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OBJECTIVE: Recent evidence suggests that the fimbriated end of the fallopian tube harbors the precursor cells for many high-grade ovarian cancers, opening the door for development of better screening methods that directly assess the fallopian tube in women at risk for malignancy. Previously we have shown that the karyometric signature is abnormal in the fallopian tube epithelium in women at hereditary risk of ovarian cancer. In this study, we sought to determine whether the karyometric signature in serous tubal intraepithelial carcinoma (STIC) is significantly different from normal, and whether an abnormal karyometric signature can be detected in histologically normal tubal epithelial cells adjacent to STIC lesions. METHODS: The karyometric signature was measured in epithelial cells from the proximal and fimbriated portion of the fallopian tube in fallopian tube specimens removed from women at: 1) average risk for ovarian cancer undergoing surgery for benign gynecologic indications (n = 37), 2) hereditary risk of ovarian cancer (germline BRCA alterations) undergoing risk-reducing surgery (n = 44), and 3) diagnosed with fimbrial STICs (n = 17). RESULTS: The karyometric signature in tubes with fimbrial STICs differed from that of tubes with benign histology. The degree of karyometric alteration increased with increasing proximity to fimbrial STICs, ranging from moderate in the proximal portion of the tube, to greatest in both normal appearing fimbrial cells near STICs as well as in fimbrial STIC lesions. CONCLUSION: These data demonstrate an abnormal karyometric signature in STICs that may extend beyond the STIC, potentially providing an opportunity for early detection of fallopian tube neoplasia.
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Carcinoma in Situ , Neoplasias de las Trompas Uterinas , Trompas Uterinas , Humanos , Femenino , Neoplasias de las Trompas Uterinas/patología , Neoplasias de las Trompas Uterinas/genética , Carcinoma in Situ/patología , Carcinoma in Situ/genética , Trompas Uterinas/patología , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/genética , Persona de Mediana Edad , Adulto , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , CariotipoRESUMEN
Patients with cancer have the unique ability of being able to offer valuable insights into how cancer therapeutics may impact the overall patient experience and improve clinical outcomes. Patient engagement could therefore contribute to tailoring treatment strategies and research design according to patient needs. This study evaluated patient engagement in prostate cancer research by identifying patient input in the prostate cancer literature. We performed a keyword cluster analysis of articles from multiple databases and congresses in which patients provided input on disease management or were involved in study design, manuscript authorship or presentation of results (patient voice). In total, 112 studies were included. Patients were involved in the design of 11 studies and were credited as authors in four studies. This review suggests a lack of meaningful patient involvement in prostate cancer research and publications.
Patients with cancer have first-hand knowledge of what does and does not work for their care. Therefore, their voice is valuable to help improve treatment and guide research. Our goal was to find prostate cancer articles with patient input. We searched databases using keywords related to patient voice. We looked for articles involving patients in designing, writing or presenting the study. Only four out of the 112 articles we identified were published in journals focused on involving patients. Eleven articles involved patients in designing the study. Four articles involved patients in writing the published work. Overall, we did not find many articles where patients had a meaningful role in the study. Prostate cancer treatment and research will likely benefit from more patient input.
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Obesity has become a growing global epidemic, demanding effective solutions for its management. Bariatric-metabolic surgery is currently the best therapeutic option for patients with morbid obesity and associated comorbidities. This review article addresses the importance of endoscopy in the preoperative and postoperative evaluation, as well as in the detection and management of complications associated with bariatric surgery.
