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Concentrated acid solutions, particularly HCl, have been studied extensively to examine the proton hopping and infrared spectral signatures of hydronium ions. Much less attention has been given to the structural dynamics of concentrated HCl solutions. Here, we apply optical heterodyne detected-optical Kerr effect (OHD-OKE) measurements to examine HCl concentration-dependent dynamics from moderate (0.8 m) to very high (15.5 m) concentrations and compare the results to the dynamics of NaCl solutions, as Na+ is similar in size to the hydronium cation. Both HCl and NaCl OHD-OKE signals decay as triexponentials at all concentrations, in contrast to pure water, which decays as a biexponential. Two remarkable features of the HCl dynamics are the following: (1) the bulk viscosity is linearly related to the slowest decay constant, t3, and (2) the concentration-dependent proton hopping times, determined by ab initio MD simulations and 2D IR chemical exchange experiments, both obtained from the literature, fall on the same line as the slowest structural dynamics relaxation time, t3, within experimental error. The structural dynamics of hydronium/chloride/water clusters, with relaxation times t3, are responsible for the concentration dependence of microscopic property of proton hopping and the macroscopic bulk viscosity. The slowest time constant (t3), which does not have a counterpart in pure water, is 3 ps at 0.8 m and increases by a factor of â¼2 by 15.5 m. The two fastest HCl decay constants, t1 and t2, are similar to those of pure water and increase mildly with the concentration.
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We recently identified epigallocatechin gallate (EGCG), a trihydroxyphenolic compound, as a dual inhibitor of lysyl oxidase-like2 and transforming growth factor-ß1 (TGFß1) receptor kinase that when given orally to patients with idiopathic pulmonary fibrosis (IPF) reversed profibrotic biomarkers in their diagnostic biopsies. Here, we extend these findings to advanced pulmonary fibrosis using cultured precision-cut lung slices from explants of patients with IPF undergoing transplantation. During these experiments, we were surprised to discover that not only did EGCG attenuate TGFß1 signalling and new collagen accumulation but also activated matrix metalloproteinase-dependent collagen I turnover, raising the possibility of slow fibrosis resolution with continued treatment.
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Aminoácido Oxidorreductasas/metabolismo , Colágeno Tipo I/metabolismo , Fibrosis Pulmonar Idiopática/metabolismo , Pulmón/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Células Cultivadas , Humanos , Fibrosis Pulmonar Idiopática/patología , Immunoblotting , Pulmón/patología , Transducción de SeñalRESUMEN
BACKGROUND: We previously identified two acute kidney injury (AKI) sub-phenotypes (AKI-SP1 and AKI-SP2) with different risk of poor clinical outcomes and response to vasopressor therapy. Plasma biomarkers of endothelial dysfunction (tumor necrosis factor receptor-1, angiopoietin-1 and 2) differentiated the AKI sub-phenotypes. However, it is unknown whether these biomarkers are simply markers or causal mediators in the development of AKI sub-phenotypes. METHODS: We tested for associations between single-nucleotide polymorphisms within the Angiopoietin-1, Angiopoietin-2, and Tumor Necrosis Factor Receptor 1A genes and AKI- SP2 in 421 critically ill subjects of European ancestry. Top performing single-nucleotide polymorphisms (FDR < 0.05) were tested for cis-biomarker expression and whether genetic risk for AKI-SP2 is mediated through circulating biomarkers. We also completed in vitro studies using human kidney microvascular endothelial cells. Finally, we calculated the renal clearance of plasma biomarkers using 20 different timed urine collections. RESULTS: A genetic variant, rs2920656C > T, near ANGPT2 was associated with reduced risk of AKI-SP2 (odds ratio, 0.45; 95% CI, 0.31-0.66; adjusted FDR = 0.003) and decreased plasma angiopoietin-2 (p = 0.002). Causal inference analysis showed that for each minor allele (T) the risk of developing AKI-SP2 decreases by 16%. Plasma angiopoietin-2 mediated 41.5% of the rs2920656 related risk for AKI-SP2. Human kidney microvascular endothelial cells carrying the T allele of rs2920656 produced numerically lower levels of angiopoietin-2 although this was not statistically significant (p = 0.07). Finally, analyses demonstrated that angiopoietin-2 is minimally renally cleared in critically ill subjects. CONCLUSION: Genetic mediation analysis provides supportive evidence that angiopoietin-2 plays a causal role in risk for AKI-SP2.
