RESUMEN
BACKGROUND: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models. METHODS: We used genetic studies, RNA sequencing, spatial transcriptome, micro-computed tomography, fluorescence-activated cell sorting, multiplex immunofluorescence, coculture studies, and imaging techniques to reveal that sustained mild hypoxia via the CX3CR1-CX3CL1 (CX3C motif chemokine receptor 1/chemokine [CX3C motif] ligand 1) signaling pathway influences cell-specific neuroinflammatory interactions, contributing to heterogeneity in CCM severity. RESULTS: Histological and expression profiles of CCM neurovascular lesions (Slco1c1-iCreERT2;Pdcd10fl/fl; Pdcd10BECKO) in male and female mice found that sustained mild hypoxia (12% O2, 7 days) accelerates CCM disease. Our findings indicate that a small reduction in oxygen levels can significantly increase angiogenesis, neuroinflammation, and thrombosis in CCM disease by enhancing the interactions between endothelium, astrocytes, and immune cells. Our study indicates that the interactions between CX3CR1 and CX3CL1 are crucial in the maturation of CCM lesions and propensity to CCM immunothrombosis. In particular, this pathway regulates the recruitment and activation of microglia and other immune cells in CCM lesions, which leads to lesion growth and thrombosis. We found that human CX3CR1 variants are linked to lower lesion burden in familial CCMs, proving it is a genetic modifier in human disease and a potential marker for aggressiveness. Moreover, monoclonal blocking antibody against CX3CL1 or reducing 1 copy of the Cx3cr1 gene significantly reduces hypoxia-induced CCM immunothrombosis. CONCLUSIONS: Our study reveals that interactions between CX3CR1 and CX3CL1 can modify CCM neuropathology when lesions are accelerated by environmental hypoxia. Moreover, a hypoxic environment or hypoxia signaling caused by CCM disease influences the balance between neuroinflammation and neuroprotection mediated by CX3CR1-CX3CL1 signaling. These results establish CX3CR1 as a genetic marker for patient stratification and a potential predictor of CCM aggressiveness.
Asunto(s)
Receptor 1 de Quimiocinas CX3C , Quimiocina CX3CL1 , Modelos Animales de Enfermedad , Hemangioma Cavernoso del Sistema Nervioso Central , Transducción de Señal , Animales , Femenino , Humanos , Masculino , Ratones , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/genética , Receptor 1 de Quimiocinas CX3C/genética , Receptor 1 de Quimiocinas CX3C/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/genética , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Hipoxia/metabolismo , Hipoxia/complicaciones , Ratones Endogámicos C57BL , Ratones Noqueados , Neovascularización Patológica/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/genéticaRESUMEN
PURPOSE OF REVIEW: While the use of enteral nutrition (EN) has increased, and more medical centers have developed inpatient programs to address the unique needs of these patients, our collective experience at a few large institutions indicates that there is very little systemic support for patients after discharge. Here, we discuss what we have observed to be some of the barriers to providing outpatient follow up care, summarize the impact we have seen on patients, and propose some possible solutions. RECENT FINDINGS: We have observed and identified some of the root causes to include financial barriers; uncoordinated care transitions; high complexity of care, including medication management; and diffuse leadership to a multidisciplinary problem. Systematic support for outpatient care for patients discharged on enteral nutrition is rare and limited, due to many root causes. There are a few tools and tips that we have summarized here for individual providers, and a few promising methods in development, but a systematic approach is in great need.
Asunto(s)
Nutrición Enteral , Alta del Paciente , Humanos , Pacientes AmbulatoriosRESUMEN
To better understand the challenges of generally implementing and adapting computational phenotyping approaches, the performance of a Phenotype KnowledgeBase (PheKB) algorithm for rheumatoid arthritis (RA) was evaluated on a University of California, Los Angeles (UCLA) patient population, focusing on examining its performance on ambiguous cases. The algorithm was evaluated on a cohort of 4,766 patients, along with a chart review of 300 patients by rheumatologists against accepted diagnostic guidelines. The performance revealed low sensitivity towards specific subtypes of positive RA cases, which suggests revisions in features used for phenotyping. A close examination of select cases also indicated a significant portion of patients with missing data, drawing attention to the need to consider data integrity as an integral part of phenotyping pipelines, as well as issues around the usability of various codes for distinguishing cases. We use patterns in the PheKB algorithm's errors to further demonstrate important considerations when designing a phenotyping algorithm.
