vivo developed substantially less cardiac necrosis in the area-at-risk in comparison with their WT littermates. Furthermore, we found that membrane depolarization in murine heart mitochondria was sensitized to Ca(2+) by the presence of oxidized PUFAs. Because mitochondrial membrane depolarization and calcium are known to activate iPLA2γ, these results are consistent with salvage of myocardium after I/R by iPLA2γ loss of function through decreasing mPTP opening, diminishing production of proinflammatory oxidized fatty acids, and attenuating the deleterious effects of abrupt increases in calcium ion on membrane potential during reperfusion.
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Ácidos Grasos Insaturados/metabolismo , Fosfolipasas A2 Grupo VI/metabolismo , Potencial de la Membrana Mitocondrial , Mitocondrias Cardíacas/enzimología , Daño por Reperfusión Miocárdica/enzimología , Miocardio/enzimología , Miocitos Cardíacos/enzimología , Animales , Calcio/metabolismo , Fosfolipasas A2 Grupo VI/genética , Ratones , Ratones Noqueados , Mitocondrias Cardíacas/genética , Daño por Reperfusión Miocárdica/genética , Especificidad de Órganos , Oxidación-ReducciónRESUMEN
This study examines risk and protective factors associated with experiencing homelessness in the year after "aging out" of foster care. Using a state-level integrated administrative database, we identified 1,202 emerging adults in Washington State who exited foster care between July 2010 and June 2012. Initial bivariate analyses were conducted to assess the association between candidate predictive factors and an indicator of homelessness in a 12-month follow-up period. After deploying a stepwise regression process, the final logistic regression model included 15 predictive factors. Youth who were parents, who had recently experienced housing instability, or who were African American had approximately twice the odds of experiencing homelessness in the year after exiting foster care. In addition, youth who had experienced disrupted adoptions, had multiple foster care placements (especially in congregate care settings), or had been involved with the juvenile justice system were more likely to become homeless. In contrast, youth were less likely to experience homelessness if they had ever been placed with a relative while in foster care or had a high cumulative grade point average relative to their peers.
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Etnicidad/estadística & datos numéricos , Cuidados en el Hogar de Adopción , Personas con Mala Vivienda/estadística & datos numéricos , Rendimiento Académico , Adolescente , Adopción , Adulto , Negro o Afroamericano , Asiático/estadística & datos numéricos , Protección a la Infancia , Derecho Penal , Femenino , Hogares para Grupos , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Modelos Logísticos , Masculino , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Oportunidad Relativa , Padres , Factores Protectores , Factores de Riesgo , Washingtón , Población Blanca , Adulto JovenRESUMEN
An anomalous right coronary artery (RCA) takeoff, a rare congenital condition often characterized by an interarterial RCA course between the pulmonary artery and the ascending aorta, can lead to symptoms of angina pectoris (chest pain) or even sudden cardiac death (SCD) due to compression of the RCA, although most patients remain asymptomatic. In this case report, we highlight the utility of computed tomography angiography (CTA)-derived fractional flow reserve (FFR), a minimally invasive technique used to assess the hemodynamic significance of coronary lesions, in the risk stratification and surgical decision-making process for a 46-year-old female patient presenting with exertional dyspnea and an anomalous RCA takeoff with an interarterial course. The information obtained from this imaging modality was instrumental in determining that surgical repair did not need to be performed urgently and could be scheduled as an elective case in the future.
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Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin. Recently, an inducible tafazzin shRNA knockdown mouse model was generated to deconvolute the complex bioenergetic phenotype of this disease. To investigate the underlying cause of hemodynamic dysfunction in Barth syndrome, we interrogated the cardiac structural and signaling lipidome of this mouse model as well as its myocardial bioenergetic phenotype. A decrease in the distribution of cardiolipin molecular species and robust increases in monolysocardiolipin and dilysocardiolipin were demonstrated. Additionally, the contents of choline and ethanolamine glycerophospholipid molecular species containing precursors for lipid signaling at the sn-2 position were altered. Lipidomic analyses revealed specific dysregulation of HETEs and prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as decreases in Complex III and V activities. Transgenic expression of cardiolipin synthase or iPLA2γ ablation in tafazzin-deficient mice did not rescue the observed phenotype. These results underscore the complex nature of alterations in cardiolipin metabolism mediated by tafazzin loss of function. Collectively, we identified specific lipidomic, bioenergetic, and signaling alterations in a murine model that parallel those of Barth syndrome thereby providing novel insights into the pathophysiology of this debilitating disease.