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Lesión Renal Aguda/genética , Angiopoyetina 2/genética , Células Endoteliales/metabolismo , Lesión Renal Aguda/clasificación , Adulto , Anciano , Angiopoyetina 1/genética , Angiopoyetina 2/sangre , Enfermedad Crítica , Femenino , Predisposición Genética a la Enfermedad , Humanos , Técnicas In Vitro , Masculino , Microvasos/citología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores Tipo I de Factores de Necrosis Tumoral/sangre , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Población BlancaRESUMEN
Postembryonic development in Caenorhabditis elegans is a powerful model for the study of the temporal regulation of development and for the roles of microRNAs in controlling gene expression. Stable switch-like changes in gene expression occur during development as stage-specific microRNAs are expressed and subsequently down-regulate other stage-specific factors, driving developmental progression. Key genes in this regulatory network are phylogenetically conserved and include the post-transcriptional microRNA repressor LIN-28; the nuclear hormone receptor DAF-12; and the microRNAs LIN-4, LET-7, and the three LET-7 family miRNAs (miR-48, miR-84, and miR-241). DAF-12 is known to regulate transcription of miR-48, miR-84 and miR-241, but its contribution is insufficient to account for all of the transcriptional regulation implied by the mutant phenotypes. In this work, the GATA-family transcription factor ELT-1 is identified from a genetic enhancer screen as a regulator of developmental timing in parallel to DAF-12, and is shown to do so by promoting the expression of the LET-7, miR-48, miR-84, and miR-241 microRNAs. The role of ELT-1 in developmental timing is shown to be separate from its role in cell-fate maintenance during post-embryonic development. In addition, analysis of Chromatin Immnoprecipitation (ChIP) data from the modENCODE project and this work suggest that the contribution of ELT-1 to the control of let-7 family microRNA expression is likely through direct transcription regulation.
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Proteínas de Caenorhabditis elegans/biosíntesis , Diferenciación Celular/genética , Factores de Transcripción GATA/biosíntesis , MicroARNs/biosíntesis , Transcripción Genética , Animales , Caenorhabditis elegans/genética , Caenorhabditis elegans/crecimiento & desarrollo , Proteínas de Caenorhabditis elegans/genética , Factores de Transcripción GATA/genética , Regulación del Desarrollo de la Expresión Génica , MicroARNs/genética , Mutación , Receptores Citoplasmáticos y Nucleares/genéticaRESUMEN
The objective of this study was to evaluate the effect of sterile ozonated saline endometrial irrigation on sonographic and histological endometrial parameters. This prospective investigation was performed in 12 healthy, ovulating women over three consecutive menstrual cycles: control cycle (endometrial irrigation with 10 cc of normal saline at day 10), no intervention cycle and study cycle (irrigation with 10 cc of sterile ozonated saline at day 10). Endometrial thickness was measured by transvaginal ultrasound at days 10 and 12 of the control and study cycles, and endometrial samplings were obtained from the participants two days after the irrigations (i.e. on day 12) for histological evaluation. Ozonated saline irrigation, compared to normal saline irrigation, resulted in a statistically significant elevation of the columnar epithelial height (30.30 ± 3.04 vs. 25.82 ± 3.28 µm, p < 0.003), increased number of endometrial blood vessels (30.48 ± 11.38 vs. 19.12 ± 8.74, p < 0.005) and increased number of stromal cells (191.30 ± 34.40 vs. 151.29 ± 29.98, p < 0.01). In conclusion, sterile ozonated saline irrigation of the endometrium has a significant favourable effect on various histological endometrial parameters. Further studies are needed to evaluate the effect of these changes on endometrial receptivity and pregnancy rates.
