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1.
Int J Mol Sci ; 22(8)2021 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-33924243

RESUMEN

We recently reported that isoflurane conditioning provided multifaceted protection against subarachnoid hemorrhage (SAH)-induced delayed cerebral ischemia (DCI), and this protection was through the upregulation of endothelial nitric oxide synthase (eNOS). SIRT1, an NAD-dependent deacetylase, was shown to be one of the critical regulators of eNOS. The aim of our current study is to examine the role of SIRT1 in isoflurane conditioning-induced neurovascular protection against SAH-induced DCI. Mice were divided into four groups: sham, SAH, or SAH with isoflurane conditioning (with and without EX-527). Experimental SAH via endovascular perforation was performed. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. EX-527, a selective SIRT1 inhibitor, 10 mg/kg was injected intraperitoneally immediately after SAH in the EX-527 group. SIRT1 mRNA expression and activity levels were measured. Vasospasm, microvessel thrombosis, and neurological outcome were assessed. SIRT1 mRNA expression was downregulated, and no difference in SIRT1 activity was noted after isoflurane exposure. Isoflurane conditioning with and without EX-527 attenuated vasospasm, microvessel thrombosis and improved neurological outcomes. Our data validate our previous findings that isoflurane conditioning provides strong protection against both the macro and micro vascular deficits induced by SAH, but this protection is likely not mediated through the SIRT1 pathway.


Asunto(s)
Isquemia Encefálica/etiología , Precondicionamiento Isquémico , Isoflurano/farmacología , Neuroprotección , Sirtuina 1/genética , Hemorragia Subaracnoidea/complicaciones , Animales , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente , Expresión Génica , Precondicionamiento Isquémico/métodos , Ratones , Neuroprotección/efectos de los fármacos , Sirtuina 1/metabolismo , Vasoespasmo Intracraneal/etiología , Vasoespasmo Intracraneal/metabolismo , Vasoespasmo Intracraneal/prevención & control
2.
Int J Vitam Nutr Res ; 90(1-2): 42-48, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-30816822

RESUMEN

Low concentrations of serum vitamin K accompany high concentrations of undercarboxylated osteocalcin (ucOC) and osteoporotic fractures. Although vitamin K2 (MK-4) is approved as a therapeutic agent for the treatment of osteoporosis in some countries, the dose-response is unknown. The objective of this study was to assess the improvement in carboxylation of osteocalcin (OC) in response to escalating doses of MK-4 supplementation. A nine-week, open-labeled, prospective cohort study was conducted in 29 postmenopausal women who suffered hip or vertebral compression fractures. Participants took low-dose MK-4 (0.5 mg) for 3 weeks (until the second visit), then medium-dose MK-4 (5 mg) for 3 weeks (until the third visit), then high-dose MK-4 (45 mg) for 3 weeks. The mean ± SD age of the participants was 69 ± 9 years. MK-4 dose (p < 0.0001), but neither age nor other relevant medications (e.g. bisphosphonates) correlated with improvement in %ucOC. As compared to baseline concentrations (geometric mean ± SD) of 16.8 ± 2.4, 0.5 mg supplementation halved %ucOC to 8.7 ± 2.2 (p < 0.0001) and the 5-mg dose halved %ucOC again (to 3.9 ± 2.2; p = 0.0002 compared to 0.5-mg dose). However, compared to 5 mg/day, there was no additional benefit of 45 mg/day (%ucOC 4.6; p = NS vs. 5-mg dose). MK-4 supplementation resulted in borderline increases in γ-carboxylated osteocalcin (glaOC; p = 0.07). There were no major side effects of MK-4 supplementation. In postmenopausal women with osteoporotic fractures, supplementation with either 5 or 45 mg/day of MK-4 reduces ucOC to concentrations typical of healthy, pre-menopausal women.


