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1.
Artículo en Inglés | MEDLINE | ID: mdl-38745354

RESUMEN

BACKGROUND: Leak following surgical repair of traumatic duodenal injuries results in prolonged hospitalization and oftentimes nil per os(NPO) treatment. Parenteral nutrition(PN) has known morbidity; however, duodenal leak(DL) patients often have complex injuries and hospital courses resulting in barriers to enteral nutrition(EN). We hypothesized EN alone would be associated with 1)shorter duration until leak closure and 2)less infectious complications and shorter hospital length of stay(HLOS) compared to PN. METHODS: This was a post-hoc analysis of a retrospective, multicenter study from 35 Level-1 trauma centers, including patients >14 years-old who underwent surgery for duodenal injuries(1/2010-12/2020) and endured post-operative DL. The study compared nutrition strategies: EN vs PN vs EN + PN using Chi-Square and Kruskal-Wallis tests; if significance was found pairwise comparison or Dunn's test were performed. RESULTS: There were 113 patients with DL: 43 EN, 22 PN, and 48 EN + PN. Patients were young(median age 28 years-old) males(83.2%) with penetrating injuries(81.4%). There was no difference in injury severity or critical illness among the groups, however there were more pancreatic injuries among PN groups. EN patients had less days NPO compared to both PN groups(12 days[IQR23] vs 40[54] vs 33[32],p = <0.001). Time until leak closure was less in EN patients when comparing the three groups(7 days[IQR14.5] vs 15[20.5] vs 25.5[55.8],p = 0.008). EN patients had less intra-abdominal abscesses, bacteremia, and days with drains than the PN groups(all p < 0.05). HLOS was shorter among EN patients vs both PN groups(27 days[24] vs 44[62] vs 45[31],p = 0.001). When controlling for predictors of leak, regression analysis demonstrated EN was associated with shorter HLOS(ß -24.9, 95%CI -39.0 to -10.7,p < 0.001). CONCLUSION: EN was associated with a shorter duration until leak closure, less infectious complications, and shorter length of stay. Contrary to some conventional thought, PN was not associated with decreased time until leak closure. We therefore suggest EN should be the preferred choice of nutrition in patients with duodenal leaks whenever feasible. LEVEL OF EVIDENCE: IV.

2.
J Surg Res ; 295: 370-375, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38064978

RESUMEN

INTRODUCTION: The management of traumatic colon injuries has evolved over the past two decades. Recent evidence suggests that primary repair or resection over colostomy may decrease morbidity and mortality. Data comparing patients undergoing primary repair versus resection are lacking. We sought to compare the outcomes of patients undergoing primary repair versus resection for low-grade colon injuries. METHODS: A retrospective review of all patients who presented with American Association for the Surgery of Trauma grade I and II traumatic colon injuries to our Level I trauma center between 2011 and 2021 was performed. Patients were further dichotomized based on whether they underwent primary repair or resection with anastomosis. Outcome measures included length of stay data, infectious complications, and mortality. RESULTS: A total of 120 patients met inclusion criteria. The majority of patients (76.7%) were male, and the average age was 35.6 ± 13.1 y. Most patients also underwent primary repair (80.8%). There were no statistically significant differences between the groups in arrival physiology or in injury severity score. Length of stay data including hospital length of stay, intensive care unit length of stay, and ventilator days were similar between groups. Postoperative complications including pneumonia, surgical site infections, fascial dehiscence, the development of enterocutaneous fistulas, and unplanned returns to the operating room were also all found to be similar between groups. The group who underwent resection with anastomosis did demonstrate a higher rate of intra-abdominal abscess development (3.1% versus 26.1%, P < 0001). Mortality between both groups was not found to be statistically significant (7.2% versus 4.3%, P = 0.4) CONCLUSIONS: For low-grade (American Association for the Surgery of Trauma I and II) traumatic colon injuries, patients undergoing primary repair demonstrated a decreased rate of intra-abdominal abscess development when compared to patients who underwent resection with anastomosis.