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Endometrio/efectos de los fármacos , Ozono/administración & dosificación , Cloruro de Sodio/administración & dosificación , Irrigación Terapéutica/métodos , Adolescente , Adulto , Endometrio/fisiología , Femenino , Voluntarios Sanos , Humanos , Ciclo Menstrual , Ovulación , Estudios Prospectivos , Adulto JovenRESUMEN
We present concentration-dependent dynamics of highly concentrated LiBr solutions and LiCl temperature-dependent dynamics for two high concentrations and compare the results to those of prior LiCl concentration-dependent data. The dynamical data are obtained using ultrafast optical heterodyne-detected optical Kerr effect (OHD-OKE). The OHD-OKE decays are composed of two pairs of biexponentials, i.e., tetra-exponentials. The fastest decay (t1) is the same as pure water's at all concentrations within error, while the second component (t2) slows slightly with concentration. The slower components (t3 and t4), not present in pure water, slow substantially, and their contributions to the decays increase significantly with increasing concentration, similar to LiCl solutions. Simulations of LiCl solutions from the literature show that the slow components arise from large ion/water clusters, while the fast components are from ion/water structures that are not part of large clusters. Temperature-dependent studies (15-95 °C) of two high LiCl concentrations show that decreasing the temperature is equivalent to increasing the room temperature concentration. The LiBr and LiCl concentration dependences and the two LiCl concentrations' temperature dependences all have bulk viscosities that are linearly dependent on τcslow, the correlation time of the slow dynamics (weighted averages of t3 and t4). Remarkably, all four viscosity vs 1/τCslow plots fall on the same line. Application of transition state theory to the temperature-dependent data yields the activation enthalpies and entropies for the dynamics of the large ion/water clusters, which underpin the bulk viscosity.
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Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGFß1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Biopsies from untreated patients showed higher fibroblast TGFß1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGFß1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzle-like receptor protein 2 (sFRP2), an unrecognized TGFß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision cut lung slices (PCLS) from non-diseased donors, we found TGFß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature Krt5+ basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGFß1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify TGFß1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.
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Síndrome de Lemierre/etiología , Lupus Eritematoso Sistémico/complicaciones , Adulto , Anticoagulantes/uso terapéutico , Inhibidores Enzimáticos/uso terapéutico , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Hidroxicloroquina/uso terapéutico , Síndrome de Lemierre/diagnóstico , Síndrome de Lemierre/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Ácido Micofenólico/uso terapéutico , Tomografía Computarizada por Rayos XRESUMEN
Fast microfluidic mixers are a valuable tool for studying solution-phase chemical reaction kinetics and molecular processes with spectroscopy. However, microfluidic mixers that are compatible with infrared vibrational spectroscopy have seen only limited development due to the poor infrared transparency of the current microfabrication material. We describe the design, fabrication, and characterization of CaF2-based continuous flow turbulent mixers, which are capable of measuring kinetics in the millisecond time window with infrared spectroscopy, when integrated into an infrared microscope. Kinetics measurements demonstrate the ability to resolve relaxation processes with 1 millisecond time resolution, and straightforward improvements are described that should result in sub-100 µs time-resolution.
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Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFß) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFß signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFß signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFb signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.
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Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate this, we administered the fibroblast-selective TGFß1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Unexposed biopsy samples showed higher fibroblast TGFß1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG significantly downregulated TGFß1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted Frizzle-like Receptor Protein 2 (sFRP2), an unrecognized TGFß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s). In human AEC2-fibroblast coculture organoids, sFRP2 was essential for AEC2 trans-differentiation to basal cells. Precision cut lung slices (PCLS) from normal donors demonstrated that TGFß1 promoted KRT17 expression and AEC2 morphological change, while sFRP2 was necessary for KRT5 expression in AEC2-derived basaloid cells. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin-related signaling in AEC2s were required for sFRP2-induced KRT5 expression. These findings highlight stage-specific TGFß1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify the TGFß1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.