Asunto(s)
Fracturas por Compresión , Osteocalcina/sangre , Osteoporosis , Fracturas de la Columna Vertebral , Vitamina K 2/análogos & derivados , Vitamina K 2/metabolismo , Femenino , Humanos , Osteocalcina/química , Estudios Prospectivos , Vitamina K 2/administración & dosificación , Vitamina K 2/uso terapéutico , Vitaminas/administración & dosificación , Vitaminas/metabolismo
3.
J Immunol ; 194(4): 1945-53, 2015 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-25582853

RESUMEN

Because NK cells secrete cytotoxic granules and cytokines that can destroy surrounding cells and help shape the subsequent immune response, they must be kept under tight control. Several mechanisms, at different levels, are in place to control NK cell function. In this study, we describe a novel mechanism regulating NK cell function in which NK cells acquire ligands for activating receptors from target cells by trogocytosis, rendering the NK cells hyporesponsive. In this model, murine NK cells acquire m157, the murine CMV-encoded ligand for the Ly49H-activating receptor, from target cells both in vitro and in vivo. Although acquisition of m157 requires cell-to-cell contact, it does not require the expression of the Ly49H receptor by the NK cell. Acquired m157 protein is expressed on the NK cell surface with a glycosylphosphatidylinisotol linkage and interacts with the Ly49H receptor expressed on the NK cell. This interaction results in blocking the Ly49H receptor that prevents the NK cells from recognizing m157-expressing targets and continuous engagement of the Ly49H-activating receptor, which results in the hyporesponsiveness of the Ly49H(+) NK cell to stimulation through other activating receptors. Thus, NK cell acquisition of a ligand for an activation receptor by trogocytosis renders them hyporesponsive. This mechanism, by which mature NK cell function can be altered, has important implications in regard to how NK cells respond to tumors in specific microenvironments as well as the use of expanded NK cells in treating various malignancies.


Asunto(s)
Antígenos Virales/inmunología , Células Asesinas Naturales/inmunología , Activación de Linfocitos/inmunología , Traslado Adoptivo , Animales , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Muromegalovirus/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/inmunología
5.
STAR Protoc ; 5(3): 103224, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39068650

RESUMEN

Variable-rate delivery of intravenous drugs is difficult to achieve with a tethered infusion system in a freely moving animal. Here, we present a protocol for continuous intravenous delivery of oxytocin in pregnant rats and mice. We describe steps for using an implantable, preprogrammed, microprocessor-controlled infusion pump connected to the jugular vein to induce labor. This protocol can be adapted to a variety of experimental paradigms in non-pregnant animals where precise intravenous pharmacological manipulation is desired. For complete details on the use and execution of this protocol, please refer to Giri et al.1,2.


Asunto(s)
Bombas de Infusión Implantables , Oxitocina , Animales , Ratas , Ratones , Femenino , Embarazo , Oxitocina/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Sistemas de Liberación de Medicamentos/instrumentación , Infusiones Intravenosas , Administración Intravenosa
6.
BJA Open ; 10: 100268, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38545566

RESUMEN

Background: Altered patterns of genetic expression induced by isoflurane preconditioning in mouse brain have not yet been investigated. The aim of our pilot study is to examine the temporal sequence of changes in the transcriptome of mouse brain cortex produced by isoflurane preconditioning. Methods: Twelve-wk-old wild-type (C57BL/6J) male mice were randomly assigned for the experiments. Mice were exposed to isoflurane 2% in air for 1 h and brains were harvested at the following time points-immediately (0 h), and at 6, 12, 24, 36, 48, and 72 h after isoflurane exposure. A separate cohort of mice were exposed to three doses of isoflurane on days 1, 2, and 3 and brains were harvested after the third exposure. The NanoString mouse neuropathology panel was used to analyse isoflurane-induced gene expression in the cortex. The neuropathology panel included 760 genes covering pathways involved in neurodegeneration and other nervous system diseases, and 10 internal reference genes for data normalisation. Results: Genes involving several pathways were upregulated and downregulated by isoflurane preconditioning. Interestingly, a biphasic response was noted, meaning, an early expression of genes (until 6 h), followed by a transient pause (until 24 h), and a second wave of genomic response beginning at 36 h of isoflurane exposure was noted. Conclusions: Isoflurane preconditioning induces significant alterations in the genes involved in neurodegeneration and other nervous system disorders in a temporal sequence. These data could aid in the identification of molecular mechanisms behind isoflurane preconditioning-induced neuroprotection in various central nervous system diseases.

