RESUMEN
PURPOSE: To evaluate the clinical feasibility and tolerability of large volume subcutaneous delivery at different injection depths for lean and non-lean subjects. METHODS: A single-center, randomized, subject-blinded, crossover study in 62 healthy subjects was conducted to evaluate delivery of a 10-cP solution containing hyaluronic acid. Subjects were separated into lean and non-lean cohort by SC thickness. A syringe pump was used to study the effect of different volumes (5, 12, 25 mL) of a viscous placebo solution and needle lengths (6, 9 and 12 mm) delivered at 0.5 mL/min. RESULTS: Across all treatments, injection sites were observed to have negligible leakage, ~34 kPa of back pressure, and VAS of mild pain with higher pain from needle insertion than during injection. While mild to moderate erythema was the most frequently reported ISR and edema was most prominent for 25 mL injections, all ISRs were resolved within 4 hours post injection. Subjects were unbothered by ISRs across all treatments and rated them as low distress scores (average 1.0-1.5 out of 6). CONCLUSION: SC injection of 25 mL is feasible and tolerable using a low-pain formulation for abdomen injection irrespective of subcutaneous thickness and injection depths at a delivery rate of 0.5 mL/min.
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Dolor , Tejido Subcutáneo , Humanos , Inyecciones Subcutáneas , Estudios Cruzados , Dolor/tratamiento farmacológicoRESUMEN
The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role of the BAF complex, we deleted BAF155/BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in neural crest cells (NCCs). Neural crest-specific deletion of BAF155/BAF170 leads to embryonic lethality due to a wide range of developmental defects including craniofacial, pharyngeal arch artery, and OFT defects. RNAseq and transcription factor enrichment analysis revealed that the BAF complex modulates the expression of multiple signaling pathway genes including Hippo and Notch, essential for the migration, proliferation, and differentiation of the NCCs. Furthermore, we demonstrated that the BAF complex is essential for the Brg1-Yap-Tead-dependent transcription of target genes in NCCs. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.
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Ensamble y Desensamble de Cromatina , Proteínas de Unión al ADN/genética , Regulación del Desarrollo de la Expresión Génica , Cresta Neural/embriología , Cresta Neural/metabolismo , Neurogénesis/genética , Animales , Diferenciación Celular/genética , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Desarrollo Embrionario/genética , Eliminación de Gen , Redes Reguladoras de Genes , Genes Reporteros , Ratones , Ratones Transgénicos , Especificidad de Órganos , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcripción GenéticaRESUMEN
Organic anion transporting polypeptide 2B1 (OATP2B1) is a widely expressed membrane transporter with diverse substrate specificity. In vitro and clinical studies suggest a role for intestinal OATP2B1 in the oral absorption of medications. Moreover, OATP2B1 is highly expressed in hepatocytes where it is thought to promote liver drug clearance. However, until now, a shortcoming of studies implicating OATP2B1 in drug disposition has been a lack of in vivo models. Here, we report the development of a knockout (KO) mouse model with targeted, global disruption of the Slco2b1 gene to examine the disposition of two confirmed mOATP2B1 substrates, namely, fexofenadine and rosuvastatin. The plasma pharmacokinetics of intravenously administered fexofenadine was not different between KO and wild-type (WT) mice. However, after oral fexofenadine administration, KO mice had 70% and 41% lower maximal plasma concentration (C max) and area under the plasma concentration-time curve (AUC0-last) than WT mice, respectively. In WT mice, coadministration of fexofenadine with grapefruit juice (GFJ) or apple juice (AJ) was associated with reduced C max by 80% and 88%, respectively, while the AUC0-last values were lower by 35% and 70%, respectively. In KO mice, AJ coadministration reduced oral fexofenadine C max and AUC0-last values by 67% and 59%, respectively, while GFJ had no effects. Intravenous and oral rosuvastatin pharmacokinetics were similar among WT and KO mice. We conclude that intestinal OATP2B1 is a determinant of oral fexofenadine absorption, as well as a target for fruit juice interactions. OATP2B1 does not significantly influence rosuvastatin disposition in mice. SIGNIFICANCE STATEMENT: A novel mouse model with targeted disruption of the Slco2b1 gene revealed that OATP2B1 is a determinant of oral absorption but not systemic disposition of fexofenadine, as well as a target of fruit juice interactions. Rosuvastatin oral and intravenous pharmacokinetics were not dependent on OATP2B1. These findings support the utility of the Slco2b1 KO mouse model for defining mechanisms of drug disposition at the intersection of in vitro and clinical pharmacology.