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Síndrome de Barth/metabolismo , Cardiolipinas/metabolismo , Metabolismo de los Lípidos , Lípidos/biosíntesis , Mitocondrias Cardíacas/metabolismo , Animales , Animales Modificados Genéticamente , Síndrome de Barth/patología , Cardiolipinas/genética , Modelos Animales de Enfermedad , Metabolismo Energético , Regulación de la Expresión Génica , Humanos , Lípidos/genética , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias Cardíacas/patología , Membranas Mitocondriales/metabolismo , Transducción de Señal , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismoRESUMEN
Calcium-independent phospholipase A(2)γ (iPLA(2)γ) (PNPLA8) is the predominant phospholipase activity in mammalian mitochondria. However, the chemical mechanisms that regulate its activity are unknown. Here, we utilize iPLA(2)γ gain of function and loss of function genetic models to demonstrate the robust activation of iPLA(2)γ in murine myocardial mitochondria by Ca(2+) or Mg(2+) ions. Calcium ion stimulated the production of 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) from 1-palmitoyl-2-[(14)C]arachidonoyl-sn-glycero-3-phosphocholine during incubations with wild-type heart mitochondrial homogenates. Furthermore, incubation of mitochondrial homogenates from transgenic myocardium expressing iPLA(2)γ resulted in 13- and 25-fold increases in the initial rate of radiolabeled 2-AA-LPC and arachidonic acid (AA) production, respectively, in the presence of calcium ion. Mass spectrometric analysis of the products of calcium-activated hydrolysis of endogenous mitochondrial phospholipids in transgenic iPLA(2)γ mitochondria revealed the robust production of AA, 2-AA-LPC, and 2-docosahexaenoyl-LPC that was over 10-fold greater than wild-type mitochondria. The mechanism-based inhibitor (R)-(E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one (BEL) (iPLA(2)γ selective), but not its enantiomer, (S)-BEL (iPLA(2)ß selective) or pyrrolidine (cytosolic PLA(2)α selective), markedly attenuated Ca(2+)-dependent fatty acid release and polyunsaturated LPC production. Moreover, Ca(2+)-induced iPLA(2)γ activation was accompanied by the production of downstream eicosanoid metabolites that were nearly completely ablated by (R)-BEL or by genetic ablation of iPLA(2)γ. Intriguingly, Ca(2+)-induced iPLA(2)γ activation was completely inhibited by long-chain acyl-CoA (IC(50) â¼20 µm) as well as by a nonhydrolyzable acyl-CoA thioether analog. Collectively, these results demonstrate that mitochondrial iPLA(2)γ is activated by divalent cations and inhibited by acyl-CoA modulating the generation of biologically active metabolites that regulate mitochondrial bioenergetic and signaling functions.
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Ácido Araquidónico/metabolismo , Calcio/metabolismo , Fosfolipasas A2 Grupo VI/metabolismo , Magnesio/metabolismo , Mitocondrias Cardíacas/enzimología , Animales , Ácido Araquidónico/genética , Cationes Bivalentes/metabolismo , Activación Enzimática/efectos de los fármacos , Fosfolipasas A2 Grupo VI/antagonistas & inhibidores , Fosfolipasas A2 Grupo VI/genética , Lisofosfatidilcolinas/genética , Lisofosfatidilcolinas/metabolismo , Ratones , Ratones Noqueados , Mitocondrias Cardíacas/genética , Modelos Genéticos , Naftalenos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Pironas/farmacologíaRESUMEN
Herein, we demonstrate that calcium-independent phospholipase A(2)γ (iPLA(2)γ) is a critical mechanistic participant in the calcium-induced opening of the mitochondrial permeability transition pore (mPTP). Liver mitochondria from iPLA(2)γ(-/-) mice were markedly resistant to calcium-induced swelling in the presence or absence of phosphate in comparison with wild-type littermates. Furthermore, the iPLA(2)γ enantioselective inhibitor (R)-(E)-6-(bromomethylene)-3-(1-naphthalenyl)-2H-tetrahydropyran-2-one ((R)-BEL) was markedly more potent than (S)-BEL in inhibiting mPTP opening in mitochondria from wild-type liver in comparison with hepatic mitochondria from iPLA(2)γ(-/-) mice. Intriguingly, low micromolar concentrations of long chain fatty acyl-CoAs and the non-hydrolyzable thioether analog of palmitoyl-CoA