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Cirugía Bariátrica , Obesidad Mórbida , Complicaciones Posoperatorias , Humanos , Cirugía Bariátrica/métodos , Cirugía Bariátrica/efectos adversos , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/diagnóstico , Obesidad Mórbida/cirugía , Obesidad Mórbida/complicaciones , Endoscopía Gastrointestinal/métodos , Resultado del TratamientoRESUMEN
AIMS/HYPOTHESIS: There is a lack of e-health systems that integrate the complex variety of aspects relevant for diabetes self-management. We developed and field-tested an e-health system (POWER2DM) that integrates medical, psychological and behavioural aspects and connected wearables to support patients and healthcare professionals in shared decision making and diabetes self-management. METHODS: Participants with type 1 or type 2 diabetes (aged >18 years) from hospital outpatient diabetes clinics in the Netherlands and Spain were randomised using randomisation software to POWER2DM or usual care for 37 weeks. This RCT assessed the change in HbA1c between the POWER2DM and usual care groups at the end of the study (37 weeks) as a primary outcome measure. Participants and clinicians were not blinded to the intervention. Changes in quality of life (QoL) (WHO-5 Well-Being Index [WHO-5]), diabetes self-management (Diabetes Self-Management Questionnaire - Revised [DSMQ-R]), glycaemic profiles from continuous glucose monitoring devices, awareness of hypoglycaemia (Clarke hypoglycaemia unawareness instrument), incidence of hypoglycaemic episodes and technology acceptance were secondary outcome measures. Additionally, sub-analyses were performed for participants with type 1 and type 2 diabetes separately. RESULTS: A total of 226 participants participated in the trial (108 with type 1 diabetes; 118 with type 2 diabetes). In the POWER2DM group (n=111), HbA1c decreased from 60.6±14.7 mmol/mol (7.7±1.3%) to 56.7±12.1 mmol/mol (7.3±1.1%) (means ± SD, p<0.001), compared with no change in the usual care group (n=115) (baseline: 61.7±13.7 mmol/mol, 7.8±1.3%; end of study: 61.0±12.4 mmol/mol, 7.7±1.1%; p=0.19) (between-group difference 0.24%, p=0.008). In the sub-analyses in the POWER2DM group, HbA1c in participants with type 2 diabetes decreased from 62.3±17.3 mmol/mol (7.9±1.6%) to 54.3±11.1 mmol/mol (7.1±1.0%) (p<0.001) compared with no change in HbA1c in participants with type 1 diabetes (baseline: 58.8±11.2 mmol/mol [7.5±1.0%]; end of study: 59.2±12.7 mmol/mol [7.6±1.2%]; p=0.84). There was an increase in the time during which interstitial glucose levels were between 3.0 and 3.9 mmol/l in the POWER2DM group, but no increase in clinically relevant hypoglycaemia (interstitial glucose level below 3.0 mmol/l). QoL improved in participants with type 1 diabetes in the POWER2DM group compared with the usual care group (baseline: 15.7±3.8; end of study: 16.3±3.5; p=0.047 for between-group difference). Diabetes self-management improved in both participants with type 1 diabetes (from 7.3±1.2 to 7.7±1.2; p=0.002) and those with type 2 diabetes (from 6.5±1.3 to 6.7±1.3; p=0.003) within the POWER2DM group. The POWER2DM integrated e-health support was well accepted in daily life and no important adverse (or unexpected) effects or side effects were observed. CONCLUSIONS/INTERPRETATION: POWER2DM improves HbA1c levels compared with usual care in those with type 2 diabetes, improves QoL in those with type 1 diabetes, improves diabetes self-management in those with type 1 and type 2 diabetes, and is well accepted in daily life. TRIAL REGISTRATION: ClinicalTrials.gov NCT03588104. FUNDING: This study was funded by the European Union's Horizon 2020 Research and Innovation Programme (grant agreement number 689444).
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Hipoglucemia , Automanejo , Telemedicina , Humanos , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Calidad de Vida , Automonitorización de la Glucosa Sanguínea , Glucemia , Toma de Decisiones Conjunta , Hipoglucemia/tratamiento farmacológico , Hipoglucemiantes/uso terapéuticoRESUMEN
High levels of the amyloid-beta (Aß) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aß-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aß accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aß, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aß accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aß-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.
