RESUMEN
BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies. METHODS AND RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells. CONCLUSION: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.
Asunto(s)
Leucocitos Mononucleares , RecQ Helicasas , Adulto , Femenino , Humanos , Masculino , ADN Helicasas/genética , ADN Helicasas/metabolismo , Reparación del ADN/genética , Leucocitos Mononucleares/metabolismo , RecQ Helicasas/genética , RecQ Helicasas/metabolismo , Telómero/metabolismo , Telómero/genética , Homeostasis del Telómero/genéticaRESUMEN
Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial (clinicaltrials gov. Identifier: NCT02055456), 17 patients with short telomeres and/or germline pathogenic variants in telomere biology genes associated with at least one cytopenia and/or radiologic diagnosis of interstitial lung disease were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-fluorescence in situ hybridization (average increase, 0.87 kb; 95% confidence interval: 0.20-1.55 kb; P=0.01). At 24 months, all ten evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% confidence interval: 0.24-1.23 kb; P=0.18). Hematologic response was achieved in eight of 16 patients (50%) with marrow failure at 12 months, and in ten of 16 patients (63%) at 24 months. Seven patients had interstitial lung disease at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No adverse events grade ≥4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events.
Asunto(s)
Enfermedades Pulmonares Intersticiales , Humanos , Hibridación Fluorescente in Situ , Nandrolona Decanoato , Estudios Prospectivos , Estudios Retrospectivos , TelómeroRESUMEN
BACKGROUND: Despite recent policy efforts to increase price transparency, obtaining estimated prices for surgery remains difficult for most patients and families. PURPOSE: Assess availability and variability of cost and self-pay discounts for pediatric anterior cruciate ligament (ACL) reconstruction in the United States. METHODS: This was a prospective study using scripted telephone calls to obtain price estimates and self-pay discounts for pediatric ACL reconstruction. From July to August 2020, investigators called 102 hospitals, 51 "top-ranked" pediatric orthopaedic hospitals and 51 "non-top ranked" hospitals randomly selected, to impersonate the parent of an uninsured child with a torn ACL. Hospital, surgeon, and anesthesia price estimates, availability of a self-pay discount, and number of calls and days required to obtain price estimates were recorded for each hospital. Hospitals were compared on the basis of ranking, teaching status, and region. RESULTS: Only 31/102 (30.3%) hospitals provided a complete price estimate. Overall, 52.9% of top-ranked hospitals were unable to provide any price information versus 31.4% of non-top-ranked hospitals ( P =0.027). There was a 6.1-fold difference between the lowest and highest complete price estimates (mean estimate $29,590, SD $14,975). The mean complete price estimate for top-ranked hospitals was higher than for non-top-ranked hospitals ($34,901 vs. $25,207; P =0.07). The mean complete price estimate varied significantly across US region ( P =0.014), with the greatest mean complete price in the Northeast ($41,812). Altogether, 38.2% hospitals specified a self-pay discount, but only a fraction disclosed exact dollar or percentage discounts. The mean self-pay discount from top-ranked hospitals was larger than that of non-top-ranked hospitals ($18,305 vs. $9902; P =0.011). An average of 3.1 calls (range 1.0 to 12.0) over 5 days (range 1 to 23) were needed to obtain price estimates. CONCLUSION: Price estimates for pediatric sports medicine procedures can be challenging to obtain, even for the educated consumer. Top-ranked hospitals and hospitals in the Northeast region may charge more than their counterparts. In all areas, self-pay discounts can be substantial if they can be identified but they potentially create an information disadvantage for unaware patients needing to pay out-of-pocket. STUDY DESIGN: Economic; Level of Evidence II. WHAT IS KNOWN ABOUT THE SUBJECT: Previous studies have highlighted the importance of value-based health care decisions and deficits of price transparency in various fields including pediatric and orthopaedics procedures. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE: This study is the first to examine availability and variability of health care cost in pediatric sports medicine and the first to assess availability and magnitude of self-pay discounts, setting expectations for the uninsured patient incurring large out-of-pocket expenses.