7.
iScience ; 27(2): 108960, 2024 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-38327784

RESUMEN

Despite six decades of the use of exogenous oxytocin for management of labor, little is known about its effects on the developing brain. Motivated by controversial reports suggesting a link between oxytocin use during labor and autism spectrum disorders (ASDs), we employed our recently validated rat model for labor induction with oxytocin to address this important concern. Using a combination of molecular biological, behavioral, and neuroimaging assays, we show that induced birth with oxytocin leads to sex-specific disruption of oxytocinergic signaling in the developing brain, decreased communicative ability of pups, reduced empathy-like behaviors especially in male offspring, and widespread sex-dependent changes in functional cortical connectivity. Contrary to our hypothesis, social behavior, typically impaired in ASDs, was largely preserved. Collectively, our foundational studies provide nuanced insights into the neurodevelopmental impact of birth induction with oxytocin and set the stage for mechanistic investigations in animal models and prospective longitudinal clinical studies.

8.
PLoS One ; 18(7): e0281033, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37437040

RESUMEN

Despite differences in the clinical presentation of coronavirus disease-19 and pandemic influenza in pregnancy, fundamental mechanistic insights are currently lacking because of the difficulty in recruiting critically ill pregnant subjects for research studies. Therefore, to better understand host-pathogen interaction during pregnancy, we performed a series of foundational experiments in pregnant rats at term gestation to assess the expression of host entry factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus (IAV) and genes associated with innate immune response in the lower respiratory tract. We report that pregnancy is characterized by a decrease in host factors mediating SARS-CoV-2 entry and an increase in host factors mediating IAV entry. Furthermore, using flow cytometric assessment of immune cell populations and immune provocation studies, we show an increased prevalence of plasmacytoid dendritic cells and a Type I interferon-biased environment in the lower respiratory tract of pregnancy, contrary to the expected immunological indolence. Our findings, therefore, suggest that the dissimilar clinical presentation of COVID-19 and pandemic influenza A in pregnancy could partly be due to differences in the extent of innate immune activation from altered viral tropism and indicate the need for comparative mechanistic investigations with live virus studies.


Asunto(s)
COVID-19 , Virus de la Influenza A , Gripe Humana , Femenino , Embarazo , Animales , Ratas , Humanos , SARS-CoV-2 , Internalización del Virus , Sistema Respiratorio
9.
Heliyon ; 8(5): e09407, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35592667

RESUMEN

Despite the increased severity of influenza A infection in pregnancy, knowledge about the expression of cell entry factors for influenza A virus (IAV) and the innate immune response in the nasal epithelium, the primary portal of viral entry, is limited. Here, we compared the expression of IAV cell entry factors and the status of the innate immune response in the nasal epithelium of pregnant vs. non-pregnant female rats. IAV cell entry factors - sialic acid [SA] α-2,3- and α-2,6-linked glycans for avian and human IAV, respectively - were detected and quantified with lectin-based immunoblotting and flow cytometry. Baseline frequencies of innate immune cell phenotypes in single cell suspensions of the nasal epithelium were studied with flow cytometry. Subsequently, the magnitude of interferon and cytokine responses was studied with ELISA and cytokine arrays after intranasal resiquimod, a Toll-like receptor 7/8 agonist that mimics IAV infection. We noted substantially increased expression of cell entry factors for both avian and human IAV in the nasal epithelium during pregnancy. Assessment of the innate immune state of the nasal epithelium during pregnancy revealed two previously unreported features: (i) increased presence of tissue-resident plasmacytoid dendritic cells, and (ii) markedly enhanced release of interferon-α but not of the other interferons or cytokines 2 h after intranasal resiquimod. Collectively, our findings challenge the conventional notion of pregnancy-induced immunosuppression as a cause for severe influenza A disease and suggest the need for focused studies on viral tropism during pregnancy to better understand the proximate cause for the observed immunopathology.