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Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Corteza Entorrinal/metabolismo , Tauopatías/genética , Proteínas tau/genética , Potenciales de Acción/fisiología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animales de Enfermedad , Electrodos Implantados , Corteza Entorrinal/patología , Femenino , Regulación de la Expresión Génica , Vectores Genéticos/química , Vectores Genéticos/metabolismo , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismo , Neuronas/patología , Agregado de Proteínas , Técnicas Estereotáxicas , Tauopatías/metabolismo , Tauopatías/patología , Tauopatías/terapia , Ritmo Teta/fisiología , Transducción Genética , Transgenes , Proteínas tau/metabolismoRESUMEN
We report hematology and biochemistry reference intervals (RI) for the critically endangered Cuban crocodile (Crocodylus rhombifer). In November 2019, we sampled 43 adult crocodiles (6 male, 37 female) under human care at the Zapata Swamp Crocodile Farm in Matanzas, Cuba. These crocodiles are part of a breeding program for the species registered by the Convention on International Trade in Endangered Species (CITES). Visual health evaluations were performed immediately after manual restraint, and blood was collected from the postoccipital sinus. We performed packed cell volume (PCV), total solids (TS), complete blood counts (CBC), and biochemistry profiles for each crocodile on the day of sampling. Mean PCV (n = 42) was 21.1 ± 5.0% and TS (n = 42) 7.3 ± 1.2 mg/dl, respectively. Absolute white blood cell (WBC) (n = 40) was 9.6 ± 5.7 ï½ 109/L. Similar to other crocodilian species, the dominant leukocyte was lymphocytes (70.7 ± 10.4%), followed by heterophils (18.7 ± 9.7%). Two of the crocodiles had a high heterophil:lymphocyte ratio (0.87 and 0.74), although on visual exam they were both considered healthy. The range of creatine kinase was 41-1,482 U/L, and the higher values may be a reflection of muscle exertion at time of handling. Limitations to the study included skewed sex ratios and high lipemia and hemolysis in most samples collected. These are the first reference intervals reported for this species, including the first descriptions of WBC morphology. These data are valuable for the management of animals at the Zapata Swamp Crocodile Farm, for comparison with free-living Cuban crocodiles in Cuba, and for comparison with those managed under human care outside of Cuba.
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Caimanes y Cocodrilos , Hematología , Humanos , Masculino , Animales , Femenino , Cuba , Comercio , Granjas , InternacionalidadRESUMEN
BACKGROUND: Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels. OBJECTIVE: We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes. STUDY DESIGN: Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy. RESULTS: Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones. CONCLUSION: Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.
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Neoplasias Ováricas , Salpingooforectomía , Estradiol , Femenino , Hormonas Esteroides Gonadales , Humanos , Neoplasias Ováricas/prevención & control , Posmenopausia , Estudios ProspectivosRESUMEN
OBJECTIVES: Lymphangioleiomyomatosis (LAM) patients with severe lung disease may be considered for lung transplantation. Clinical, physiologic, and quality of life data are usually employed for referral. The aim of this study was to determine whether computed tomographic measurement of lung volume occupied by cysts (cyst score) complemented clinical and physiologic data in supporting referral for transplantation. METHODS: Forty-one patients were studied. Pre-referral clinical data, pulmonary function tests, exercise testing, and high-resolution computed tomography (HRCT) scans were obtained. From HRCT, a computer-aided diagnostic program was employed to calculate cyst scores. These data were compared to those of 41 age-matched LAM patients not referred for lung transplantation. RESULTS: Cyst score, and % predicted FEV1 and DLCO were respectively, 48.1 ± 9.4%, 36.5 ± 9.1%, and 35.0 ± 10.7%. For the control group, cyst score, FEV1, and DLCO were respectively, 14.8 ± 8.3%, 77.2 ± 20.3%, and 66.7 ± 19.3%. Cyst score values showed a normal distribution. However, the frequency distribution of FEV1 was skewed to the right while the distribution of DLCO was bimodal. Correlations between cyst score and FEV1 and DLCO for the study group were respectively, r = - 0.319 and r = - 0.421. CONCLUSIONS: LAM patients referred for lung transplantation had nearly 50% of lungs occupied by cysts. Correlations between cyst score and FEV1 or DLCO were weak; as shown previously, DLCO was better related to cyst number while FEV1 had a better association with cyst size. Given its normal distribution, cyst score measurements may assist in evaluation of pre-transplant severity of lung disease before referral for transplantation.