markedly accelerated Ca(2+)-induced mPTP opening in liver mitochondria from wild-type mice. The addition of l-carnitine enabled the metabolic channeling of acyl-CoA through carnitine palmitoyltransferases (CPT-1/2) and attenuated the palmitoyl-CoA-mediated amplification of calcium-induced mPTP opening. In contrast, mitochondria from iPLA(2)γ(-/-) mice were insensitive to fatty acyl-CoA-mediated augmentation of calcium-induced mPTP opening. Moreover, mitochondria from iPLA(2)γ(-/-) mouse liver were resistant to Ca(2+)/t-butyl hydroperoxide-induced mPTP opening in comparison with wild-type littermates. In support of these findings, cytochrome c release from iPLA(2)γ(-/-) mitochondria was dramatically decreased in response to calcium in the presence or absence of either t-butyl hydroperoxide or phenylarsine oxide in comparison with wild-type littermates. Collectively, these results identify iPLA(2)γ as an important mechanistic component of the mPTP, define its downstream products as potent regulators of mPTP opening, and demonstrate the integrated roles of mitochondrial bioenergetics and lipidomic flux in modulating mPTP opening promoting the activation of necrotic and necroapoptotic pathways of cell death.
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Calcio/metabolismo , Fosfolipasas A2 Grupo VI/metabolismo , Mitocondrias Hepáticas/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Animales , Carnitina/genética , Carnitina/metabolismo , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Muerte Celular , Citocromos c/genética , Citocromos c/metabolismo , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/genética , Inhibidores Enzimáticos/farmacología , Fosfolipasas A2 Grupo VI/antagonistas & inhibidores , Fosfolipasas A2 Grupo VI/genética , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Ratones , Ratones Noqueados , Mitocondrias Hepáticas/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Poro de Transición de la Permeabilidad Mitocondrial , Palmitoil Coenzima A/genética , Palmitoil Coenzima A/metabolismo , ConejosRESUMEN
Lipidomic regulation of mitochondrial cardiolipin content and molecular species composition is a prominent regulator of bioenergetic efficiency. However, the mechanisms controlling cardiolipin metabolism during health or disease progression have remained elusive. Herein, we demonstrate that cardiac myocyte-specific transgenic expression of cardiolipin synthase results in accelerated cardiolipin lipidomic flux that impacts multiple aspects of mitochondrial bioenergetics and signaling. During the postnatal period, cardiolipin synthase transgene expression results in marked changes in the temporal maturation of cardiolipin molecular species during development. In adult myocardium, cardiolipin synthase transgene expression leads to a marked increase in symmetric tetra-18:2 molecular species without a change in total cardiolipin content. Mechanistic analysis demonstrated that these alterations result from increased cardiolipin remodeling by sequential phospholipase and transacylase/acyltransferase activities in conjunction with a decrease in phosphatidylglycerol content. Moreover, cardiolipin synthase transgene expression results in alterations in signaling metabolites, including a marked increase in the cardioprotective eicosanoid 14,15-epoxyeicosatrienoic acid. Examination of mitochondrial bioenergetic function by high resolution respirometry demonstrated that cardiolipin synthase transgene expression resulted in improved mitochondrial bioenergetic efficiency as evidenced by enhanced electron transport chain coupling using multiple substrates as well as by salutary changes in Complex III and IV activities. Furthermore, transgenic expression of cardiolipin synthase attenuated maladaptive cardiolipin remodeling and bioenergetic inefficiency in myocardium rendered diabetic by streptozotocin treatment. Collectively, these results demonstrate the unanticipated role of cardiolipin synthase in maintaining physiologic membrane structure and function even under metabolic stress, thereby identifying cardiolipin synthase as a novel therapeutic target to attenuate mitochondrial dysfunction in diabetic myocardium.