Asunto(s)
Artritis Reumatoide , Registros Electrónicos de Salud , Humanos , Algoritmos , Bases del Conocimiento , Fenotipo , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/epidemiologíaRESUMEN
INTRODUCTION/OBJECTIVES: Psychological stress worsens rheumatoid arthritis (RA) disease activity, and the COVID-19 pandemic has increased stress/anxiety in rheumatic patients. The purpose of this study was to determine if stress during the COVID-19 pandemic specifically impacts RA disease activity as reported by the patient. METHOD: This was a cross-sectional COVID-19 RA survey study. University of California, Los Angeles rheumatology clinic patients were emailed a link to a survey in July and November 2020. The 30-question survey pertained to COVID-19-related stress, RA disease activity, and demographics. For the survey responders, anti-cyclic citrullinated antibody, rheumatoid factor, and age were extracted from the electronic health record. Analyses were performed to examine the association between the 4-item Perceived Stress Scale (PSS-4) and other COVID-19-related stress measures with the Routine Assessment of Patient Index Data 3 (RAPID3). RESULTS: A total of 1138/5037 subjects completed the emailed survey (22.6% response rate). When examining responses across RAPID3 categories (near remission, low, moderate, and high disease severity), there were significant increases in PSS-4 and other stress variables. Multiple linear regression models showed that PSS-4, financial stress, age, seropositivity, disease duration, and Black race were independently associated with worsened RAPID3 scores, when controlling for other confounding factors. CONCLUSIONS: This study suggests that stress overall negatively impacts RAPID3, and Black RA patients had a higher RAPID3 scores during the COVID-19 pandemic. Despite colossal efforts to combat the pandemic, RA patients currently suffer from stress/anxiety, and methods to mitigate these psychological effects are needed.
Asunto(s)
Artritis Reumatoide , COVID-19 , Artritis Reumatoide/epidemiología , COVID-19/epidemiología , Estudios Transversales , Humanos , Pandemias , Factor Reumatoide , SARS-CoV-2 , Índice de Severidad de la Enfermedad , Estrés Psicológico/epidemiologíaRESUMEN
Cerebral cavernous malformations (CCMs) are common brain vascular dysplasias that are prone to acute and chronic hemorrhage with significant clinical sequelae. The pathogenesis of recurrent bleeding in CCM is incompletely understood. Here, we show that central nervous system hemorrhage in CCMs is associated with locally elevated expression of the anticoagulant endothelial receptors thrombomodulin (TM) and endothelial protein C receptor (EPCR). TM levels are increased in human CCM lesions, as well as in the plasma of patients with CCMs. In mice, endothelial-specific genetic inactivation of Krit1 (Krit1 ECKO ) or Pdcd10 (Pdcd10 ECKO ), which cause CCM formation, results in increased levels of vascular TM and EPCR, as well as in enhanced generation of activated protein C (APC) on endothelial cells. Increased TM expression is due to upregulation of transcription factors KLF2 and KLF4 consequent to the loss of KRIT1 or PDCD10. Increased TM expression contributes to CCM hemorrhage, because genetic inactivation of 1 or 2 copies of the Thbd gene decreases brain hemorrhage in Pdcd10 ECKO mice. Moreover, administration of blocking antibodies against TM and EPCR significantly reduced CCM hemorrhage in Pdcd10 ECKO mice. Thus, a local increase in the endothelial cofactors that generate anticoagulant APC can contribute to bleeding in CCMs, and plasma soluble TM may represent a biomarker for hemorrhagic risk in CCMs.