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Quistes , Enfermedades Pulmonares , Neoplasias Pulmonares , Linfangioleiomiomatosis , Computadores , Quistes/diagnóstico por imagen , Humanos , Pulmón/diagnóstico por imagen , Neoplasias Pulmonares/complicaciones , Linfangioleiomiomatosis/complicaciones , Linfangioleiomiomatosis/diagnóstico por imagen , Calidad de Vida , Derivación y Consulta , Índice de Severidad de la EnfermedadRESUMEN
Most wastewater treatment facilities are built using procedures from previous designs which are predominantly from sites and regions not located at high elevation. Recognizing this limitation, we assessed the effects of elevation above sea level on the suitability of process configurations and technologies as well as their associated energy costs. Using the International Water Association (IWA) benchmark simulation model No. 2 (modified Ludzack-Ettinger process layout) as a reference, we simulated scenarios including different activated sludge process configurations, operating under different environmental and process conditions. In order to include a wide sample of environmental conditions, data on atmospheric pressure, wastewater temperature, air temperature, and relative humidity (for average, warmest, and coldest months) were collected from municipal wastewater treatment plants located at different latitudes and elevations. The results confirm that elevation is a driver against the selection of diffused aeration technologies. Aeration costs for aerobic wastewater treatment are highly influenced by local project conditions, particularly by elevation and wastewater temperature, which together influence the driving force for oxygen transfer into water. When the driving force is low, operating costs are high. Recommendations for designing treatment processes effectively, including diffused aeration systems operating at high elevations above sea level, are proposed.
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Eliminación de Residuos Líquidos , Purificación del Agua , Reactores Biológicos , Oxígeno , Aguas del Alcantarillado , Aguas ResidualesRESUMEN
Heterosis occurs when the F1s outperform their parental lines for a trait. Reciprocal hybrids are obtained by changing the cross direction of parental genotypes. Both biological phenomena could affect the external and internal attributes of fleshy fruits. This work aimed to detect reciprocal effects and heterosis in tomato (Solanum lycopersicum) fruit quality traits and metabolite content. Twelve agronomic traits and 28 metabolites identified and estimated by 1H-NMR were evaluated in five cultivars grown in two environments. Given that the genotype component was more important than the phenotype, the traits were evaluated following a full diallel mating design among those cultivars, in a greenhouse. Hybrids showed a higher phenotypic diversity than parental lines. Interestingly, the metabolites, mainly amino acids, displayed more reciprocal effects and heterosis. Agronomic traits were more influenced by general combining ability (GCA) and metabolites by specific combining ability (SCA). Furthermore, the genetic distance between parental lines was not causally related to the occurrence of reciprocal effects or heterosis. Hybrids with heterosis and a high content of metabolites linked to tomato flavour and nutritious components were obtained. Our results highlight the impact of selecting a cultivar as male or female in a cross to enhance the variability of fruit attributes through hybrids as well as the possibility to exploit heterosis for fruit composition.
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Vigor Híbrido , Solanum lycopersicum , Cruzamientos Genéticos , Frutas/genética , Vigor Híbrido/genética , Solanum lycopersicum/genética , FenotipoRESUMEN
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease with mortality driven primarily by respiratory failure. Patients with LAM frequently have respiratory infections, suggestive of a dysregulated microbiome. Here we demonstrate that end-stage LAM patients have a distinct microbiome signature compared to patients with end-stage chronic obstructive pulmonary disease.