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Diabetes Mellitus Experimental/metabolismo , Metabolismo Energético , Proteínas de la Membrana/metabolismo , Miocardio/enzimología , Miocitos Cardíacos/enzimología , Fosfatidilgliceroles/metabolismo , Transferasas (Grupos de Otros Fosfatos Sustitutos)/metabolismo , Animales , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patología , Complejo III de Transporte de Electrones/genética , Complejo III de Transporte de Electrones/metabolismo , Humanos , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Mitocondrias Cardíacas/enzimología , Mitocondrias Cardíacas/genética , Mitocondrias Cardíacas/patología , Miocardio/patología , Miocitos Cardíacos/metabolismo , Fosfatidilgliceroles/genética , Transferasas (Grupos de Otros Fosfatos Sustitutos)/genéticaRESUMEN
A highly sensitive, specific, and robust method for the analysis of oxidized metabolites of linoleic acid (LA), arachidonic acid (AA), and docosahexaenoic acid (DHA) was developed using charge-switch derivatization, liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI MS/MS) with selected reaction monitoring (SRM) and quantitation by high mass accuracy analysis of product ions, thereby minimizing interferences from contaminating ions. Charge-switch derivatization of LA, AA, and DHA metabolites with N-(4-aminomethylphenyl)-pyridinium resulted in a 10- to 30-fold increase in ionization efficiency. Improved quantitation was accompanied by decreased false positive interferences through accurate mass measurements of diagnostic product ions during SRM transitions by ratiometric comparisons with stable isotope internal standards. The limits of quantitation were between 0.05 and 6.0pg, with a dynamic range of 3 to 4 orders of magnitude (correlation coefficient r(2)>0.99). This approach was used to quantitate the levels of representative fatty acid metabolites from wild-type (WT) and iPLA2γ(-/-) mouse liver identifying the role of iPLA2γ in hepatic lipid second messenger production. Collectively, these results demonstrate the utility of high mass accuracy product ion analysis in conjunction with charge-switch derivatization for the highly specific quantitation of diminutive amounts of LA, AA, and DHA metabolites in biologic systems.
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Ácido Araquidónico/análisis , Ácido Araquidónico/química , Ácidos Docosahexaenoicos/análisis , Ácidos Docosahexaenoicos/química , Ácido Linoleico/análisis , Ácido Linoleico/química , Animales , Ácido Araquidónico/metabolismo , Cromatografía Liquida , Ácidos Docosahexaenoicos/metabolismo , Ácido Linoleico/metabolismo , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en TándemRESUMEN
OBJECTIVE: To describe the incidence of respiratory complications, postoperative hemorrhage, length of stay, and cost of care in children with mucopolysaccharidosis (MPS) undergoing adenotonsillectomy (AT). METHODS: Analysis of the 2009, 2012, and 2016 editions of the Healthcare Cost and Utilization Project Kids' Inpatient Database (HCUP KID) identified 24,700 children who underwent AT (40 children with MPS). Demographics, respiratory complications, postoperative hemorrhage, length of stay, and total cost were compared across children with and without MPS. RESULTS: Children with MPS had a higher likelihood of being male (P < 0.017). There was a higher rate of respiratory complications in children with MPS compared with children without MPS [6/40 (15%) vs. 586/24,660 (2.4%), P < 0.001], which remained significant after adjusting for sex [adjusted odds ratio 6.88 (95% CI 2.87-16.46)]. There was also a higher risk of postoperative hemorrhage [4/40 (10%) vs. 444/24,660 (1.8%), P < 0.001), with sex-adjusted odds ratio of 5.97 (95% CI 2.12-16.86). Median (IQR) length of stay was increased in children with MPS (3 days, 1-4) compared with children without MPS (1 day, 1-2, P < 0.001). There was an increase in median (IQR) charges for hospital stay in children with MPS compared with their peers [$33,016 ($23,208.50-$72,280.50 vs. $15,383 ($9937-$24,462), P < 0.001]. CONCLUSIONS: Children with MPS undergoing AT had an increased risk of respiratory complications, postoperative hemorrhage, longer length of stay, and a higher cost of treatment when compared with children without MPS. This information may help inform interventional, perioperative, and postoperative decision making.