10.
Pediatr Obes ; 17(4): e12871, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34783173

RESUMEN

BACKGROUND: Despite the importance of oxytocinergic signalling for satiety regulation and energy balance, the impact of exposure to synthetic oxytocin during childbirth on obesity during childhood remains unknown. OBJECTIVES: To examine the association between oxytocin exposure during labour and the risk of being overweight or obese during childhood. METHODS: Synthetic oxytocin exposure data of mothers from the Danish Medical Birth Registry were linked with self-reported anthropometric data of their children from the Danish National Birth Cohort (5 months-11 years of age). Multinomial logistic regression and latent class growth analyses were performed to determine the association between oxytocin exposure and obesity during childhood. RESULTS: With the exception of the normal weight-to-overweight group between ages 5 and 12 months, none of the other analyses revealed a significant association between synthetic oxytocin use and the risk of being overweight until the age of 11 years. Furthermore, latent class growth analysis did not reveal an association between oxytocin exposure at birth and the risk of being overweight or obese during childhood. CONCLUSIONS: Our analysis of a large cohort of children who varied in their synthetic oxytocin exposure status at childbirth did not reveal an association between oxytocin exposure and the risk of childhood overweight/obesity.


Asunto(s)
Oxitocina , Obesidad Infantil , Peso al Nacer , Índice de Masa Corporal , Niño , Femenino , Humanos , Lactante , Recién Nacido , Sobrepeso/epidemiología , Oxitocina/efectos adversos , Obesidad Infantil/inducido químicamente , Obesidad Infantil/epidemiología , Factores de Riesgo
11.
Sci Rep ; 12(1): 3143, 2022 02 24.
Artículo en Inglés | MEDLINE | ID: mdl-35210555

RESUMEN

Despite the widespread use of oxytocin for induction of labor, mechanistic insights into fetal/neonatal wellbeing are lacking because of the absence of an animal model that recapitulates modern obstetric practice. Here, we create and validate a hi-fidelity pregnant rat model that mirrors labor induction with oxytocin in laboring women. The model consists of an implantable preprogrammed microprocessor-controlled infusion pump that delivers a gradually escalating dose of intravenous oxytocin to induce birth at term gestation. We validated the model with molecular biological experiments on the uterine myometrium and telemetry-supported assessment of changes in intrauterine pressure. Finally, we applied this model to test the hypothesis that labor induction with oxytocin would be associated with oxidative stress in the newborn brain. Analysis of biomarkers of oxidative stress and changes in the expression of associated genes were no different between oxytocin-exposed and saline-treated pups, suggesting that oxytocin-induced labor was not associated with oxidative stress in the developing brain. Collectively, we provide a viable and realistic animal model for labor induction and augmentation with oxytocin that would enable new lines of investigation related to the impact of perinatal oxytocin exposure on the mother-infant dyad.


Asunto(s)
Encéfalo/metabolismo , Feto/metabolismo , Trabajo de Parto Inducido , Estrés Oxidativo/efectos de los fármacos , Oxitocina/farmacología , Animales , Femenino , Embarazo , Ratas , Ratas Sprague-Dawley
12.
Sci Rep ; 11(1): 9798, 2021 05 07.
Artículo en Inglés | MEDLINE | ID: mdl-33963277

RESUMEN

Use of maternal oxygen for intrauterine resuscitation is contentious because of the lack of evidence for its efficacy and the possibility of fetal harm through oxidative stress. Because the developing brain is rich in lipids and low in antioxidants, it remains vulnerable to oxidative stress. Here, we tested this hypothesis in a term pregnant rat model with oxytocin-induced fetal distress followed by treatment with either room air or 100% oxygen for 6 h. Fetal brains from both sexes were subjected to assays for biomarkers of oxidative stress (4-hydroxynonenal, protein carbonyl, or 8-hydroxy-2'-deoxyguanosine), expression of genes mediating oxidative stress, and mitochondrial oxidative phosphorylation. Contrary to our hypothesis, maternal hyperoxia was not associated with increased biomarkers of oxidative stress in the fetal brain. However, there was significant upregulation of the expression of select genes mediating oxidative stress, of which some were male-specific. These observations, however, were not accompanied by changes in the expression of proteins from the mitochondrial electron transport chain. In summary, maternal hyperoxia in the setting of acute uteroplacental ischemia-hypoxia does not appear to cause oxidative damage to the developing brain.


Asunto(s)
Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Enfermedades Fetales , Feto/metabolismo , Estrés Oxidativo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Resucitación , Animales , Encéfalo/patología , Femenino , Enfermedades Fetales/metabolismo , Enfermedades Fetales/patología , Enfermedades Fetales/terapia , Feto/patología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Ratas , Ratas Sprague-Dawley
13.
Clin Cancer Res ; 27(8): 2326-2339, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33547198

RESUMEN

PURPOSE: In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples. EXPERIMENTAL DESIGN: HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing. RESULTS: HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity. CONCLUSIONS: These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.