Asunto(s)
Anticoagulantes/metabolismo , Proteínas Reguladoras de la Apoptosis/fisiología , Hemorragia Cerebral/diagnóstico , Endotelio Vascular/patología , Hemangioma Cavernoso del Sistema Nervioso Central/complicaciones , Proteína KRIT1/fisiología , Proteínas de la Membrana/fisiología , Proteína C/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Trombomodulina/sangre , Adulto , Animales , Coagulación Sanguínea , Estudios de Casos y Controles , Hemorragia Cerebral/sangre , Hemorragia Cerebral/etiología , Receptor de Proteína C Endotelial/metabolismo , Endotelio Vascular/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/fisiopatología , Humanos , Factor 4 Similar a Kruppel , Ratones , Ratones Noqueados , Transducción de Señal , Adulto JovenRESUMEN
Seemingly mutualistic relationships can be exploited, in some cases reducing fitness of the exploited species. In plants, the insufficient receipt of pollen limits reproduction. While infrequent pollination commonly underlies pollen limitation (PL), frequent interactions with low-efficiency, exploitative pollinators may also cause PL. In the widespread protandrous herb Campanula americana, visitation by three pollinators explained 63% of the variation in PL among populations spanning the range. Bumblebees and the medium-sized Megachile campanulae enhanced reproductive success, but small solitary bees exacerbated PL. To dissect mechanisms behind these relationships, we scored sex-specific floral visitation, and the contributions of each pollinator to plant fitness using single flower visits. Small bees and M. campanulae overvisited male-phase flowers, but bumblebees frequently visited female-phase flowers. Fewer bumblebee visits were required to saturate seed set compared to other bees. Scaling pollinator efficiency metrics to populations, small bees deplete large amounts of pollen due to highly male-biased flower visitation and infrequent pollen deposition. Thus, small bees reduce plant reproduction by limiting pollen available for transfer by efficient pollinators, and appear to exploit the plant-pollinator mutualism, acting as functional parasites to C. americana It is therefore unlikely that small bees will compensate for reproductive failure in C. americana when bumblebees are scarce.
Asunto(s)
Abejas/fisiología , Campanulaceae/fisiología , Polen , Polinización , Simbiosis , Animales , Tamaño Corporal , Flores/fisiología , Especificidad de la EspecieRESUMEN
Drug-induced lupus is an autoimmune phenomenon characterized by the development of systemic lupus erythematosus-like clinical features after drug exposure. The entity is a clinical diagnosis. Evaluation consists of recognizing systemic lupus erythematosus-like features, identifying an appropriate causative agent, observing elevations of characteristic autoantibodies, and obtaining positive response with drug discontinuation. Vedolizumab is an anti-α4ß7 antibody used in the treatment of ulcerative colitis and Crohn's disease. We report a novel case of drug-induced lupus recurrence secondary to vedolizumab use in a patient with Crohn's disease, emphasizing diagnostic evaluation, and provide a brief review of the published literature.
RESUMEN
BACKGROUND: Micronutrient deficiencies associated with malnutrition in patients with inflammatory bowel disease (IBD) can lead to complications including anemia, coagulopathy, poor wound healing, and colorectal cancer. This study aimed to investigate micronutrient deficiencies (copper, vitamins A, B9, E, and K) in IBD patients and highlight associated symptoms to aid in the recognition of micronutrient deficiencies. METHODS: A retrospective electronic chart review was performed on adults diagnosed with Crohn's disease or ulcerative colitis hospitalized at a tertiary care center for IBD flare between January 2013 and June 2017. Patients with serum or whole blood micronutrient levels were included. Pregnant and incarcerated patients were excluded. RESULTS: A total of 611 IBD patients (440 Crohn's disease, 171 ulcerative colitis) met the inclusion criteria. Micronutrients were assessed in a subset of IBD patients (copper: 12.3%, A: 10.1%, B9â :â 95.9%, E: 10.3%, and K: 4.6%). Overall, 10.1% of patients had micronutrient deficiencies. The proportion of patients with copper, A, B9, E, and K deficiencies were 25.4, 53.3, 1.9, 23.7, and 29.4% for Crohn's disease and 50, 52.9, 1.2, 43.8, and 18.2% for ulcerative colitis, respectively. The most common symptoms or historical features associated with micronutrient deficiency were anemia (copper, B9), muscle weakness (copper, E) thrombocytopenia, fatigue (copper, B9), diarrhea (B9), dry skin, hyperkeratosis, pruritus, significant weight loss, elevated C-reactive protein (A), bleeding, and osteoporosis (K). CONCLUSION: Micronutrient deficiencies are common in IBD patients, yet they are not routinely assessed. Copper, vitamins A, E, and K deficiencies are particularly underrecognized. Associated historical features should raise suspicion and prompt assessment and treatment.