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Mucopolisacaridosis , Apnea Obstructiva del Sueño , Tonsilectomía , Niño , Humanos , Masculino , Femenino , Apnea Obstructiva del Sueño/cirugía , Adenoidectomía , Hemorragia Posoperatoria/epidemiología , Hemorragia Posoperatoria/etiología , Mucopolisacaridosis/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/cirugía , Estudios RetrospectivosRESUMEN
The endothelium comprises a cellular barrier between the circulation and tissues. We have previously shown that activation of protease-activated receptor 1 (PAR-1) and PAR-2 on the surface of human coronary artery endothelial cells by tryptase or thrombin increases group VIA phospholipase A(2) (iPLA(2)ß) activity and results in production of multiple phospholipid-derived inflammatory metabolites. We isolated cardiac endothelial cells from hearts of iPLA(2)ß-knockout (iPLA(2)ß-KO) and wild-type (WT) mice and measured arachidonic acid (AA), prostaglandin I(2) (PGI(2)), and platelet-activating factor (PAF) production in response to PAR stimulation. Thrombin (0.1 IU/ml) or tryptase (20 ng/ml) stimulation of WT endothelial cells rapidly increased AA and PGI(2) release and increased PAF production. Selective inhibition of iPLA(2)ß with (S)-bromoenol lactone (5 µM, 10 min) completely inhibited thrombin- and tryptase-stimulated responses. Thrombin or tryptase stimulation of iPLA(2)ß-KO endothelial cells did not result in significant PAF production and inhibited AA and PGI(2) release. Stimulation of cardiac endothelial cells from group VIB (iPLA(2)γ)-KO mice increased PAF production to levels similar to those of WT cells but significantly attenuated PGI(2) release. These results indicate that cardiac endothelial cell PAF production is dependent on iPLA(2)ß activation and that both iPLA(2)ß and iPLA(2)γ may be involved in PGI(2) release.
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Vasos Coronarios/citología , Células Endoteliales/enzimología , Fosfolipasas A2 Grupo VI/metabolismo , Isoenzimas/metabolismo , Animales , Ácido Araquidónico/metabolismo , Células Cultivadas , Células Endoteliales/citología , Activación Enzimática , Epoprostenol/metabolismo , Fosfolipasas A2 Grupo VI/genética , Humanos , Isoenzimas/genética , Ratones , Ratones NoqueadosRESUMEN
Phospholipases are critical enzyme mediators participating in many aspects of cellular function through modulating the generation of lipid 2nd messengers, membrane physical properties, and cellular bioenergetics. Here, we demonstrate that mice null for calcium-independent phospholipase A(2)γ (iPLA(2)γ(-/-)) are completely resistant to high fat diet-induced weight gain, adipocyte hypertrophy, hyperinsulinemia, and insulin resistance, which occur in iPLA(2)γ(+/+) mice after high fat feeding. Notably, iPLA(2)γ(-/-) mice were lean, demonstrated abdominal lipodystrophy, and remained insulin-sensitive despite having a marked impairment in glucose-stimulated insulin secretion after high fat feeding. Respirometry of adipocyte explants from iPLA(2)γ(-/-) mice identified increased rates of oxidation of multiple different substrates in comparison with adipocyte explants from wild-type littermates. Shotgun lipidomics of adipose tissue from wild-type mice demonstrated the anticipated 2-fold increase in triglyceride content after high fat feeding. In sharp contrast, the adipocyte triglyceride content was identical in iPLA(2)γ(-/-) mice fed either a standard diet or a high fat diet. Respirometry of skeletal muscle mitochondria from iPLA(2)γ(-/-) mice demonstrated marked decreases in state 3 respiration using multiple substrates whose metabolism was uncoupled from ATP production. Shotgun lipidomics of skeletal muscle revealed a decreased content of cardiolipin with an altered molecular species composition thereby identifying the mechanism underlying mitochondrial uncoupling in the iPLA(2)γ(-/-) mouse. Collectively, these results identify iPLA(2)γ as an obligatory upstream enzyme that is necessary for efficient electron transport chain coupling and energy production through its participation in the alterations of cellular bioenergetics that promote the development of the metabolic syndrome.