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Pulmón/microbiología , Linfangioleiomiomatosis/microbiología , Microbiota , Enfermedad Pulmonar Obstructiva Crónica/microbiología , Infecciones del Sistema Respiratorio/microbiología , Progresión de la Enfermedad , Disbiosis , Humanos , Enfermedades Pulmonares Fúngicas/diagnóstico , Enfermedades Pulmonares Fúngicas/microbiología , Linfangioleiomiomatosis/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Infecciones del Sistema Respiratorio/diagnóstico , RibotipificaciónRESUMEN
OBJECTIVE: Molecular tumor profiling and next-generation sequencing are being increasingly utilized, but there are limited data on the therapeutic implications and potential benefits of targeted treatments. We aim to characterize gynecologic oncology patients referred for somatic tumor genetic mutation testing and assess survival outcomes, efficacy, and toxicities of those receiving targeted therapy. METHODS: We conducted a retrospective chart review of gynecologic oncology patients referred for somatic tumor testing by next generation sequencing between 1/1/2012-8/23/2019. The primary objective was to compare overall and progression free survival between those treated with targeted therapy (group 1) versus traditional treatment (group 2). RESULTS: Most patients (70%) had additional treatment options available based on actionable mutations. The median number of somatic mutations identified was 5 (range 0-53). Patients in group 1 had more actionable somatic mutations (median 2 versus 0, p < 0.001). There was no difference in OS (median 64 versus 76 months, p = 0.97) or PFS (median 2 versus 8 months, p = 0.05) between the groups. While fewer patients in group 1 experienced neuropathy (0 versus 5, p = 0.02), grade I/II thrombocytopenia (7 versus 13, p = 0.03), grade III/IV thrombocytopenia (0 versus 4, p = 0.02), and grade III/IV neutropenia (1 versus 9, p = 0.002), all other non-hematologic toxicities were similar in the two groups. CONCLUSIONS: Most gynecologic cancer patients have actionable mutations and may benefit from a personalized targeted therapy treatment plan. Next generation sequencing can be used to identify clinically actionable mutations in gynecologic cancers and guide the selection of treatments, thereby expanding treatment options without worsening survival or toxicity.
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Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de los Genitales Femeninos/tratamiento farmacológico , Secuenciación de Nucleótidos de Alto Rendimiento , Anciano , Antineoplásicos/farmacología , Biomarcadores de Tumor/antagonistas & inhibidores , Análisis Mutacional de ADN/métodos , Femenino , Pruebas Genéticas , Neoplasias de los Genitales Femeninos/genética , Neoplasias de los Genitales Femeninos/mortalidad , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Mutación , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Neutropenia/prevención & control , Planificación de Atención al Paciente , Medicina de Precisión/métodos , Supervivencia sin Progresión , Estudios Retrospectivos , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Trombocitopenia/prevención & controlRESUMEN
KEY MESSAGE: Reciprocal effects were found for tomato fruit quality and DNA methylation. The epigenetic identity of reciprocal hybrids indicates that DNA methylation might be one of the mechanisms involved in POEs. Crosses between different genotypes and even between different species are commonly used in plant breeding programs. Reciprocal hybrids are obtained by changing the cross direction (or the sexual role) of parental genotypes in a cross. Phenotypic differences between these hybrids constitute reciprocal effects (REs). The aim of this study was to evaluate phenotypic differences in tomato fruit traits and DNA methylation profiles in three inter- and intraspecific reciprocal crosses. REs were detected for 13 of the 16 fruit traits analyzed. The number of traits with REs was the lowest in the interspecific cross, whereas the highest was found in the cross between recombinant inbred lines (RILs) derived from the same interspecific cross. An extension of gene action analysis was proposed to incorporate parent-of-origin effects (POEs). Maternal and paternal dominance were found in four fruit traits. REs and paternal inheritance were found for epiloci located at coding and non-coding regions. The epigenetic identity displayed by the reciprocal hybrids accounts for the phenotypic differences among them, indicating that DNA methylation might be one of the mechanisms involved in POEs.