RESUMEN
BACKGROUND AND OBJECTIVE: Colonic dysbiosis contributes to the development of colonic inflammation in ulcerative colitis (UC). Fecal microbial transplantation (FMT) is being proposed as a novel treatment for UC because it can eliminate dysbiosis; however, no prospective data exist. We initiated a pilot study to evaluate feasibility and safety of FMT in children with UC. METHODS: Ten children, 7 to 21 years of age, with mild-to-moderate UC (pediatric UC activity index [PUCAI] between 15 and 65) received freshly prepared fecal enemas daily for 5 days. Data on tolerability, adverse events, and disease activity were collected during FMT and weekly for 4 weeks after FMT. Clinical response was defined as decrease in PUCAI by >15, and decrease in PUCAI to <10 was considered clinical remission. RESULTS: No serious adverse events were noted. Mild (cramping, fullness, flatulence, bloating, diarrhea, and blood in stool) to moderate (fever) adverse events were self-limiting. One subject could not retain fecal enemas. Average tolerated enema volume by remaining 9 subjects was 165 mL/day. After FMT, 7 of the 9 (78%) subjects showed clinical response within 1 week, 6 of the 9 (67%) subjects maintained clinical response at 1 month, and 3 of the 9 (33%) subjects achieved clinical remission at 1 week after FMT. Median PUCAI significantly improved after FMT (P = 0.03) compared with the baseline. CONCLUSIONS: Fecal enemas were feasible and tolerated by children with UC. Adverse events were acceptable, self-limiting, and manageable by subjects. FMT indicated efficacy in the treatment of UC.
Asunto(s)
Terapia Biológica , Colitis Ulcerosa/terapia , Disbiosis/prevención & control , Heces/microbiología , Terapias en Investigación , Administración Rectal , Adolescente , Adulto , Terapia Biológica/efectos adversos , Niño , Colitis Ulcerosa/microbiología , Colitis Ulcerosa/fisiopatología , Selección de Donante , Disbiosis/etiología , Familia , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Hospitales Pediátricos , Humanos , Masculino , Michigan , Servicio Ambulatorio en Hospital , Proyectos Piloto , Inducción de Remisión , Índice de Severidad de la Enfermedad , Terapias en Investigación/efectos adversos , Adulto JovenRESUMEN
Achalasia is primarily a smooth muscle motility disorder of the esophagus driven by aberrant peristalsis and failure of sphincter relaxation. Notably, achalasia is a heterogeneous disease with primarily 3 possible pattern subtypes. According to the review of current cases and literature regarding achalasia, patients primarily present with dysphagia, usually to solids and, if progressed, to solids and liquids. Rarely, untreated achalasia may result in thiamine deficiency and present as Wernicke-Korsakoff syndrome (WKS). This acute neurologic condition primarily affects the central and peripheral nervous system and is known by the triad of ataxia, ophthalmoplegia, and confusion. Individuals who present with WKS typically have a notable history of chronic alcohol abuse with decreased thiamine intake and metabolism. Although less common, individuals with WKS may have a pertinent history of starvation, anorexia nervosa, and malnutrition. This case highlights a unique presentation of Wernicke's encephalopathy (WE) in a 30-year-old woman with severe type II achalasia complicated by a 60-pound weight loss in a span of 2 months. According to our literature review, there have only been 2 previously reported cases of severe achalasia leading to the development of WE. Considering the limited number of case reports available, WE must be in the differentials in patients with underlying achalasia, and our case report highlights this unusual presentation with corresponding brain imaging and manometry testing.