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Adipocitos/metabolismo , Calcio/metabolismo , Grasas de la Dieta/administración & dosificación , Ácidos Grasos/química , Fosfolipasas A2 Grupo IV/fisiología , Resistencia a la Insulina , Mitocondrias Musculares/fisiología , Obesidad/prevención & control , Animales , Western Blotting , Composición Corporal , Metabolismo Energético , Ácidos Grasos/metabolismo , Insulina/metabolismo , Metabolismo de los Lípidos , Masculino , Ratones , Ratones Noqueados , Músculo Esquelético/citología , Músculo Esquelético/metabolismo , Oxidación-Reducción , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción , Triglicéridos/metabolismoRESUMEN
Vocal fold immobility in children can affect breathing, swallowing, and speech function. Although sometimes idiopathic, it is often caused by injury to the recurrent laryngeal nerve during cardiac surgery. A detailed history and physical examination can identify risk factors, which affect the rate of resolution and overall prognosis. Fiberoptic laryngoscopy can be used to confirm the diagnosis and evaluate laryngeal anatomy. Many treatment options exist to improve function and quality of life, including vocal fold injection and laryngeal innervation. [Pediatr Ann. 2021;50(7):e286-e291.].
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Parálisis de los Pliegues Vocales , Pliegues Vocales , Niño , Humanos , Laringoscopía , Pronóstico , Calidad de Vida , Parálisis de los Pliegues Vocales/diagnóstico , Parálisis de los Pliegues Vocales/terapia , Pliegues Vocales/cirugíaRESUMEN
Genetic ablation of calcium-independent phospholipase A(2)gamma (iPLA(2)gamma) results in profound alterations in hippocampal phospholipid metabolism and mitochondrial phospholipid homeostasis resulting in enlarged and degenerating mitochondria leading to autophagy and cognitive dysfunction. Shotgun lipidomics demonstrated multiple alterations in hippocampal lipid metabolism in iPLA(2)gamma(-/-) mice including: 1) a markedly elevated hippocampal cardiolipin content with an altered molecular species composition characterized by a shift to shorter chain length molecular species; 2) alterations in both choline and ethanolamine glycerophospholipids, including a decreased plasmenylethanolamine content; 3) increased oxidized phosphatidylethanolamine molecular species; and 4) an increased content of ceramides. Electron microscopic examination demonstrated the presence of enlarged heteromorphic lamellar structures undergoing degeneration accompanied by the presence of ubiquitin positive spheroid inclusion bodies. Purification of these enlarged heteromorphic lamellar structures by buoyant density centrifugation and subsequent SDS-PAGE and proteomics identified them as degenerating mitochondria. Collectively, these results identify the obligatory role of iPLA(2)gamma in neuronal mitochondrial lipid metabolism and membrane structure demonstrating that iPLA(2)gamma loss of function results in a mitochondrial neurodegenerative disorder characterized by degenerating mitochondria, autophagy, and cognitive dysfunction.
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Autofagia , Cardiolipinas/metabolismo , Trastornos del Conocimiento/enzimología , Hipocampo/enzimología , Metabolismo de los Lípidos , Mitocondrias/enzimología , Fosfolipasas A2 Calcio-Independiente/metabolismo , Animales , Cardiolipinas/genética , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/patología , Hipocampo/ultraestructura , Ratones , Ratones Noqueados , Mitocondrias/ultraestructura , Membranas Mitocondriales/enzimología , Membranas Mitocondriales/ultraestructura , Fosfolipasas A2 Calcio-Independiente/genéticaRESUMEN
Activation of phospholipases leads to the release of arachidonic acid and lysophospholipids that play prominent roles in regulating vasomotor tone. To identify the role of calcium-independent phospholipase A(2)beta (iPLA(2)beta) in vasomotor function, we measured vascular responses to phenylephrine (PE) and ACh in mesenteric arterioles from wild-type (WT; iPLA(2)beta(+/+)) mice and those lacking the beta-isoform (iPLA(2)beta(-/-)) both ex vivo and in vivo. Vessels isolated from iPLA(2)beta(-/-) mice demonstrated increased constriction to PE, despite lower basal smooth muscle calcium levels, and decreased vasodilation to ACh compared with iPLA(2)beta(+/+) mice. PE constriction resulted in initial intracellular calcium release with subsequent steady-state constriction that depended on extracellular calcium influx. Endothelial denudation had no effect on vessel tone or PE-induced constriction although the dilation to ACh was significantly reduced in iPLA(2)beta(+/+) vessels. In contrast, vessels from iPLA(2)beta(-/-) constricted by 54% after denudation, indicating smooth muscle hypercontractility. In vivo, blood pressure, resting vessel diameter, and constriction of mesenteric vessels to PE were not different in iPLA(2)beta(-/-) vessels compared with WT mouse vessels. However, relaxation after ACh administration in situ was attenuated, indicating an endothelial inability to induce dilation in response to ACh. In cultured endothelial cells, inhibition of iPLA(2)beta with (S)-(E)-6-(bromomethylene)tetrahydro-3-(1-naphthalenyl)-2H-pyran-2-one (BEL) decreased endothelial nitric oxide synthase phosphorylation and reduced endothelial agonist-induced intracellular calcium release as well as extracellular calcium influx. We conclude that iPLA(2)beta is an important mediator of vascular relaxation and intracellular calcium homeostasis in both smooth muscle and endothelial cells and that ablation of iPLA(2)beta causes agonist-induced smooth muscle hypercontractility and reduced agonist-induced endothelial dilation.