Asunto(s)
Resistencia a Antineoplásicos/genética , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Piridonas/farmacología , Pirimidinonas/farmacología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Proteínas Señalizadoras YAP/metabolismo , Animales , Biopsia , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Técnicas de Inactivación de Genes , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Vía de Señalización Hippo/genética , Humanos , Sistema de Señalización de MAP Quinasas/genética , Ratones , Piridonas/uso terapéutico , Pirimidinonas/uso terapéutico , RNA-Seq , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Secuenciación del Exoma , Ensayos Antitumor por Modelo de Xenoinjerto , Proteínas Señalizadoras YAP/genética
14.
J Am Heart Assoc ; 9(20): e017477, 2020 10 20.
Artículo en Inglés | MEDLINE | ID: mdl-33030094

RESUMEN

Background Delayed cerebral ischemia remains a common and profound risk factor for poor outcome after subarachnoid hemorrhage (SAH). The aim of our current study is to define the role of endothelial nitric oxide synthase (eNOS) in isoflurane conditioning-induced neurovascular protection after SAH. Methods and Results Ten- to 14-week-old male wild-type mice (C57BL/6) as controls and eNOS knockout male mice (strain # 002684) were obtained for the study. Animals underwent either sham surgery, SAH surgery, or SAH with isoflurane conditioning. Anesthetic post conditioning was performed with isoflurane 2% for 1 hour, 1 hour after SAH. Normothermia was maintained with the homeothermic blanket. In a separate cohort, nitric oxide synthase was inhibited by a pan nitric oxide synthase inhibitor, L-nitroarginine methyl ester. Vasospasm measurement was assessed 72 hours after SAH and neurological function was assessed daily. Isoflurane-induced changes in the eNOS protein expression were measured. eNOS protein expression was significantly increased by isoflurane conditioning in naïve mice as well as mice subjected to SAH. Vasospasm of the middle cerebral artery and neurological deficits were evident following SAH versus sham surgery, both in wild-type mice and eNOS knockout mice. Isoflurane conditioning attenuated vasospasm and neurological deficits in wild-type mice. This delayed cerebral ischemia protection was lost in L-nitroarginine methyl ester -administered mice and eNOS knockout mice. Conclusions Our data indicate isoflurane conditioning provides robust protection against SAH-induced vasospasm and neurological deficits, and that this delayed cerebral ischemia protection is critically mediated via isoflurane-induced augmentation of eNOS.


Asunto(s)
Isquemia Encefálica , Endotelio Vascular/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Anestésicos por Inhalación/farmacología , Animales , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/prevención & control , Modelos Animales de Enfermedad , Poscondicionamiento Isquémico , Precondicionamiento Isquémico , Isoflurano/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroprotección , Hemorragia Subaracnoidea/complicaciones , Hemorragia Subaracnoidea/metabolismo
15.
JCI Insight ; 5(10)2020 05 21.
Artículo en Inglés | MEDLINE | ID: mdl-32434985

RESUMEN

The impact of transient ischemic-hypoxemic insults on the developing fetal brain is poorly understood despite evidence suggesting an association with neurodevelopmental disorders such as schizophrenia and autism. To address this, we designed an aberrant uterine hypercontractility paradigm with oxytocin to better assess the consequences of acute, but transient, placental ischemia-hypoxemia in term pregnant rats. Using MRI, we confirmed that oxytocin-induced aberrant uterine hypercontractility substantially compromised uteroplacental perfusion. This was supported by the observation of oxidative stress and increased lactate concentration in the fetal brain. Genes related to oxidative stress pathways were significantly upregulated in male, but not female, offspring 1 hour after oxytocin-induced placental ischemia-hypoxemia. Persistent upregulation of select mitochondrial electron transport chain complex proteins in the anterior cingulate cortex of adolescent male offspring suggested that this sex-specific effect was enduring. Functionally, offspring exposed to oxytocin-induced uterine hypercontractility showed male-specific abnormalities in social behavior with associated region-specific changes in gene expression and functional cortical connectivity. Our findings, therefore, indicate that even transient but severe placental ischemia-hypoxemia could be detrimental to the developing brain and point to a possible mitochondrial link between intrauterine asphyxia and neurodevelopmental disorders.