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Loss of alveolar type 2 cells (AEC2s) and the ectopic appearance of basal cells in the alveoli characterize severe lung injuries such as idiopathic pulmonary fibrosis (IPF). Here we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, transdifferentiate into basal cells in response to fibrotic signalling in the lung mesenchyme, in vitro and in vivo. Single-cell analysis of normal hAEC2s and mesenchymal cells in organoid co-cultures revealed the emergence of pathologic fibroblasts and basaloid cells previously described in IPF. Transforming growth factor-ß1 and anti-bone morphogenic protein signalling in the organoids promoted transdifferentiation. Trajectory and histologic analyses of both hAEC2-derived organoids and IPF epithelium indicated that hAEC2s transdifferentiate into basal cells through alveolar-basal intermediates that accumulate in proximity to pathologic CTHRC1hi/TGFB1hi fibroblasts. Our study indicates that hAEC2 loss and expansion of alveolar metaplastic basal cells in severe human lung injuries are causally connected through an hAEC2-basal cell lineage trajectory driven by aberrant mesenchyme.
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Transdiferenciación Celular/fisiología , Células Epiteliales/citología , Fibrosis Pulmonar Idiopática/patología , Queratina-5/metabolismo , Alveolos Pulmonares/citología , Mucosa Respiratoria/citología , Células Epiteliales Alveolares/metabolismo , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Diferenciación Celular , Células Cultivadas , Células Epidérmicas/citología , Fibroblastos/citología , Humanos , Mesodermo/citología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones SCID , Ratones Transgénicos , Transducción de Señal/fisiología , Análisis de la Célula Individual , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Immune channel inhibitor-induced myocarditis is rare, and its management is challenging. Recently, guidelines were established for all ICIs, yet they do not take into account individual drug toxicities or screening protocols for prevention. We present a rare case of rapidly progressive pembrolizumab-induced fatal myocarditis in an initially asymptomatic patient. (Level of Difficulty: Beginner.).
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Coronavirus disease 2019 (COVID-19), the respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first identified in Wuhan, China and has since become pandemic. In response to the first cases identified in the United States, close contacts of confirmed COVID-19 cases were investigated to enable early identification and isolation of additional cases and to learn more about risk factors for transmission. Close contacts of nine early travel-related cases in the United States were identified and monitored daily for development of symptoms (active monitoring). Selected close contacts (including those with exposures categorized as higher risk) were targeted for collection of additional exposure information and respiratory samples. Respiratory samples were tested for SARS-CoV-2 by real-time reverse transcription polymerase chain reaction at the Centers for Disease Control and Prevention. Four hundred four close contacts were actively monitored in the jurisdictions that managed the travel-related cases. Three hundred thirty-eight of the 404 close contacts provided at least basic exposure information, of whom 159 close contacts had ≥1 set of respiratory samples collected and tested. Across all actively monitored close contacts, two additional symptomatic COVID-19 cases (i.e., secondary cases) were identified; both secondary cases were in spouses of travel-associated case patients. When considering only household members, all of whom had ≥1 respiratory sample tested for SARS-CoV-2, the secondary attack rate (i.e., the number of secondary cases as a proportion of total close contacts) was 13% (95% CI: 4-38%). The results from these contact tracing investigations suggest that household members, especially significant others, of COVID-19 cases are at highest risk of becoming infected. The importance of personal protective equipment for healthcare workers is also underlined. Isolation of persons with COVID-19, in combination with quarantine of exposed close contacts and practice of everyday preventive behaviors, is important to mitigate spread of COVID-19.