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Mucosa Intestinal/metabolismo , Transportadores de Anión Orgánico/metabolismo , Rosuvastatina Cálcica/farmacocinética , Terfenadina/análogos & derivados , Administración Intravenosa , Administración Oral , Animales , Área Bajo la Curva , Interacciones Alimento-Droga , Jugos de Frutas y Vegetales , Células HEK293 , Células HeLa , Humanos , Absorción Intestinal , Masculino , Ratones , Ratones Noqueados , Transportadores de Anión Orgánico/genética , Rosuvastatina Cálcica/administración & dosificación , Terfenadina/administración & dosificación , Terfenadina/farmacocinéticaRESUMEN
BACKGROUND: The current lack of effective drug therapies for Alzheimer's disease (AD) has prompted researchers to seek alternative nutritional therapies, such as medium chain triglycerides (MCTs). However, results are inconclusive. OBJECTIVE: This systematic review and meta-analysis aims to summarize current evidence on the effect of MCT on cognitive function in patients with mild cognitive impairment (MCI) or AD. METHODS: A systematic search was conducted up until December 16, 2022, to identify human interventions reporting the effects of MCT on cognitive functioning of MCI or AD patients. 995 non-duplicated publications were identified, of which nine (nâ=â10 studies) met the inclusion criteria. RESULTS: Meta-analysis showed cognitive improvements in general (SMDâ=â0.64; 95% CI [0.05, 1.24]), but not in memory, language, and attention domains after oral MCT administration, compared to placebo. The effect of MCT was greater among APOEÉ4 (-) subjects than APOEÉ4 (+) subjects (SMDâ=â1.87; 95% CI [0.35, 3.40]). CONCLUSION: This review provides some evidence that treatment with MCT could improve general cognitive function in APOEÉ4 (-) cognitive impaired patients. Better characterized clinical studies are warranted before making a definitive conclusion on the use of MCT for MCI and AD management.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Cognición , Triglicéridos/uso terapéuticoRESUMEN
OBJECTIVE: To evaluate folding in infrarenal stent grafts in relation to oversizing, barb angle, and barb length using computed tomography images of stent grafts deployed in explanted bovine aortas. METHODS: Computed tomography data from an in vitro investigation on the effect of oversizing of 4% to 45% (n = 19), barb length of 2 to 7 mm (n = 11), and barb angle of 10° to 90° (n = 7) on device fixation were examined for instances of folding. Folding was classified as circumferential or longitudinal and quantified on an ordinal scale based on codified criteria. Cumulative fold ranking from 0 (no fold) to 6 (two severe folds) for each deployment was used as the measure of folding observed. RESULTS: Of the 37 cases, cumulative mean ± standard deviation fold ranking for stent grafts oversized >30% (n = 5) was significantly greater than the rest (3.4 ± 1.7 vs 0.5 ± 1.2, respectively; Mann-Whitney U test; P < .005). When barb length was varied from 2 to 7 mm (oversizing held at 10%-20%), folding was noted in one of 11 cases. Similarly, when barb angle was varied from 0° (vertical) to 90° (horizontal), folding was not noted in any of the seven cases. The pullout force was not significantly different between stent grafts with and without folding (5.4 ± 1.95 vs 5.12 ± 1.89 N, respectively; P > .5). At least one instance of folding was noted in the seven of seven (100%) stent grafts with oversizing >23.5% and in only five of 30 (14%) stent grafts with oversizing <23.5%. CONCLUSIONS: Stent graft folding was prevalent when oversized >30%. Large variations in barb length and angle did not aggravate folding risk when oversized within the recommended range of 10% to 20%.