Asunto(s)
Feto/embriología , Trastornos del Neurodesarrollo/metabolismo , Estrés Oxidativo , Placenta , Daño por Reperfusión/metabolismo , Animales , Femenino , Feto/patología , Trastornos del Neurodesarrollo/patología , Placenta/irrigación sanguínea , Placenta/metabolismo , Placenta/patología , Embarazo , Ratas
17.
J Pediatric Infect Dis Soc ; 4(3): 182-8, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26336601

RESUMEN

BACKGROUND: Vitamin D deficiency at birth has been reported as a risk factor for respiratory syncytial virus (RSV) lower respiratory tract infection during the first year of life. Limited data are available on whether an infant's vitamin D status is associated with the severity of acute RSV bronchiolitis. METHODS: Infants < 1 year of age and hospitalized with their first episode of RSV bronchiolitis were enrolled into the RSV Bronchiolitis in Early Life II cohort. We investigated the relationships between vitamin D status at enrollment and the following indicators of bronchiolitis severity: duration of hospitalization, lowest oxygen saturation measured during hospitalization, and bronchiolitis severity score. RESULTS: Among the 145 enrolled infants, the median (quartile 1 [Q1], Q3) serum 25-OH-VitD level was 36.8 (29.8, 42.3) ng/mL, with 14 infants (9.7%) having deficient serum vitamin D levels (25-OH-VitD <20 ng/mL). Vitamin D-deficient infants were younger than infants with 25-OH-VitD ≥ 20 ng/mL (2.8 vs 4.5 months, respectively; P = .04) and were less likely to consume infant's formula (42.9% vs 87.0%, respectively; P < .01). The following indicators of acute bronchiolitis severity did not differ between infants who were vitamin D-deficient and nondeficient: duration of hospitalization (P = .53), lowest oxygen saturation (P = .45), and bronchiolitis severity score (P = .97), even after adjusting for age, and for infant's formula consumption. CONCLUSIONS: Among this cohort of infants that were hospitalized for RSV bronchiolitis, vitamin D status at the time of bronchiolitis was not associated with indicators of acute bronchiolitis severity.


Asunto(s)
Bronquiolitis Viral/fisiopatología , Infecciones por Virus Sincitial Respiratorio/fisiopatología , Virus Sincitial Respiratorio Humano , Vitamina D/sangre , Bronquiolitis Viral/complicaciones , Estudios de Cohortes , Femenino , Humanos , Factores Inmunológicos/sangre , Lactante , Masculino , Estudios Prospectivos , Infecciones por Virus Sincitial Respiratorio/complicaciones , Índice de Severidad de la Enfermedad , Deficiencia de Vitamina D/sangre , Deficiencia de Vitamina D/complicaciones , Deficiencia de Vitamina D/fisiopatología
18.
PLoS One ; 10(11): e0142649, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26587832

RESUMEN

Severe infection with respiratory syncytial virus (RSV) during infancy is strongly associated with the development of asthma. To identify genetic variation that contributes to asthma following severe RSV bronchiolitis during infancy, we sequenced the coding exons of 131 asthma candidate genes in 182 European and African American children with severe RSV bronchiolitis in infancy using anonymous pools for variant discovery, and then directly genotyped a set of 190 nonsynonymous variants. Association testing was performed for physician-diagnosed asthma before the 7th birthday (asthma) using genotypes from 6,500 individuals from the Exome Sequencing Project (ESP) as controls to gain statistical power. In addition, among patients with severe RSV bronchiolitis during infancy, we examined genetic associations with asthma, active asthma, persistent wheeze, and bronchial hyperreactivity (methacholine PC20) at age 6 years. We identified four rare nonsynonymous variants that were significantly associated with asthma following severe RSV bronchiolitis, including single variants in ADRB2, FLG and NCAM1 in European Americans (p = 4.6x10-4, 1.9x10-13 and 5.0x10-5, respectively), and NOS1 in African Americans (p = 2.3x10-11). One of the variants was a highly functional nonsynonymous variant in ADRB2 (rs1800888), which was also nominally associated with asthma (p = 0.027) and active asthma (p = 0.013) among European Americans with severe RSV bronchiolitis without including the ESP. Our results suggest that rare nonsynonymous variants contribute to the development of asthma following severe RSV bronchiolitis in infancy, notably in ADRB2. Additional studies are required to explore the role of rare variants in the etiology of asthma and asthma-related traits following severe RSV bronchiolitis.