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Trazado de Contacto , Infecciones por Coronavirus/transmisión , Neumonía Viral/transmisión , Adolescente , Adulto , Anciano , Betacoronavirus/aislamiento & purificación , COVID-19 , Niño , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Composición Familiar , Femenino , Personal de Salud , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/virología , SARS-CoV-2 , Enfermedad Relacionada con los Viajes , Estados Unidos , Adulto JovenRESUMEN
BACKGROUND: A clear understanding of patients' understanding and perceived risk of medical errors is needed. Multiwave telephone interviews were conducted in 2002 with 1,656 inpatients from 12 Midwestern hospitals regarding patients' conceptualization of medical errors and perceived risk of seven types of medical errors. RESULTS: Patients defined medical errors to include not only clinical mistakes but also falls, communication problems, and responsiveness. Ninety-four percent of respondents reported their medical safety as good, very good, or excellent, but 39% experienced at least one error-related concern, most commonly medication errors (17% of respondents), nursing mistakes (15%), and problems with medical equipment (10%). Frequency of concerns was associated with reduced willingness to recommend the hospital (p < .001). DISCUSSION: If patients' definition of medical errors is broader than the traditional medical definition, providers should clarify the term "error" to ensure effective communication. Most patients felt a high level of medical safety but a sizeable proportion experienced a concern about an error during hospitalization. The selective nature of concerns and the impact of patient and hospital characteristics provide insight into ways to engage patients in error prevention programs.
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Hospitalización , Errores Médicos/psicología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Comunicación , Etnicidad , Femenino , Humanos , Lactante , Recién Nacido , Seguro de Salud , Tiempo de Internación , Masculino , Persona de Mediana Edad , Medición de Riesgo , Seguridad , Terminología como AsuntoRESUMEN
OBJECTIVE: Despite large numbers of emergency encounters, little is known about how emergency department (ED) patients conceptualize their risk of medical errors. This study examines how safe ED patients feel from medical errors, which errors are of greatest concern, how concerns differ by patient and hospital characteristics, and the relationship between concerns and willingness to return for future care. METHODS: Multiwave telephone interviews of 767 patients from 12 EDs were conducted. Patients were asked about their medical safety, concern about eight types of medical errors, and satisfaction with care. RESULTS: Eighty-eight percent of patients believed that their safety from medical errors had been good, very good, or excellent; 38% of patients reported experiencing at least one specific error-related concern, most commonly misdiagnosis (22% of all patients), physician errors (16%), medication errors (16%), nursing errors (12%), and wrong test/procedure (10%). Concerns were associated with gender (p < 0.01), age (p < 0.0001), ethnicity (p < 0.001), length of stay (p < 0.001), ED volume (p < 0.0001), day of week (p < 0.0001), and hospital type (p < 0.0001). Concerns were highly related to a patient's willingness to return to the ED. CONCLUSIONS: The majority of ED patients felt relatively safe from medical errors, yet a significant percentage of patients experienced concern about a specific error during their emergency encounter. Concerns varied by both patient and hospital characteristics and were highly linked to patient satisfaction. The selective nature of concerns may suggest that patients are attuned to cues they perceive to be linked to specific medical errors, but efforts to involve patients in error detection/prevention programs will be challenging given the stressful and intimidating nature of ED encounters.
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Competencia Clínica , Servicio de Urgencia en Hospital/normas , Errores Médicos/estadística & datos numéricos , Satisfacción del Paciente/estadística & datos numéricos , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Niño , Servicio de Urgencia en Hospital/tendencias , Femenino , Encuestas de Atención de la Salud , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Participación del Paciente , Probabilidad , Medición de Riesgo , Factores Sexuales , Encuestas y Cuestionarios , Estados UnidosRESUMEN
Fourteen consecutive patients with a diagnosis of isthmic spondylolisthesis (grade I and II) underwent provocative lumbar diskography (L2-S1) to evaluate the disk adjacent to the spondylolisthesis. Seven (50%) of 14 patients had concordant pain at the disk above the slip and 2 patients had no pain at the slip level. Surgical treatment included anteroposterior fusion of the slip level and any adjacent concordant levels. Clinical results included 3 excellent, 7 good, 2 fair, and 1 poor outcome. This data supports the hypothesis that the disk adjacent to an isthmic slip is predisposed to symptomatic degeneration in the adult patient with axial pain. It does not prove that a fusion is indicated or that clinical outcomes would be improved with this approach.