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Aorta Torácica/cirugía , Implantación de Prótesis Vascular/instrumentación , Prótesis Vascular , Procedimientos Endovasculares/instrumentación , Stents , Animales , Aorta Torácica/diagnóstico por imagen , Aortografía/métodos , Implantación de Prótesis Vascular/efectos adversos , Bovinos , Simulación por Computador , Endofuga/etiología , Procedimientos Endovasculares/efectos adversos , Análisis de Elementos Finitos , Migración de Cuerpo Extraño/etiología , Modelos Cardiovasculares , Diseño de Prótesis , Medición de Riesgo , Factores de Riesgo , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVES: There are conflicting recommendations for lay rescuer management of patients who are unresponsive and apneic due to opioid overdose. We evaluated the management of such patients at an urban supervised consumption site. METHODS: At a single urban supervised consumption site in Vancouver, BC, we conducted a retrospective chart review and administrative database linkage of consecutive patients who were unresponsive and apneic following witnessed opioid overdose between January 1, 2012 and December 31, 2017. We linked these visits with regional hospital records to define the entire care episode, which concluded when the patient was discharged from the supervised consumption site, ED, or hospital, or died. The primary outcome was successful resuscitation, defined as alive and neurologically intact (ambulatory and speaking coherently, or alert and oriented, or Glasgow Coma Scale 15) at the conclusion of the care episode. Secondary outcomes included mortality and predefined complications of resuscitation. RESULTS: We collected 767 patients, with a median age of 43 and 81.6% male, with complete follow-up on 763 patients (99.5%). All patients were managed with oxygen and ventilation (100%, 95% CI 0.995-1.0); 715 (93.2%, 95% CI 0.911-0.949) received naloxone; no patients underwent chest compressions (0%, 95% CI 0-0.005). All patients with complete follow-up were alive and neurologically intact at the end of their care episode (100%, 95% CI 0.994-1.0). Overall, 191 (24.9%) patients were transported to hospital, and 15 (2.0%) patients required additional naloxone after leaving the supervised consumption site; 16 (2.1%) developed complications, and 1 patient was admitted to hospital. CONCLUSIONS: At an urban supervised consumption site, all unresponsive, apneic patients with witnessed opioid overdose were successfully resuscitated with oxygen and/or naloxone. No patients required chest compressions.
RéSUMé: OBJECTIFS: Il existe des recommandations contradictoires concernant la prise en charge par des secouristes non professionnels des patients qui ne réagissent pas et sont apnéiques en raison d'une surdose d'opioïdes. Nous avons évalué la prise en charge de ces patients dans un site urbain de consommation supervisée. MéTHODES: Dans un seul site de consommation supervisée urbain à Vancouver, en Colombie-Britannique, nous avons effectué un examen rétrospectif des dossiers et un couplage de bases de données administratives de patients consécutifs qui étaient insensibles et apnéiques après avoir été témoins d'une surdose d'opioïdes entre le 1er janvier 2012 et le 31 décembre 2017. Le résultat primaire était la réussite de la réanimation, définie comme étant vivante et neurologiquement intacte (ambulatoire et parlant de manière cohérente, ou alerte et orientée, ou échelle de coma de Glasgow 15) à la fin de l'épisode de soins. Les résultats secondaires comprenaient la mortalité et les complications prédéfinies de la réanimation. RéSULTATS: Nous avons recueilli 767 patients, avec un âge médian de 43 ans et 81,6 % d'hommes, avec un suivi complet de 763 patients (99,5 %). Tous les patients ont été pris en charge avec de l'oxygène et la ventilation (100 %, IC à 95 % : 0,995-1,0) ; 715 (93,2 %, IC à 95 % : 0,911-0,949) ont reçu de la naloxone ; aucun patient n'a subi de compressions thoraciques (0 %, IC à 95 % : 0-0,005). Tous les patients ayant fait l'objet d'un suivi complet étaient vivants et intacts sur le plan neurologique à la fin de leur épisode de soins (100 %, IC à 95 % : 0,994-1,0). Dans l'ensemble, 191 (24,9 %) patients ont été transportés à l'hôpital, et 15 (2,0 %) patients ont eu besoin de naloxone supplémentaire après avoir quitté le site de consommation supervisée ; 16 (2,1 %) ont développé des complications, et 1 patient a été admis à l'hôpital. CONCLUSIONS: Dans un centre de consommation supervisée urbain, tous les patients apnéiques non réceptifs ayant été témoins d'une surdose d'opioïdes ont été réanimés avec succès avec de l'oxygène et/ou de la naloxone. Aucun patient n'a eu besoin de compressions thoraciques.