Asunto(s)
Alcoholismo , Acalasia del Esófago , Deficiencia de Tiamina , Encefalopatía de Wernicke , Femenino , Humanos , Adulto , Encefalopatía de Wernicke/etiología , Encefalopatía de Wernicke/complicaciones , Tiamina/uso terapéutico , Acalasia del Esófago/complicaciones , Acalasia del Esófago/diagnóstico , Deficiencia de Tiamina/complicaciones , Alcoholismo/complicaciones , Enfermedad AgudaRESUMEN
Background and Aims: Late adolescents and young adults (AYA) with inflammatory bowel disease (IBD) are a vulnerable population as they transition to adult healthcare. We aim to provide a real-world data on their healthcare utilization patterns and medication use through a large database. Methods: We performed a retrospective cohort study from January 1, 2012, to June 30, 2020, using OneFlorida Data-Trust, an electronic health record-based data repository representing over half of the Florida population. Outcomes of interest included demographics, healthcare utilization, medications, and disease severity. Chi-square tests and logistic regression were used to compare the rates of medication use, healthcare utilization, and disease severity by age groups. Results: The number of patients who met our inclusion criteria was 10,578 with 2731 (25.8%) in the 17-25-year-old group. AYA patients had fewer ambulatory visits vs children (90% vs 95%; P value <.05). AYA patients were admitted more frequently from emergency facilities vs children (22.3% vs 10.9%; P value <.05). AYA patients received steroids more often than adults and younger patients (48.9% vs 45.3 vs 44.3% P value <.05, respectively). AYA patients received more narcotic (41.1% vs 22.3 % P value <.05) and antidepressant prescriptions (15.9% vs 9.5%; P value <.05) compared with children. With advancing age, a decrease in biologic use was noted (51% vs 40% vs 25.4% P value <.05, respectively). Conclusion: AYA patients with IBD have higher rates of hospital admissions from emergency department, fewer ambulatory health visits and they receive more steroids compared to children. Our study demonstrates the need for age-specific IBD programs for AYA patients.
RESUMEN
BACKGROUND: Limited evidence is available to describe the prevalence, causes, and consequences of zinc and vitamin B6 deficiencies in those with acutely exacerbated inflammatory bowel disease (IBD). Zinc is important for immune function and wound healing, and B6 is needed for metabolic and neurological function. Patients with IBD are at risk of micronutrient deficiencies, particularly during flares. PRESENTATIONS: The cases of 2 patients with IBD exacerbations were reviewed in which deficiencies of both zinc and vitamin B6 were identified. CONCLUSIONS: These cases highlight the need for increased screening for zinc and pyridoxine deficiencies in IBD population, especially during disease exacerbation. Therefore, we recommend a comprehensive nutrition workup with physical exam, diet history, and a complete micronutrient panel while ruling out contributing factors. If patients are susceptible to deficiencies during flares, prophylactic oral zinc and pyridoxine supplementation may be considered, with close monitoring for subsequent iron and copper deficiencies.