Asunto(s)
Lesiones del Ligamento Cruzado Anterior , Reconstrucción del Ligamento Cruzado Anterior , Lesiones del Ligamento Cruzado Anterior/cirugía , Reconstrucción del Ligamento Cruzado Anterior/métodos , Niño , Costos de la Atención en Salud , Hospitales Pediátricos , Humanos , Estudios Prospectivos , Estados UnidosRESUMEN
BACKGROUND & AIMS: Short telomeres and genetic telomerase defects are risk factors for some human liver diseases, ranging from non-alcoholic fatty liver disease and non-alcoholic steatohepatitis to cirrhosis. In murine models, telomere dysfunction has been shown to metabolically compromise hematopoietic cells, liver and heart via the activation of the p53-PGC axis. METHODS: Tert- and Terc-deficient mice were challenged with liquid high-fat diet. Liver metabolic contents were analysed by CE-TOFMS and liver fat content was confirmed by confocal and electronic microscopy. RESULTS: Tert-deficient but not Terc-deficient mice develop hepatocyte injury and frank steatosis when challenged with liquid high-fat diet. Upon high-fat diet, Tert-/- hepatocytes fail to engage the citric acid cycle (TCA), with an imbalance of NADPH/NADP+ and NADH/NAD+ ratios and depletion of intermediates of TCA cycle, such as cis-aconitic acid. Telomerase deficiency caused an intrinsic metabolic defect unresponsive to environmental challenge. Chemical inhibition of telomerase by zidovudine recapitulated the abnormal Tert-/- metabolic phenotype in Terc-/- hepatocytes. CONCLUSIONS: Our findings indicate that in telomeropathies short telomeres are not the only molecular trigger and telomerase enzyme deficiency provokes hepatocyte metabolic dysfunction, abrogates response to environmental challenge, and causes cellular injury and steatosis, providing a mechanism for liver damage in telomere diseases.
Asunto(s)
Dieta Alta en Grasa , Metabolismo Energético , Hígado Graso/enzimología , Hepatocitos/enzimología , Metabolismo de los Lípidos , Hígado/enzimología , Telomerasa/deficiencia , Acortamiento del Telómero , Animales , Glucemia/metabolismo , Modelos Animales de Enfermedad , Metabolismo Energético/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Hígado Graso/sangre , Hígado Graso/genética , Hígado Graso/patología , Hepatocitos/efectos de los fármacos , Hepatocitos/patología , Metabolismo de los Lípidos/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , ARN/genética , Telomerasa/antagonistas & inhibidores , Telomerasa/genética , Zidovudina/farmacologíaRESUMEN
BACKGROUND: A significant gap presently exists between box-lap and virtual-reality simulators and live surgery. Live animal and cadaver use has significant downsides. We have developed a high fidelity, real tissue simulator that allows training in laparoscopic foregut operations. METHODS: Our foregut surgery model is based on porcine tissue blocks that include lungs, heart, aorta, esophagus, diaphragm, stomach, duodenum, liver, and spleen. The tissue block is mounted in a human mannequin and perfused with artificial blood. The anterior abdominal wall is constructed so as to allow for laparoscopic or robotic surgical training. We sought to test the model with procedures performed by expert surgeons. After completing the procedures, face validity was measured by surgeon responses to a questionnaire defining the perceived relationship to real surgery. RESULTS: Five expert foregut surgeons performed laparoscopic Heller myotomy, Nissen fundoplication, and sleeve gastrectomy on the model. The simulator was rated as highly realistic in terms of tissue feel, instrument usage, and conduct of the operation for all three procedures. In addition, all surgeons felt the model could significantly shorten the learning curve for performing these procedures. CONCLUSIONS: The results of this study show that our simulation model, based on animal tissue blocks, offers a very realistic representation of laparoscopic foregut operations, thus achieving a high level of face validity. The model should be very useful for training surgeons in laparoscopic foregut procedures.
Asunto(s)
Competencia Clínica , Fundoplicación/educación , Laparoscopía/educación , Modelos Animales , Simulación de Paciente , Animales , Hospitales Universitarios , Humanos , North Carolina , Cirujanos , Encuestas y Cuestionarios , PorcinosRESUMEN
PURPOSE: Glaucoma patients with markedly elevated intraocular pressure (IOP) are at risk for developing severe hypotony-related complications. The goal of this study was to compare the surgical outcomes of the Ahmed Glaucoma Valve (AGV) and the Baerveldt Glaucoma Implant (BGI) in this patient population. METHODS: Patients with preoperative IOP≥30 mm Hg were included. Outcome measures were: (1) surgical failure (IOP>21 mm Hg or <30% reduction from baseline or IOP≤5 mm Hg on 2 consecutive follow-up visits after 3 mo, or additional glaucoma surgery, or loss of light perception) and (2) surgical complications. RESULTS: A total of 75 patients were included: 37 in the AGV group and 38 in the BGI group. The mean±SD follow-up was 2.3±1.6 years for the AGV group and 2.4±1.7 years for the BGI group (P=0.643). Mean preoperative IOP was 38.7±6.5 mm Hg for the AGV group and 40.8±7.6 mm Hg for the BGI group. At the last follow-up, 10 (27.0%) patients failed in the AGV group compared with 6 (15.8%) patients in the BGI group (P=0.379). The BGI group had higher rate of flat or shallow anterior chamber (n=4, 10%) compared with the AGV group (n=0, 0%) (P=0.043). CONCLUSIONS: Failure rates of AGV and BGI in patients with IOP≥30 mm Hg were comparable. There were more early hypotony-related complications in the BGI group; however, none were vision threatening. Both glaucoma drainage implants were effective in treating patients with uncontrolled glaucoma in an emergency setting.