Asunto(s)
Absceso Abdominal , Traumatismos Abdominales , Enfermedades del Colon , Traumatismos Torácicos , Heridas Penetrantes , Humanos , Masculino , Femenino , Adulto Joven , Adulto , Persona de Mediana Edad , Colon/cirugía , Colon/lesiones , Colostomía/efectos adversos , Enfermedades del Colon/cirugía , Colectomía , Traumatismos Abdominales/cirugía , Traumatismos Torácicos/cirugía , Resultado del Tratamiento , Absceso Abdominal/cirugía , Estudios Retrospectivos , Heridas Penetrantes/cirugía
4.
J Trauma Acute Care Surg ; 95(1): 151-159, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37072889

RESUMEN

BACKGROUND: Duodenal leak is a feared complication of repair, and innovative complex repairs with adjunctive measures (CRAM) were developed to decrease both leak occurrence and severity when leaks occur. Data on the association of CRAM and duodenal leak are sparse, and its impact on duodenal leak outcomes is nonexistent. We hypothesized that primary repair alone (PRA) would be associated with decreased duodenal leak rates; however, CRAM would be associated with improved recovery and outcomes when leaks do occur. METHODS: A retrospective, multicenter analysis from 35 Level 1 trauma centers included patients older than 14 years with operative, traumatic duodenal injuries (January 2010 to December 2020). The study sample compared duodenal operative repair strategy: PRA versus CRAM (any repair plus pyloric exclusion, gastrojejunostomy, triple tube drainage, duodenectomy). RESULTS: The sample (N = 861) was primarily young (33 years) men (84%) with penetrating injuries (77%); 523 underwent PRA and 338 underwent CRAM. Complex repairs with adjunctive measures were more critically injured than PRA and had higher leak rates (CRAM 21% vs. PRA 8%, p < 0.001). Adverse outcomes were more common after CRAM with more interventional radiology drains, prolonged nothing by mouth and length of stay, greater mortality, and more readmissions than PRA (all p < 0.05). Importantly, CRAM had no positive impact on leak recovery; there was no difference in number of operations, drain duration, nothing by mouth duration, need for interventional radiology drainage, hospital length of stay, or mortality between PRA leak versus CRAM leak patients (all p > 0.05). Furthermore, CRAM leaks had longer antibiotic duration, more gastrointestinal complications, and longer duration until leak resolution (all p < 0.05). Primary repair alone was associated with 60% lower odds of leak, whereas injury grades II to IV, damage control, and body mass index had higher odds of leak (all p < 0.05). There were no leaks among patients with grades IV and V injuries repaired by PRA. CONCLUSION: Complex repairs with adjunctive measures did not prevent duodenal leaks and, moreover, did not reduce adverse sequelae when leaks did occur. Our results suggest that CRAM is not a protective operative duodenal repair strategy, and PRA should be pursued for all injury grades when feasible. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.


Asunto(s)
Traumatismos Abdominales , Heridas Penetrantes , Masculino , Humanos , Estudios Retrospectivos , Complicaciones Posoperatorias , Heridas Penetrantes/cirugía , Traumatismos Abdominales/cirugía , Anastomosis Quirúrgica/métodos
5.
Am Surg ; 89(11): 4459-4468, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-35575200

RESUMEN

BACKGROUND: Necrotizing pancreatitis (NP) may result de novo or following procedures such as ERCP or partial pancreatectomy (post-procedural), and may require surgical debridement. Video-assisted retroperitoneal debridement (VARD) is a standard approach for NP that employs a 5 cm incision with varying degrees of blind and open debridement. We describe our technique and outcomes of a modified VARD called laparoscopic-assisted pancreatic necrosectomy (LAPN) performed through a single 12 mm incision that uses direct laparoscopic visualization during debridement. METHODS: At one medical center, all LAPN patients (2012-2020) were assessed for demographics, disease factors, and outcomes. Bivariate logistic regression analyses were performed to identify factors independently associated with recovery after LAPN for patients with de novo vs post-procedural necrosum. RESULTS: Over 9 years, 60 patients underwent LAPN for NP. Median age was 57 years (IQR: 47-66) and 43 (69%) were men. Pancreas necrosum was de novo in 39 (63%) patients and post-procedural in 23 (37%). NP resolved with a median of 1 LAPN procedure and median hospitalization was 33 days. The LAPN major morbidity rate and in-hospital mortality rate were 47% and 5%. No significant differences were seen between NP etiology cohorts, although post-procedure NP patients trended towards a faster clinical recovery to baseline compared to de novo patients (193 vs 394 days; p-value = .07). CONCLUSIONS: LAPN offers a smaller incision with excellent visualization and non-inferior outcomes, regardless of etiology, with likely faster recovery for patients with post-procedural vs de novo necrotizing pancreatitis.