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Acetilcolina/farmacología , Endotelio Vascular/fisiología , Músculo Liso Vascular/fisiología , Fosfolipasas A2 Calcio-Independiente/genética , Fosfolipasas A2 Calcio-Independiente/fisiología , Vasoconstricción/fisiología , Vasodilatación/fisiología , Animales , Calcio/metabolismo , Células Cultivadas , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Fosfolipasas A2 Grupo VI/genética , Fosfolipasas A2 Grupo VI/fisiología , Homeostasis/fisiología , Masculino , Arterias Mesentéricas/citología , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo III/metabolismo , Fenilefrina/farmacología , Fosforilación , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatación/efectos de los fármacos , Vasodilatadores/farmacologíaRESUMEN
BACKGROUND: Substance abuse is a major determinant of morbidity, mortality, and health care resource consumption. We evaluated a screening, brief intervention, and referral to treatment (SBIRT) program, implemented in 9 hospital emergency departments (ED) in Washington State. METHODS: Working-age, disabled Medicaid patients who were screened and received a brief intervention (BI) from April 12, 2004 through September 30, 2006 were included in the study's intervention group (N = 1557). The comparison group (N = 1557), constructed using (one-to-one) propensity score matching, consisted of Medicaid patients who received care in one of the counties in which an intervention hospital ED was located but who did not receive a BI. We estimated difference-in-difference (DiD) regression models to assess the effects of the SBIRT program for different patient groups. RESULTS: The SBIRT program was associated with an estimated reduction in Medicaid costs per member per month of $366 (P = 0.05) for all patients, including patients who received a referral for chemical dependency (CD) treatment. For patients who received a BI only and had no CD treatment in the year before or the year after the ED visit, the estimated reduction in Medicaid per member per month costs was $542 (P = 0.06). The SBIRT program was also associated with decreased inpatient utilization (P = 0.04). CONCLUSION: SBIRT programs have potential to limit resource consumption among working-age, disabled Medicaid patients. The hospital ED seems especially well suited for SBIRT programs given the large number of injured patients treated in the ED and the fact that many conditions treated are related to substance abuse.
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Servicio de Urgencia en Hospital/organización & administración , Tamizaje Masivo/organización & administración , Medicaid/organización & administración , Trastornos Relacionados con Sustancias/diagnóstico , Trastornos Relacionados con Sustancias/economía , Adolescente , Adulto , Factores de Edad , Costos y Análisis de Costo , Servicio de Urgencia en Hospital/economía , Femenino , Capacidad de Camas en Hospitales , Humanos , Revisión de Utilización de Seguros/estadística & datos numéricos , Masculino , Tamizaje Masivo/economía , Medicaid/economía , Persona de Mediana Edad , Derivación y Consulta/organización & administración , Factores Sexuales , Trastornos Relacionados con Sustancias/terapia , Estados Unidos , Washingtón , Adulto JovenRESUMEN
Myocardial function is intimately dependent on the precise spatiotemporal regulation of membrane-bound proteins and ion channels. Phospholipases play critical roles in the maintenance of membrane structure and function, thereby fundamentally integrating dynamic alterations in myocardial performance with membrane composition and dynamics. The major phospholipases in myocardium belong to a family of proteins known as calcium-independent phospholipases (iPLA2s). In addition to their role in maintaining normal membrane structure and function, iPLA2 catalytic activity results in the generation of a variety of lipid second messengers that facilitate cellular signaling. Through its multiple effects on cardiac myocyte bioenergetics, cellular signaling, and membrane function, the iPLA2 family of enzymes is of primary importance in modulating the pathologic sequelae of myocardial ischemia, diabetic cardiomyopathy, and remodeling during hemodynamic stress. This review will provide a brief overview of myocardial iPLA2s and their significance in cardiac pathology and physiology.