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Sobredosis de Droga , Sobredosis de Opiáceos , Analgésicos Opioides/uso terapéutico , Sobredosis de Droga/tratamiento farmacológico , Sobredosis de Droga/terapia , Femenino , Hospitales , Humanos , Masculino , Naloxona/uso terapéutico , Oxígeno/uso terapéutico , Estudios RetrospectivosRESUMEN
Hypertrophic cardiomyopathy (HCM) is a well-established risk factor for cardiovascular mortality worldwide. Although hypertrophy is traditionally regarded as an adaptive response to physiological or pathological stress, prolonged hypertrophy can lead to heart failure. Here we demonstrate that Prdm16 is dispensable for cardiac development. However, it is required in the adult heart to preserve mitochondrial function and inhibit hypertrophy with advanced age. Cardiac-specific deletion of Prdm16 results in cardiac hypertrophy, excessive ventricular fibrosis, mitochondrial dysfunction, and impaired metabolic flexibility, leading to heart failure. We demonstrate that Prdm16 and euchromatic histone-lysine N-methyltransferase factors (Ehmts) act together to reduce expression of fetal genes reactivated in pathological hypertrophy by inhibiting the functions of the pro-hypertrophic transcription factor Myc. Although young Prdm16 knockout mice show normal cardiac function, they are predisposed to develop heart failure in response to metabolic stress. Our study demonstrates that Prdm16 protects the heart against age-dependent cardiac hypertrophy and heart failure.
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Cardiomegalia/genética , Proteínas de Unión al ADN/genética , Insuficiencia Cardíaca/genética , Factores de Transcripción/genética , Animales , Remodelación Atrial/genética , Cardiomegalia/metabolismo , Cardiomiopatía Hipertrófica/metabolismo , Línea Celular , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Femenino , Insuficiencia Cardíaca/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Miocitos Cardíacos/metabolismo , Ratas , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) are risk factors for development of metabolic dysfunction and severity of depressive symptoms. RESEARCH DESIGN AND METHODS: We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges. Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First- or second-degree relatives with type-2 diabetes defined fam-Hx-DM2. RESULTS: Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weight and BMI. Moreover, we report a relationship and interaction between Fam-Hx-DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-Hx-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals reporting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam-Hx-Dm2 may define two different metabolic endophenotypes. CONCLUSIONS: Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Fam-Hx-DM2.