Asunto(s)
Implantes de Drenaje de Glaucoma , Glaucoma/cirugía , Presión Intraocular/fisiología , Implantación de Prótesis , Adulto , Anciano , Antihipertensivos , Femenino , Estudios de Seguimiento , Glaucoma/fisiopatología , Humanos , Complicaciones Intraoperatorias , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/cirugía , Estudios Retrospectivos , Tonometría Ocular , Resultado del Tratamiento , Agudeza Visual/fisiologíaRESUMEN
Background: Taeniasis and cysticercosis are major causes of seizures and epilepsy. Infection by the causative parasite Taenia solium requires transmission between humans and pigs. The disease is considered to be eradicable, but data on attempts at regional elimination are lacking. We conducted a three-phase control program in Tumbes, Peru, to determine whether regional elimination would be feasible. Methods: We systematically tested and compared elimination strategies to show the feasibility of interrupting the transmission of T. solium infection in a region of highly endemic disease in Peru. In phase 1, we assessed the effectiveness and feasibility of six intervention strategies that involved screening of humans and pigs, antiparasitic treatment, prevention education, and pig replacement in 42 villages. In phase 2, we compared mass treatment with mass screening (each either with or without vaccination of pigs) in 17 villages. In phase 3, we implemented the final strategy of mass treatment of humans along with the mass treatment and vaccination of pigs in the entire rural region of Tumbes (107 villages comprising 81,170 people and 55,638 pigs). The effect of the intervention was measured after phases 2 and 3 with the use of detailed necropsy to detect pigs with live, nondegenerated cysts capable of causing new infection. The necropsy sampling was weighted in that we preferentially included more samples from seropositive pigs than from seronegative pigs. Results: Only two of the strategies implemented in phase 1 resulted in limited control over the transmission of T. solium infection, which highlighted the need to intensify the subsequent strategies. After the strategies in phase 2 were implemented, no cyst that was capable of further transmission of T. solium infection was found among 658 sampled pigs. One year later, without further intervention, 7 of 310 sampled pigs had live, nondegenerated cysts, but no infected pig was found in 11 of 17 villages, including all the villages in which mass antiparasitic treatment plus vaccination was implemented. After the final strategy was implemented in phase 3, a total of 3 of 342 pigs had live, nondegenerated cysts, but no infected pig was found in 105 of 107 villages. Conclusions: We showed that the transmission of T. solium infection was interrupted on a regional scale in a highly endemic region in Peru. (Funded by the Bill and Melinda Gates Foundation and others).