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Calcio/metabolismo , Fenómenos Electrofisiológicos , Metabolismo Energético , Isquemia Miocárdica/metabolismo , Miocardio/metabolismo , Fosfolipasas/metabolismo , Transducción de Señal , Animales , Humanos , Isquemia Miocárdica/fisiopatologíaRESUMEN
Large-scale neuronal remodeling through apoptosis occurs shortly after birth in all known mammalian species. Apoptosis, in large part, depends upon critical interactions between mitochondrial membranes and cytochrome c. Herein, we examined the hypothesis that the large-scale reorganization of neuronal circuitry after birth is accompanied by profound alterations in cardiolipin (CL) content and molecular species distribution. During embryonic development, over 100 CL molecular species were identified and quantitated in murine neuronal tissues. The embryonic CL profile was notable for the presence of abundant amounts of relatively short aliphatic chains (e.g., palmitoleic and oleic acids). In sharp contrast, after birth, the CL profile contained a remarkably complex repertoire of CL molecular species, in which the signaling fatty acids (i.e., arachidonic and docosahexaenoic acids) were markedly increased. These results identify the rapid remodeling of CL in the perinatal period with resultant alterations in the physical properties of the mitochondrial membrane. The complex distribution of aliphatic chains in the neuronal CL pool is separate and distinct from that in other organs (e.g., heart, liver, etc.), where CL molecular species contain predominantly only one major type of aliphatic chain (e.g., linoleic acid). Analyses of mRNA levels by real-time quantitative polymerase chain reactions suggested that the alterations in CL content were due to the combined effects of both attenuation of de novo CL biosynthesis and decreased remodeling of CL. Collectively, these results provide a new perspective on the complexity of CL in neuronal signaling, mitochondrial bioenergetics, and apoptosis.
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Cardiolipinas/química , Animales , Apoptosis , Encéfalo/embriología , Encéfalo/metabolismo , Ácidos Grasos/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Modelos Biológicos , Miocardio/metabolismo , Neuronas/metabolismo , Conejos , Ratas , Transducción de Señal , Factores de TiempoRESUMEN
Lipids fulfill multiple specialized roles in neuronal function. In brain, the conduction of electrical impulses, synaptic function, and complex signaling pathways depend on the temporally and spatially coordinated interactions of specialized lipids (e.g., arachidonic acid and plasmalogens), proteins (e.g., ion channels, phospholipases and cyclooxygenases) and integrative lipid-protein interactions. Recent technical advances in mass spectrometry have allowed unparalled insight into the roles of lipids in neuronal function. Through shotgun lipidomics and multidimensional mass spectrometry, in conjunction with the identification of new classes of phospholipases (e.g., calcium dependent and calcium independent intracellular phospholipases), new roles for lipids in cerebral function have been accrued. This review summarizes the advances in our understanding of the types of lipids and phospholipases in the brain and the role of functional lipidomics in increasing our chemical understanding of complex neuronal processes.
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Metabolismo de los Lípidos , Neuronas/fisiología , Animales , Cromatografía Líquida de Alta Presión , Humanos , Cinética , Lípidos/química , Espectrometría de Masas , Lípidos de la Membrana/metabolismo , Modelos Químicos , Neuronas/metabolismo , Fosfolipasas/metabolismo , Fosfolipasas A/metabolismo , Unión Proteica , Isoformas de Proteínas , Transducción de Señal , Distribución TisularRESUMEN
Managing clinically complex populations poses a major challenge for state agencies trying to control health care costs and improve quality of care for Medicaid beneficiaries. In Washington State a care coordination intervention, the Chronic Care Management program, was implemented for clinically complex Medicaid beneficiaries who met risk criteria defined by a predictive modeling algorithm. We used propensity score matching to evaluate the program's impact on health care spending and utilization and mortality. We found large and significant reductions in inpatient hospital costs ($318 per member per month) among patients who used the program. The estimated reduction in overall medical costs of $248 per member per month exceeded the cost of the intervention but did not reach statistical significance. These results suggest that well-designed targeted care coordination services could reduce health care spending for Medicaid beneficiaries with complex health care needs.