Asunto(s)
Enfermedades Inflamatorias del Intestino , Zinc , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Micronutrientes , Piridoxina/uso terapéutico , Vitamina B 6 , VitaminasRESUMEN
BACKGROUND: Very early-onset inflammatory bowel disease (VEO-IBD) secondary to interleukin 10 receptor A (IL-10RA) mutations has aggressive disease courses with increased nutrition needs compared with those in other monogenic forms of IBD. PRESENTATION: A male patient was hospitalized when he was 18 days old for bloody diarrhea, which was diagnosed as Crohn's disease at 6 months old. He showed failure to thrive (FTT) and worsening inflammation while receiving enteral nutrition (EN) and standard IBD treatment. He was hospitalized in 2016, at 28 years old, for a Crohn's flare when sequencing confirmed a heterozygous mutation in IL10-RA. His weight and plasma micronutrient levels improved when he transitioned to parenteral nutrition (PN). He was initiated on anakinra while awaiting hematopoietic stem cell transplant, with substantial decrease in inflammation. He was able to gain weight, initiate an oral diet, and decrease his PN requirement. CONCLUSION: Our patient experienced progressive FTT while receiving EN. VEO-IBD incidence is rising, and its diagnosis is often delayed. Therefore, prompt recognition with treatment initiation is essential to improving nutrition outcomes in this patient population. Further investigation is warranted to determine whether these patients would benefit from early initiation of PN.
Asunto(s)
Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Adulto , Enfermedad de Crohn/complicaciones , Insuficiencia de Crecimiento/complicaciones , Humanos , Lactante , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/terapia , Masculino , Mutación , Receptores de Interleucina-10/genéticaRESUMEN
Carnitine is an essential cofactor for fatty acid metabolism. Deficiencies can be associated with muscle weakness, fatigue, weight loss, and cardiomyopathies. A 27-year-old woman with short bowel syndrome (SBS) presented with significant weight loss, fatigue, and muscle wasting despite adequate parenteral nutrition. Her laboratory test results revealed carnitine deficiency secondary to malnutrition. Levocarnitine supplementation was initiated with normalization of her carnitine levels. Her fatigue improved, and her weight returned to baseline. Carnitine deficiencies are seldomly reported in adults, particularly those with SBS. Carnitine deficiency should be suspected and corrected in patients with SBS and malabsorptive capacity due to surgical resection.
RESUMEN
BACKGROUND: Longer hospice length of stay improves the palliation of symptoms, quality of life, and the dying process for patients and their caregivers. We used a Lean designed Rapid Improvement Event (RIE) to facilitate earlier entry into hospice. MEASURES: Our primary outcome was hospice length of stay. Secondary outcomes were avoiding unwanted inpatient utilization and hospice location. INTERVENTIONS: We conducted a five-day RIE utilizing Lean tools targeting the inpatient medicine wards. OUTCOMES: Hospice length of stay increased from a median (interquartile range [IQR]) of 11 (7,27) days prior to 37 (7,73) days following the RIE. Home hospice and outside Skilled Nursing Home (SNF) hospice use increased while use of the onsite VA hospice decreased. CONCLUSIONS/LESSONS LEARNED: LEAN tools can be used successfully to improve end of life outcomes in an inpatient VA setting. The 90-day sustainment period following the RIE uncovers barriers to implementation and allows for adjustments to implementation.
Asunto(s)
Cuidados Paliativos al Final de la Vida , Hospitales para Enfermos Terminales , Veteranos , Humanos , Cuidados Paliativos , Calidad de VidaRESUMEN
Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1α in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.