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Vértebras Lumbares/diagnóstico por imagen , Cuidados Preoperatorios , Espondilolistesis/diagnóstico por imagen , Adulto , Femenino , Humanos , Dolor de la Región Lumbar/etiología , Dolor de la Región Lumbar/cirugía , Vértebras Lumbares/patología , Masculino , Persona de Mediana Edad , Radiografía , Fusión Vertebral , Espondilolistesis/cirugíaRESUMEN
How animals coordinate gene expression in response to starvation is an outstanding problem closely linked to aging, obesity, and cancer. Newly hatched Caenorhabditis elegans respond to food deprivation by halting development and promoting long-term survival (L1 diapause), thereby providing an excellent model for the study of starvation response. Through a genetic search, we have discovered that the tumor suppressor Rb critically promotes survival during L1 diapause and most likely does so by regulating the expression of genes in both insulin-IGF-1 signaling (IIS)-dependent and -independent pathways mainly in neurons and the intestine. Global gene expression analyses suggested that Rb maintains the "starvation-induced" transcriptome and represses the "refeeding-induced" transcriptome, including the repression of many pathogen-, toxin-, and oxidative-stress-inducible and metabolic genes, as well as the activation of many other stress-resistant genes, mitochondrial respiratory chain genes, and potential IIS receptor antagonists. Notably, the majority of genes dysregulated in starved L1 Rb(-) animals were not found to be dysregulated in fed conditions. Altogether, these findings identify Rb as a critical regulator of the starvation response and suggest a link between functions of tumor suppressors and starvation survival. These results may provide mechanistic insights into why cancer cells are often hypersensitive to starvation treatment.
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Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Regulación de la Expresión Génica , Proteínas Represoras/genética , Animales , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Privación de Alimentos , Genes Supresores de Tumor , Insulina/genética , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Datos de Secuencia Molecular , Proteínas Represoras/metabolismo , Transducción de Señal , Estrés FisiológicoRESUMEN
The release and uptake of neurotransmitters by synaptic vesicles is a tightly controlled process that occurs in response to diverse stimuli at morphologically disparate synapses. To meet these architectural and functional synaptic demands, it follows that there should be diversity in the mechanisms that control their secretion and retrieval and possibly in the composition of synaptic vesicles within the same terminal. Here we pay particular attention to areas where such diversity is generated, such as the variance in exocytosis/endocytosis coupling, SNAREs defining functionally diverse synaptic vesicle populations and the adaptor-dependent sorting machineries capable of generating vesicle diversity. We argue that there are various synaptic vesicle recycling pathways at any given synapse and discuss several lines of evidence that support the role of the endosome in synaptic vesicle recycling.
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Membranas Sinápticas/metabolismo , Vesículas Sinápticas/metabolismo , Endocitosis/fisiología , Endosomas/metabolismo , Exocitosis/fisiología , Modelos Biológicos , Terminales Presinápticos , Sinapsis/metabolismo , Transmisión SinápticaRESUMEN
We present a case of adrenocorticotropic hormone (ACTH)-independent Cushing's syndrome diagnosed in a patient in the third trimester of her pregnancy, with an adrenal mass observed on imaging studies. Laparoscopic adrenalectomy was performed successfully at 32 weeks. To the best of our knowledge, this is the latest gestational age at which laparoscopic adrenalectomy has been reported. We present the various considerations for determining the surgical approach and the optimal timing for surgery. Adrenalectomy during pregnancy for the treatment of Cushing's syndrome caused by adrenocortical adenoma has been reported in 23 patients in the English-language medical literature to date and seems safe and beneficial. According to the data, surgical treatment has led to a reduction in perinatal mortality and maternal morbidity rates, but has not affected the occurrence of preterm birth and intrauterine growth restriction. The best outcome can be achieved by a multidisciplinary approach, with a team comprising a maternal-fetal medicine specialist, an endocrinologist and a surgeon. The timing of surgery and the surgical approach need to be determined according to the surgeon's expertise, the severity of the condition, the patient's preferences, and gestational age. Laparoscopy may prove to be the preferred surgical approach. The small number of cases precludes providing evidence-based recommendations.