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Metilación de ADN , Frutas/fisiología , Solanum lycopersicum/fisiología , Quimera , Cruzamientos Genéticos , Calidad de los Alimentos , Frutas/genética , Regulación de la Expresión Génica de las Plantas , Genotipo , Solanum lycopersicum/genética , Fenotipo , Fitomejoramiento , Polimorfismo GenéticoRESUMEN
Lymphangioleiomyomatosis (LAM), a rare disease of women, is associated with cystic lung destruction resulting from the proliferation of abnormal smooth muscle-like LAM cells with mutations in the tuberous sclerosis complex (TSC) genes TSC1 and/or TSC2 The mutant genes and encoded proteins are responsible for activation of the mechanistic target of rapamycin (mTOR), which is inhibited by sirolimus (rapamycin), a drug used to treat LAM. Patients who have LAM may also be treated with bronchodilators for asthma-like symptoms due to LAM. We observed stabilization of forced expiratory volume in 1 s over time in patients receiving sirolimus and long-acting beta-agonists with short-acting rescue inhalers compared with patients receiving only sirolimus. Because beta-agonists increase cAMP and PKA activity, we investigated effects of PKA activation on the mTOR pathway. Human skin TSC2+/- fibroblasts or LAM lung cells incubated short-term with isoproterenol (beta-agonist) showed a sirolimus-independent increase in phosphorylation of S6, a downstream effector of the mTOR pathway, and increased cell growth. Cells incubated long-term with isoproterenol, which may lead to beta-adrenergic receptor desensitization, did not show increased S6 phosphorylation. Inhibition of PKA blocked the isoproterenol effect on S6 phosphorylation. Thus, activation of PKA by beta-agonists increased phospho-S6 independent of mTOR, an effect abrogated by beta-agonist-driven receptor desensitization. In agreement, retrospective clinical data from patients with LAM suggested that a combination of bronchodilators in conjunction with sirolimus may be preferable to sirolimus alone for stabilization of pulmonary function.
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Agonistas Adrenérgicos beta/farmacología , Linfangioleiomiomatosis/tratamiento farmacológico , Linfangioleiomiomatosis/metabolismo , Proteínas Supresoras de Tumor/genética , Adulto , Anciano , Broncodilatadores/farmacología , Dominio Catalítico , Proliferación Celular/efectos de los fármacos , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Progresión de la Enfermedad , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Humanos , Isoproterenol/farmacología , Persona de Mediana Edad , Análisis Multivariante , Fosforilación , Pruebas de Función Respiratoria , Estudios Retrospectivos , Transducción de Señal/efectos de los fármacos , Sirolimus/farmacología , Piel/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteína 1 del Complejo de la Esclerosis Tuberosa , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de Tumor/metabolismoRESUMEN
PURPOSE OF REVIEW: To summarize evidence for the feasibility and the efficacy of mobile stroke units (MSUs) and telemedicine in the field to reduce time delays in offering acute stroke interventions. RECENT FINDINGS: A mobile stroke unit is a modified ambulance and includes sophisticated equipment, either trained personnel on board, or connection with skilled physicians via telemedicine. Stroke assessment and treatment agreeability between the on board and remote neurologist is high in MSUs. MSUs are the promising option to reduce stroke symptom onset to treatment time; telemedicine platform has a satisfactory audiovisual quality, high inter-rater reliability for remote stroke symptom assessment, diagnosis, and decision to treat. Use of MSU also avoids the need for inter-hospital transfers. MSUs improve prehospital stroke care and reduce delays in access to intravenous thrombolytic and mechanical thrombectomy in selective markets. Advancement in telecommunication and modern technology has the potential to make MSU telemedicine-aided management more cost-effective. Further research is needed before its widespread implementation.