Introducción: La teniasis y la cisticercosis son causas importantes de convulsiones y epilepsia. La infección por el parásito causal Taenia solium requiere la transmisión entre humanos y cerdos. La enfermedad se considera erradicable, pero faltan datos sobre los intentos de eliminación regional. Llevamos a cabo un programa de control de tres fases en Tumbes, Perú, para determinar si sería factible la eliminación regional. Métodos: Probamos y comparamos sistemáticamente las estrategias de eliminación para demostrar la viabilidad de interrumpir la transmisión de la infección por T. solium en una región de enfermedad altamente endémica en Perú. En la fase 1, evaluamos la eficacia y viabilidad de seis estrategias de intervención que incluyeron detección de humanos y cerdos, tratamiento antiparasitario, educación preventiva y reemplazo de cerdos en 42 aldeas. En la fase 2, comparamos el tratamiento masivo con la detección masiva (cada una con o sin vacunación de cerdos) en 17 aldeas. En la fase 3, implementamos la estrategia final de tratamiento masivo de humanos junto con el tratamiento masivo y vacunación de cerdos en toda la región rural de Tumbes (107 aldeas que comprenden 81.170 personas y 55.638 cerdos). El efecto de la intervención se midió después de las fases 2 y 3 con el uso de necropsia detallada para detectar cerdos con quistes vivos, no degenerados capaces de causar una nueva infección. El muestreo de necropsia fue ponderado de manera que incluimos preferentemente más muestras de cerdos seropositivos que de cerdos seronegativos. Resultados: Sólo dos de las estrategias implementadas en la fase 1 dieron como resultado un control limitado sobre la transmisión de la infección por T. solium, lo que destacó la necesidad de intensificar las estrategias posteriores. Después de que se implementaron las estrategias en la fase 2, no se encontró ningún quiste capaz de transmitir más la infección por T. solium entre los 658 cerdos muestreados. Un año después, sin más intervenciones, 7 de los 310 cerdos muestreados tenían quistes vivos, no degenerados, pero no se encontró ningún cerdo infectado en 11 de las 17 aldeas, incluidas todas las aldeas en las que se implementó el tratamiento antiparasitario masivo más la vacunación. Después de que se implementó la estrategia final en la fase 3, un total de 3 de 342 cerdos tenían quistes vivos, no degenerados, pero no se encontró ningún cerdo infectado en 105 de las 107 aldeas. Conclusiones: Demostramos que la transmisión de la infección por T. solium se interrumpió a escala regional en una región altamente endémica del Perú. (Financiado por la Fundación Bill y Melinda Gates y otros).
Asunto(s)
CisticercosisRESUMEN
The free fibula flap is the preferred reconstructive method for oncologic defects of the mandible. Arterial inflow of the extremity is routinely evaluated with several modalities; however, venous screening is rarely performed. Patients with cancer are at elevated risk of occult deep venous thrombosis (DVT). An asymptomatic thrombus encountered during free fibula reconstruction is a serious concern. Although such cases have been reported, we suspect the incidence of DVT during fibula free flap harvest is underappreciated. This monograph uses a case example to review risk factors for occult DVT, present a strategy for preoperative assessment, and provide a reconstructive algorithm to for mandibular reconstruction in such instances.
Asunto(s)
Peroné/irrigación sanguínea , Colgajos Tisulares Libres/irrigación sanguínea , Complicaciones Intraoperatorias/diagnóstico , Reconstrucción Mandibular/métodos , Trombosis de la Vena/diagnóstico , Anciano , Enfermedades Asintomáticas , Femenino , Peroné/trasplante , Colgajos Tisulares Libres/trasplante , Humanos , Trombosis de la Vena/etiologíaRESUMEN
The effectiveness of salvage therapy for aplastic anemia patients unresponsive to initial rabbit antithymocyte globulin (r-ATG) or cyclophosphamide is not known. We investigated the administration of standard horse ATG (h-ATG) plus cyclosporine (CsA) in patients who were refractory to initial r-ATG/CsA (n = 19) or cyclophosphamide/CsA (n = 6) (registered at clinicaltrials.gov as NCT00944749). The primary endpoint was hematologic response at 3 months and was defined as no longer meeting the criteria for severe aplastic anemia. Of the 19 patients who received r-ATG as initial therapy, 4 (21%) achieved a hematologic response by 3 months, and of the 6 patients who received cyclophosphamide, only 1 (17%) responded by 6 months. Among the responders there were no cases of relapse, and in nonresponders 2 patients evolved to monosomy 7. The overall survival for the cohort at 3 years was 68% (95% CI, 50-91%). These results suggest that only a minority can be successfully salvaged after receiving as first therapy either r-ATG or cyclophosphamide. Although h-ATG may be utilized in the salvage setting, the overall response rate probably will be lower than when h-ATG is used as initial treatment.
Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Suero Antilinfocítico/uso terapéutico , Ciclofosfamida/uso terapéutico , Ciclosporina/uso terapéutico , Adolescente , Adulto , Anciano , Anemia Aplásica/patología , Niño , Preescolar , Estudios de Cohortes , Estudios Cruzados , Femenino , Humanos , Masculino , Persona de Mediana Edad , Terapia Recuperativa/métodos , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Free tissue transfer from an abdominal donor site has become a popular method for postmastectomy breast reconstruction. The detrimental effects of adjuvant chemotherapy on healing and the resulting clinical impact on patient outcome remains somewhat unclear for abdominal bulges and hernias resulting after free tissue transfer from the abdominal donor site. METHODS: An institutional review board-approved retrospective review of 155 free muscle-sparing transverse rectus abdominis myocutaneous (MS-TRAM) flaps performed for breast reconstruction was undertaken to evaluate the effect of adjuvant chemotherapy on abdominal donor-site morbidity. The primary outcome studied was the development of hernias and bulges. Statistical analysis was performed using univariate and multivariate classification and regression tree (CART) analysis. RESULTS: Of the 155 patients, 51 underwent bilateral MS-TRAM flaps and 104 underwent unilateral MS-TRAM flap reconstruction. Thirty-nine patients underwent adjuvant chemotherapy. A statistically significant association was seen between chemotherapy treatment and the incidence of hernias alone (P < 0.05; odds ratio, 6.42; 95% confidence interval, 0.88-73.58). Multivariable CART analyses corroborated these findings and revealed that presence of diabetes mellitus (DM), bilaterality, and receiving chemotherapy treatment were related to increased incidence of hernias (P = 0.011, 0.005, and 0.017, respectively) after controlling for clinical variables such as smoking status, chronic obstructive pulmonary disease, and type of closure. Univariate analyses also revealed a statistically significant association between bilaterality in conjunction with chemotherapy treatment and the incidence of hernias alone (P = 0.0002; odds ratio, 37.56; 95% confidence interval, 4.56-476.35). This highly significant finding is further augmented by multivariable CART analyses, which found that patients who were bilateral and underwent chemotherapy treatment or those with DM were significantly more likely to develop hernias (P < 0.001 and P = 0.016, respectively). CONCLUSIONS: To date, our study is the single largest series of abdominal donor-site complications in patients receiving chemotherapy and free MS-TRAM breast reconstruction. We have demonstrated an increase in the incidence of abdominal donor-site complications, specifically abdominal bulges and hernias, in patients undergoing chemotherapy for advanced stages of breast cancer. This increased complication rate is most pronounced in patients requiring chemotherapy who undergo bilateral reconstruction, and is also a significant risk for patients receiving chemotherapy who have preexisting DM.
Asunto(s)
Pared Abdominal , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Mamoplastia , Colgajo Miocutáneo , Sitio Donante de Trasplante , Adulto , Antineoplásicos , Quimioterapia Adyuvante , Femenino , Hernia Abdominal , Humanos , Microcirugia , Análisis Multivariante , Colgajo Miocutáneo/efectos adversos , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: To determine the long-term outcomes in children with severe aplastic anemia (SAA) treated with antithymocyte globulin (ATG) and cyclosporine (CsA) through a retrospective analysis of the pediatric patients treated at our institution in all protocols that included horse ATG (h-ATG) and CsA. STUDY DESIGN: Between 1989 and 2006, a total of 406 patients, 20% of whom were children under age 18 years, received an initial course of immunosuppressive therapy (IST) at our institution. Here we report the outcome of 77 children who were treated with an h-ATG plus CsA-based regimen during this period. RESULTS: The overall response rate at 6 months was 74% (57/77); the cumulative incidence of relapse at 10 years was 33%, and the median time to relapse was 558 days. The cumulative incidence of evolution after IST was 8.5%; all 3 such events occurred in partial responders. Overall, there were 13 deaths (17%), with 4 occurring within the 3 months after IST in patients who had a pretreatment absolute neutrophil count of < 100/microL and the other 9 occurring more than 6 months after initiation of IST. The median time to death was 570 days. The overall 10-year survival for the entire cohort was 80%; long-term survival in the children who responded to IST was 89%. CONCLUSIONS: The long-term survival in pediatric patients who respond to IST is excellent, at about 90%. IST remains a good alternative in pediatric patients who lack an HLA-matched sibling donor and should be offered as initial therapy before possible hematopoietic stem cell transplantation from an unrelated donor.
Asunto(s)
Anemia Aplásica/tratamiento farmacológico , Suero Antilinfocítico/uso terapéutico , Ciclosporina/uso terapéutico , Inmunosupresores/uso terapéutico , Adolescente , Anemia Aplásica/mortalidad , Anemia Aplásica/fisiopatología , Niño , Preescolar , Estudios de Cohortes , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Incidencia , Masculino , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Despite widespread heparin use in clinical practice, the associated development of thrombocitopenia is an underrecognized and undertreaded complication. Methods:We analized data from consective hospitalized patients treated with heparin (unfractionated or low molecular weight) for four days or longer to determine the incidence, predictors, prognostic significance, and management of thrombocitopenia, defined as a platelet count less than 150x10/L, reduction in platelet count of 50% or more from teh admission level, or both...