Asunto(s)
Astrocitos/fisiología , Hemangioma Cavernoso del Sistema Nervioso Central/fisiopatología , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Reguladoras de la Apoptosis/genética , Astrocitos/patología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Células Endoteliales/metabolismo , Hemangioma Cavernoso del Sistema Nervioso Central/etiología , Hemangioma Cavernoso del Sistema Nervioso Central/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Factor 4 Similar a Kruppel , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones , Ratones Noqueados , Modelos Neurológicos , Mutación , Óxido Nítrico/biosíntesis , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor A de Crecimiento Endotelial Vascular/biosíntesisRESUMEN
Poly- and per-fluoroalkyl substances (PFAS) have attracted widespread attention in recent years due to their bioaccumulation, toxicity, and ubiquitous nature. We and others have reported that maternal exposure to PFAS is associated with adverse birth outcomes due to altered placental functions. In this study, we investigated the effects of two major PFAS compounds, perfluorobutane sulfonate (PFBS) and perfluorooctanesulfonic acid (PFOS), on the regulation of the production of angiogenic factors and stress response in placental multinucleated syncytial BeWo cells using qRT-PCR and ELISA. Using this in vitro model, we showed that 1) PFOS or PFBS treatment did not seem to interrupt BeWo cell fusion through syncytins; 2) Exposure to PFOS at 10⯵M decreased a potent angiogenic factor PlGF gene expression, which is implicated in preeclampsia; 3) Exposure to either PFOS or PFBS significantly decreased the production of CGB7 and hCG except hCG secretion in PFOS (10â¯nM) and PFBS (100â¯nM) treatment groups; 4) Exposure to PFOS (10⯵M) increased the gene expression of the stress response molecules CRH while neither PFOS nor PFBS treatment affected a stress mitigation factor 11ß-HSD2 expression. Our results demonstrate that exposure to PFOS or PFBS impacts several key pathways involved in placental cell functions. PFOS seems more potent than PFBS. These novel findings provide a potential explanation for the adverse reproductive complications associated with prenatal exposure to PFOS or PFBS, including preeclampsia and contribute to our knowledge of the reproductive toxicity of PFAS, specifically PFOS and PFBS.
Asunto(s)
Ácidos Alcanesulfónicos/toxicidad , Contaminantes Ambientales/toxicidad , Fluorocarburos/toxicidad , Ácidos Sulfónicos/toxicidad , Trofoblastos/efectos de los fármacos , Línea Celular Tumoral , Gonadotropina Coriónica/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Femenino , Productos del Gen env/genética , Humanos , Factor de Crecimiento Placentario/genética , Embarazo , Proteínas Gestacionales/genética , Estrés Fisiológico , Trofoblastos/metabolismo , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genéticaRESUMEN
Introduction: The social impact of inflammatory bowel disease (IBD) on student transition to college is significant, yet poorly understood. Methods: Two 90-min focus groups (FGs) were conducted with eight student-patients with IBD. Reflective journals were used to corroborate, elaborate, or challenge emergent FG findings. Results: Six themes emerged: (1) transitioning to college, (2) interacting with physicians, (3) affecting social life, (4) managing the disease by yourself and through support, (5) coping strategies, and (6) facing disease challenges. These themes remained relevant in the reflective writings. Analysis of serial journal entries showed that students' social life and engagement in coursework was affected 66% and 54% of the time, respectively. Conclusion: Our findings offer guidance for improving students' college success, quality of care, and enhancing physician-patient interactions. Students with IBD have a disability that may not be obvious or visible. They require specific support to help them transition and succeed in college.
RESUMEN
Chronic pancreatitis is a syndrome involving inflammation, fibrosis, and loss of acinar and islet cells which can manifest in unrelenting abdominal pain, malnutrition, and exocrine and endocrine insufficiency. The Toxic-Metabolic, Idiopathic, Genetic, Autoimmune, Recurrent and Severe Acute Pancreatitis, Obstructive (TIGAR-O) classification system categorizes known causes and factors that contribute to chronic pancreatitis. Although determining disease etiology provides a framework for focused and specific treatments, chronic pancreatitis remains a challenging condition to treat owing to the often refractory, centrally mediated pain and the lack of consensus regarding when endoscopic therapy and surgery are indicated. Further complications incurred include both exocrine and endocrine pancreatic insufficiency, pseudocyst formation, bile duct obstruction, and pancreatic cancer. Medical treatment of chronic pancreatitis involves controlling pain, addressing malnutrition via the treatment of vitamin and mineral deficiencies and recognizing the risk of osteoporosis, and administering appropriate pancreatic enzyme supplementation and diabetic agents. Cornerstones in treatment include the recognition of pancreatic exocrine insufficiency and administration of pancreatic enzyme replacement therapy, support to cease smoking and alcohol consumption, consultation with a dietitian, and a systematic follow-up to assure optimal treatment effect.