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Accidente Cerebrovascular , Telemedicina , Ambulancias , Humanos , Unidades Móviles de Salud , Reproducibilidad de los Resultados , Accidente Cerebrovascular/diagnóstico , Accidente Cerebrovascular/terapia , Terapia TrombolíticaRESUMEN
PURPOSE OF REVIEW: Coronary revascularization is a commonly performed major procedure in the hospitals. Stroke is one of the dreaded complications after coronary revascularization procedures. The focus of this review is to understand the stroke risk in percutaneous cutaneous intervention (PCI) and coronary artery bypass grafting (CABG) procedures. RECENT FINDINGS: Available data show that PCI offers less procedural stroke risk compared to CABG although the survival benefits of CABG are better in certain scenarios. Innovative advancements in techniques, pre-procedural optimum medical therapy (OMT), intraoperative neuro-monitoring, and multidisciplinary post procedural care are the few strategies in early detection and reduce stroke risk. Despite several innovations and strategies, it is evident that there is not enough data available to make concrete conclusions related to stroke risk after coronary revascularization, which warrants further investigation.
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Enfermedad de la Arteria Coronaria , Isquemia Miocárdica , Intervención Coronaria Percutánea , Accidente Cerebrovascular , Puente de Arteria Coronaria , Humanos , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Resultado del TratamientoRESUMEN
OBJECTIVES/BACKGROUND: Medical therapy is the first line of treatment for intracranial atherosclerotic disease (ICAD). Percutaneous transluminal angioplasty and stenting (PTAS) are mainly considered for those patients with severe stenosis and recurrent events despite aggressive medical therapy. In this review, we discuss the application of PTAS as a treatment option for ICAD and its future prospect. MATERIALS AND METHODS: We did the literature review of the key articles and guidelines to elaborate on the role of PTAS in the management of ICAD based on the current data and expert opinion. We searched PubMed, Google Scholar, and Scopus up to August 2020, and included articles published only in the English language. RESULTS: Since the publication of the results from SAMMPRIS and VISSIT trials, stenting is no longer recommended for secondary stroke prevention in patients with symptomatic ICAD. However, recent clinical studies on intracranial stenting for a subgroup of ICAD patients have shown promising results, likely due to better patient selection and continued advancement of endovascular techniques. CONCLUSION: There exists a lack of consensus regarding the best endovascular treatment approach (e.g., angioplasty alone or balloon mounted stent vs. self-expanding stent with or without prior angioplasty) or management of in-stent restenosis. Another area of clinical controversy relates to the ideal use and duration of antiplatelet therapy.
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Angioplastia de Balón , Arteriosclerosis Intracraneal/terapia , Accidente Cerebrovascular Isquémico/terapia , Angioplastia de Balón/efectos adversos , Angioplastia de Balón/instrumentación , Ensayos Clínicos como Asunto , Difusión de Innovaciones , Medicina Basada en la Evidencia , Humanos , Arteriosclerosis Intracraneal/diagnóstico por imagen , Arteriosclerosis Intracraneal/fisiopatología , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Accidente Cerebrovascular Isquémico/fisiopatología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Diseño de Prótesis , Factores de Riesgo , Stents , Resultado del TratamientoRESUMEN
OBJECTIVE: We aim to report intra-arterial thrombectomy transfer metrics for ischemic stroke patients that were transferred to hub hospitals for possible intra-arterial thrombectomy in multiple geographic regions throughout the state of Texas and to identify potential barriers and delays in the intra-arterial thrombectomy transfer process. METHOD: We prospectively collected data from 8 participating Texas comprehensive stroke/thrombectomy capable centers from 7 major regions in the State of Texas. We collected baseline clinical and imaging data related to the pre-transfer evaluation, transfer metrics, and post-transfer clinical and imaging data. RESULTS: A total of 103 acute ischemic stroke patients suspected/confirmed to have large vessel occlusions between December 2016 to May 2019 that were transferred to hubs as possible intra-arterial thrombectomy candidates were enrolled. A total of 56 (54%) patients were sent from the spoke to the hub via ground ambulance with 47 (46%) patients traveling via air ambulance. The median spoke arrival to hub arrival time was 174 min, median spoke arrival to departure from spoke was 131 min, and median travel time was 39 min. The spoke arrival time to transfer initiation was 68 min. CT-perfusion obtained at the spoke and earlier initiation of transfer were statistically associated with shorter transfer times. CONCLUSION: Transfer of intra-arterial thrombectomy patients in Texas may take over 4 h from spoke arrival to hub arrival. This time may be shortened by earlier transfer initiation and acceptance.