Asunto(s)
Asma/genética , Bronquiolitis Viral/genética , Estudios de Asociación Genética , Receptores Adrenérgicos beta 2/genética , Negro o Afroamericano/genética , Asma/complicaciones , Asma/patología , Asma/virología , Bronquiolitis Viral/complicaciones , Bronquiolitis Viral/patología , Antígeno CD56/genética , Niño , Preescolar , Exoma/genética , Femenino , Proteínas Filagrina , Humanos , Lactante , Masculino , Virus Sincitiales Respiratorios/patogenicidad , Proteínas S100/genética , Población Blanca/genética
19.
Acad Radiol ; 21(8): 986-93, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25018070

RESUMEN

RATIONALE AND OBJECTIVES: Previous cross-sectional studies have demonstrated that airway wall thickness and air trapping are greater in subjects with severe asthma than in those with mild-to-moderate asthma. However, a better understanding of how airway remodeling and lung density change over time is needed. This study aimed to evaluate predictors of airway wall remodeling and change in lung function and lung density over time in severe asthma. MATERIALS AND METHODS: Phenotypic characterization and quantitative multidetector-row computed tomography (MDCT) of the chest were performed at baseline and ∼2.6 years later in 38 participants with asthma (severe n = 24 and mild-to-moderate n = 14) and nine normal controls from the Severe Asthma Research Program. RESULTS: Subjects with severe asthma had a significant decline in postbronchodilator forced expiratory volume in 1 second percent (FEV1%) predicted over time (P < .001). Airway wall thickness measured by MDCT was increased at multiple airway generations in severe asthma compared to mild-to-moderate asthma (wall area percent [WA%]: P < .05) and normals (P < .05) at baseline and year 2. Over time, there was an increase in WA% and wall thickness percent (WT%) in all subjects (P = .030 and .009, respectively) with no change in emphysema-like lung or air trapping. Baseline prebronchodilator FEV1% inversely correlated with WA% and WT% (both P < .05). In a multivariable regression model, baseline WA%, race, and health care utilization were predictors of subsequent airway remodeling. CONCLUSIONS: Severe asthma subjects have a greater decline in lung function over time than normal subjects or those with mild-to-moderate asthma. MDCT provides a noninvasive measure of airway wall thickness that may predict subsequent airway remodeling.


Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/diagnóstico por imagen , Enfermedades Bronquiales/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Tomografía Computarizada Multidetector/métodos , Adulto , Asma/complicaciones , Enfermedades Bronquiales/complicaciones , Femenino , Humanos , Estudios Longitudinales , Masculino , Reproducibilidad de los Resultados , Sensibilidad y Especificidad
20.
Bone ; 55(2): 309-14, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23643682

RESUMEN

PURPOSE: Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER+) breast cancer. Bone loss and fractures are well-recognized complications from AI therapy. The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER+ breast cancer. PATIENTS AND METHODS: The subjects consisted of 97 postmenopausal women with ER+ breast cancer who were initiated on third-generation AIs. Bone mineral density (BMD) was measured by dual energy X-ray absorptiometry at baseline and at 6 and 12 months. Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months. Genotyping was done by Taqman SNP allelic discrimination assay. RESULTS: Women with the AA genotype for the rs700518 (G/A at Val(80)) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p = 0.03. There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p = 0.05; but no significant difference in changes in estradiol levels among the genotypes. CONCLUSION: Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy.


Asunto(s)
Inhibidores de la Aromatasa/efectos adversos , Aromatasa/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Osteoporosis/genética , Polimorfismo de Nucleótido Simple , Absorciometría de Fotón , Adulto , Anciano , Anciano de 80 o más Años , Densidad Ósea/genética , Neoplasias de la Mama/tratamiento farmacológico , Colágeno Tipo I/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Osteoporosis/inducido químicamente , Péptidos/sangre , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/genética
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