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Maltrato a los Niños/psicología , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/psicología , Resistencia a la Insulina , Adulto , Glucemia/análisis , Índice de Masa Corporal , Niño , Diabetes Mellitus Tipo 2/genética , Familia , Femenino , Prueba de Tolerancia a la Glucosa , Humanos , Insulina/sangre , Masculino , Persona de Mediana Edad , Escalas de Valoración PsiquiátricaRESUMEN
PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression. PURPOSE: Early life adversity is associated with both metabolic impairment and depression in adulthood, as well as with poorer responses to antidepressant medications. It is not yet known whether individual differences in sensitivity to antidiabetic medications could also be related to early life adversity. We examined whether a history of early life adversity affected the observed changes in metabolic function and depressive symptoms in a randomized trial of pioglitazone for augmentation of standard treatments for depression. FINDINGS: We found that early life adversity significantly impaired the metabolic response to pioglitazone. Effects on depressive symptoms did not reach significance, but nonetheless suggested that pioglitazone could mitigate the depressant effects of childhood adversity, only among those insulin resistant at baseline. CONCLUSIONS: We conclude that a history of early life adversity may impair the body's ability to respond to insulin sensitizing pharmacotherapy, and furthermore that its contribution to resistant depression may function in part via the generation of an insulin resistant phenotype.
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Experiencias Adversas de la Infancia , Trastorno Depresivo Resistente al Tratamiento , Acontecimientos que Cambian la Vida , Sobrepeso , Pioglitazona , Adulto , Antidepresivos/administración & dosificación , Antidepresivos/efectos adversos , Niño , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/metabolismo , Trastorno Depresivo Resistente al Tratamiento/psicología , Resistencia a Medicamentos , Femenino , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Resistencia a la Insulina , Masculino , Sobrepeso/metabolismo , Sobrepeso/psicología , Pioglitazona/administración & dosificación , Pioglitazona/efectos adversosRESUMEN
We describe the development, validation, and application of a novel PDMS-based microfluidic device for imaging leukocyte interaction with a biological substrate at defined shear force employing a parallel plate geometry that optimizes experimental throughput while decreasing reagent consumption. The device is vacuum bonded above a standard 6-well tissue culture plate that accommodates a monolayer of endothelial cells, thereby providing a channel to directly observe the kinetics of leukocyte adhesion under defined shear flow. Computational fluid dynamics (CFD) was applied to model the shear stress and the trajectory of leukocytes within the flow channels at a micron length scale. In order to test this model, neutrophil capture, rolling, and deceleration to arrest as a function of time and position was imaged in the transparent channels. Neutrophil recruitment to the substrate proved to be highly sensitive to disturbances in flow streamlines, which enhanced the rate of neutrophil-surface collisions at the entrance to the channels. Downstream from these disturbances, the relationship between receptor mediated deceleration of rolling neutrophils and dose response of stimulation by the chemokine IL-8 was found to provide a functional readout of integrin activation. This microfluidic technique allows detailed kinetic studies of cell adhesion and reveals neutrophil activation within seconds to chemotactic molecules at concentrations in the picoMolar range.
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Endotelio Vascular/citología , Endotelio Vascular/patología , Inflamación , Leucocitos/citología , Leucocitos/patología , Técnicas Analíticas Microfluídicas/instrumentación , Microfluídica/métodos , Adhesión Celular , Quimiotaxis , Simulación por Computador , Diseño de Equipo , Humanos , Interleucina-8/metabolismo , Cinética , Rodamiento de Leucocito , Neutrófilos/citología , Estrés MecánicoRESUMEN
OBJECTIVE: To report a case of spontaneous ovarian hyperstimulation resulting from an FSH-secreting pituitary adenoma. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 29-year-old previously healthy, nulligravid woman. INTERVENTION(S): Transphenoidal resection of the adenoma. MAIN OUTCOME MEASURE(S): Clinical remission. RESULT(S): After transphenoidal resection of the adenoma, the patient had an uneventful postoperative recovery with complete resolution of ovarian hyperstimulation and associated symptoms. Postoperative magnetic resonance imaging demonstrated residual tumor within the cavernous sinus. CONCLUSION(S): Follicle-stimulating hormone-secreting pituitary adenoma may present as acute spontaneous ovarian hyperstimulation.