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Fibrinolíticos/administración & dosificación , Accidente Cerebrovascular Isquémico/terapia , Transferencia de Pacientes , Trombectomía , Terapia Trombolítica , Tiempo de Tratamiento , Anciano , Ambulancias , Femenino , Fibrinolíticos/efectos adversos , Humanos , Infusiones Intraarteriales , Accidente Cerebrovascular Isquémico/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Texas , Trombectomía/efectos adversos , Terapia Trombolítica/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
This work presents a new method and tool to solve a common problem of molecular biologists and geneticists who use molecular markers in their scientific research and developments: curation of sequences. Omic studies conducted by molecular biologists and geneticists usually involve the use of molecular markers. AFLP, cDNA-AFLP, and MSAP are examples of markers that render information at the genomics, transcriptomics, and epigenomics levels, respectively. These three types of molecular markers use adaptors that are the template for PCR amplification. The sequences of the adaptors have to be eliminated for the analysis of the results. Since a large number of sequences are usually obtained in these studies, this clean-up of the data could demand long time and work. To automate this work, an R package, named CleanBSequences, was created that allows the sequences to be curated massively, quickly, without errors and can be used offline. The curating is performed by aligning the forward and/or reverse primers or ends of cloning vectors with the sequences to be removed. After the alignment, new subsequences are generated without biological fragments not desired by the user, i.e., sequences needed by the techniques. In conclusion, the CleanBSequences tool facilitates the work of researchers, reducing time, effort, and working errors. Therefore, the present tool would respond to the problems related to the curation of sequences obtained from the use of some types of molecular markers. In addition to the above, being an open source, CleanBSequences is a flexible tool that has the potential to be used in future improvements to respond to new problems.
Asunto(s)
Biología Computacional , Marcadores Genéticos/genética , Biología Molecular/métodos , Programas Informáticos , Epigenómica/métodos , Genómica/métodos , Anotación de Secuencia Molecular/métodos , Alineación de Secuencia/métodos , Análisis de Secuencia/métodos , Transcriptoma/genéticaRESUMEN
BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) and ovarian cancer screening (OCS) are management options for women at increased risk of ovarian cancer. Long-term effects of these interventions on quality of life (QOL) are not well understood. METHODS: GOG-0199 is a prospective cohort study of women at increased ovarian cancer risk who chose either RRSO or OCS as their risk management intervention. At study entry, 6, 12, 24 and 60 months of follow-up, participants completed the QOL questionnaire, which included the Medical Outcome Study Short Form-36, the Impact of Events Scales, the Center for Epidemiological Studies Depression Scale, the State-Trait Anxiety Inventory, the Functional Assessment of Cancer Therapy - Endocrine Subscale, and the Sexual Activity Questionnaire. QOL measures were compared between the RRSO and OCS cohort at baseline and over time. RESULTS: Five-hundred-sixty-two participants in the RRSO cohort and 1,010 in the OCS completed the baseline and at least one follow-up questionnaire. At baseline, participants selecting RRSO reported lower health-related QOL (HRQOL), greater ovarian cancer-related stress, greater anxiety, and more depressive symptomatology, which improved during follow-up, especially for ovarian cancer-related stress. Screening was not found to adversely impact HRQOL. Hormone-related menopausal symptoms worsened and sexual functioning declined during follow-up in both cohorts, but more so among participants who underwent RRSO. CONCLUSIONS: HRQOL improved after surgery among women who chose RRSO and remained stable among participants undergoing screening. The adverse effects of RRSO and screening on short-term and long-term sexual activity and sexual functioning warrant consideration in the decision-making process for high-risk women.