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Adenoma/complicaciones , Hormona Folículo Estimulante/metabolismo , Síndrome de Hiperestimulación Ovárica/etiología , Neoplasias Hipofisarias/complicaciones , Adenoma/metabolismo , Adulto , Femenino , Humanos , Hormona Luteinizante/sangre , Neoplasias Hipofisarias/metabolismoRESUMEN
NuvaRing, a combined contraceptive vaginal ring 54 mm in diameter, offers many advantages over oral contraceptives. To better delineate in vivo placement, we performed MRI to confirm its anatomical position. Two healthy users, one nulliparous and one parous, underwent a series of MRI: preinsertion, immediately postinsertion and after ambulation. Three-dimensional imaging of the human vagina demonstrates that in vivo, NuvaRing is located superior to the urogenital diaphragm (UGD), surrounding the cervix. The superior-most aspect of the ring lies behind (posterior) the cervix, at a level superior to the external os. The inferior aspect of the ring also lies in the vaginal canal above the UGD. The entire cervix rests inside the ring. The preambulation image in the nulliparous woman was the only exception. In this case, the upper portion of the ring was at the level of the lower-mid cervix and the lower aspect below the UGD. After ambulation, the ring moved cephalad and surrounded the cervix. In all instances, ambulation resulted in lower aspect of NuvaRing moving away from the introitus. In vivo, NuvaRing is compressed laterally forming a gentle oval in the anterior-posterior direction (5-7 mm longer than wide), an effect that is seen more in nulliparous women.
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Dispositivos Anticonceptivos Femeninos/estadística & datos numéricos , Genitales Femeninos/anatomía & histología , Imagen por Resonancia Magnética , Adulto , Femenino , Humanos , Paridad , EmbarazoRESUMEN
Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients (N=37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction.
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Adyuvantes Farmacéuticos/uso terapéutico , Antidepresivos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Tiazolidinedionas/uso terapéutico , Adulto , Factores de Edad , Glucemia/metabolismo , Trastorno Depresivo Mayor/sangre , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Insulina/sangre , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , PioglitazonaRESUMEN
This study was undertaken to characterize the molecular and pathological mechanisms of pulmonary vascular remodeling in a patient who developed chronic lung allograft dysfunction and recurrent pulmonary hypertension (PH) 22 years after undergoing a right single lung transplantation for pulmonary arterial hypertension (PAH). Histopathologic examination of the explanted lungs at the time of retransplantation showed characteristics of diffuse vascular remodeling combined with features of acute and chronic thromboemboli and evidence of bronchiolitis obliterans in the right lung allograft. In contrast, the native left lung demonstrated pulmonary arterial changes in keeping with PAH associated with disseminated pulmonary ossification. Real-time polymerase chain reaction and Western blot-performed on the first lung allograft, the native lung, and the new donor lung-demonstrated increased expression of apoptotic-related gene and protein levels in the lung allograft compared with the native PAH lung and the donor lung. Localization of cell apoptosis determined by triple immunostaining for caspase 3, CD31, and smooth muscle actin was positive in the pulmonary endothelial cells but not the smooth muscle cells of the lung allograft, while no positive staining was detected for cell death in the native PAH lung. The presence of PH in the lung allograft 22 years after transplantation was associated with upregulation of apoptotic markers and evidence of apoptotic endothelial cell death compared with the native lung and donor lung.
RESUMEN
Pulmonary arterial hypertension (PAH) is a vascular disease characterized by persistent precapillary pulmonary hypertension (PH), leading to progressive right heart failure and premature death. The pathological mechanisms underlying this condition remain elusive. Analysis of global metabolomics from lung tissue of patients with PAH (n = 8) and control lung tissue (n = 8) leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted arginine pathways with increased Nitric oxide (NO) and decreased arginine. Our results also showed specific metabolic pathways and genetic profiles with increased Sphingosine-1-phosphate (S1P) metabolites as well as increased Heme metabolites with altered oxidative pathways in the advanced stage of the human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to the vascular remodeling in severe pulmonary hypertension. Profiling metabolomic alterations of the PAH lung has provided a new understanding of the pathogenic mechanisms of PAH, which benefits therapeutic targeting to specific metabolic pathways involved in the progression of PAH.
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Arginina/análisis , Hemo/análisis , Hipertensión Pulmonar/metabolismo , Pulmón/metabolismo , Lisofosfolípidos/análisis , Metabolómica/métodos , Esfingosina/análogos & derivados , Adulto , Femenino , Humanos , Hipertensión Pulmonar/patología , Masculino , Redes y Vías Metabólicas , Persona de Mediana Edad , Óxido Nítrico/metabolismo , Esfingosina/análisis , Remodelación VascularRESUMEN
Advances in diagnostic techniques and therapies have drastically improved cancer survival rates. However, the testes are highly susceptible to chemotherapy and radiation therapy, and spermatogenesis and semen parameters can be negatively impacted either permanently or transiently. Fertility preservation is an important issue to patients, and sperm banking has a positive psychological effect that helps patients cope emotionally with cancer. Innovations in sperm freezing and assisted reproductive technologies are improving the fecundity of males regardless of sperm parameters, and now even allow for fertility potential after gonadotoxic therapy. Experimental options also exist for prepubertal males, and hold promise for use in the future. At present, sperm cryopreservation is underutilized in the setting of a cancer diagnosis, and pretreatment referrals to fertility specialists are inconsistently offered. A multidisciplinary team approach is critical to educate families on the available options and help accomplish fertility preservation in a timely manner.
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Preservación de la Fertilidad/métodos , Neoplasias/terapia , Adolescente , Adulto , Niño , Preservación de la Fertilidad/tendencias , Humanos , Masculino , Oncología Médica/métodos , Rol Profesional , Medicina Reproductiva/métodos , Bancos de Esperma , Recursos HumanosRESUMEN
OBJECTIVE: To evaluate the outcomes of microdissection testicular sperm extraction (micro-TESE) in patients with high FSH. DESIGN: Clinical retrospective study. SETTING: Department of urology at a tertiary university hospital. PATIENT(S): Seven hundred ninety-two men with nonobstructive azoospermia. INTERVENTION(S): Micro-TESE followed by intracytoplasmic sperm injection was performed. The men were classified into four groups based on serum FSH levels: <15, 15-30, 31-45, and >45 IU/mL. MAIN OUTCOME MEASURE(S): Sperm retrieval, clinical pregnancy, and live birth rates. RESULT(S): Testicular sperm were successfully retrieved in 60% of the men. Sperm retrieval rates in the groups of men with FSH values 15-30, 31-45, and >45 IU/mL was 60%, 67%, and 60% respectively; this was higher than the group of men with FSH < 15 (51%). Of those men who had sperm retrieved, clinical pregnancy and live birth rates were similar in the four groups (46%, 50%, 52%, 46% and 38%, 45%, 44%, 36%, respectively). CONCLUSION(S): The chances of sperm retrieval using micro-TESE is just as common, if not better for men with elevated FSH levels than for men with lower FSH. Micro-TESE results appear to differ from earlier series that report low retrieval rates with random biopsies for men with elevated FSH. High FSH is not a contraindication for micro-TESE.
Asunto(s)
Azoospermia/sangre , Azoospermia/terapia , Hormona Folículo Estimulante/sangre , Microdisección/métodos , Índice de Embarazo , Inyecciones de Esperma Intracitoplasmáticas/métodos , Recuperación de la Esperma , Femenino , Humanos , Masculino , Embarazo , Resultado del TratamientoRESUMEN
Based on a recent review of the medical literature, a clinical diagnosis of infertility may not agree with strict criteria. Standardized definitions of diagnostic categories are essential for accurate patient prognosis and future research.