Asunto(s)
Laparoscopía , Pancreatitis Aguda Necrotizante , Masculino , Humanos , Persona de Mediana Edad , Femenino , Desbridamiento/métodos , Páncreas/cirugía , Laparoscopía/métodos , Pancreatitis Aguda Necrotizante/cirugía , Espacio Retroperitoneal/cirugía , Drenaje/métodos , Resultado del Tratamiento
6.
Am Surg ; 86(12): 1651-1655, 2020 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-32683941

RESUMEN

BACKGROUND: Injury to the celiac artery secondary to a blunt mechanism of trauma is an extremely rare injury that accounts for only 1%-2% of all visceral vascular lesions. Although rare, this injury is associated with significant mortality. Despite this high mortality, there are currently only a few published case series of blunt celiac artery injuries in the literature. This study sought to review all cases of blunt celiac artery injuries that presented to our Level I trauma center over a 5-year period. METHODS: This was a retrospective chart review of all patients who presented with a traumatic blunt celiac artery injury between January 2012 and March 2017. RESULTS: A total of 10 patients met the inclusion criteria for this study. The majority of patients were male (7/10, 70%), the average age was 38.3 ± 16.1 years, and overall mortality was 20% (2/10). On average, patients spent 10.2 ± 6.5 days in the hospital, 4.4 ± 4.5 days in the ICU, and 1.6 ± 2.0 days on the ventilator. The majority of patients presented with either an intimal dissection (3/10, 30%) or an intraluminal thrombus (3/10, 30%). Other injuries included pseudoaneurysms (2/10, 20%), complete avulsion (1/10, 10%), and an intimal dissection with thrombus (1/10, 10%). Of these injuries, 2 (20%) were noted to have retrograde flow on imaging studies including computed tomography angiography and a visceral angiogram. The majority of patients (8/10, 80%) were managed nonoperatively, and 5 (50%) patients were discharged home on aspirin. One patient who was initially managed nonoperatively required an unplanned return to the operating room for ischemic bowel, liver, and stomach. There were no other complications noted. DISCUSSION: Traumatic blunt injury to the celiac artery is rare. Although there are multiple treatment options, there is currently no consensus in regard to management guidelines. In this case series, the majority of patients were successfully managed nonoperatively suggesting that a selective approach for intervention on patients with a blunt celiac artery injury should be considered.


Asunto(s)
Arteria Celíaca/lesiones , Heridas no Penetrantes/terapia , Adulto , Femenino , Humanos , Masculino , Sistema de Registros , Estudios Retrospectivos , Centros Traumatológicos , Heridas no Penetrantes/diagnóstico por imagen , Heridas no Penetrantes/mortalidad
7.
J Pediatr Surg ; 55(4): 702-706, 2020 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-31277980

RESUMEN

BACKGROUND: Adults with traumatic brain injury (TBI) who present hypertensive suffer worse outcomes and increased mortality compared to normotensive patients. The purpose of this study is to determine if age-adjusted hypertension on presentation is associated with worsened outcomes in pediatric TBI. METHODS: A retrospective chart review was conducted on pediatric patients with severe TBI admitted to a single system pediatric tertiary care center. The primary outcome was mortality. Secondary outcomes included length of stay, need for neurosurgical intervention, duration of mechanical ventilation, and the need for inpatient rehabilitation. RESULTS: Of 150 patients, 70% were hypertensive and 30% were normotensive on presentation. Comparing both groups, no statistically significant differences were noted in mortality (13.3% for both groups), need for neurosurgical intervention (51.4% vs 48.8%, p = 0.776), length of stay (6 vs 8 days, p = 0.732), duration of mechanical ventilation (2 vs 3 days, p = 0.912), or inpatient rehabilitation rates (48.6% vs 48.9%, p = 0.972). In comparing just the hypertensive patients, there was a trend toward increased mortality in the 95th and 99th percentile groups at 15.8% and 14.1%, versus the 90th percentile group at 6.7% but the difference was not statistically significant (p = 0.701). CONCLUSIONS: Contrary to the adult literature, pediatric patients with severe TBI and hypertension on presentation do not appear to have worsened outcomes compared to those who are normotensive. However, a trend toward increased mortality did exist at extremes of age adjusted hypertension. Larger scale studies are needed to validate these findings. STUDY TYPE: Retrospective cohort study LEVEL OF EVIDENCE: III.


Asunto(s)
Lesiones Traumáticas del Encéfalo/complicaciones , Lesiones Traumáticas del Encéfalo/mortalidad , Hipertensión/complicaciones , Presión Sanguínea , Lesiones Traumáticas del Encéfalo/rehabilitación , Lesiones Traumáticas del Encéfalo/cirugía , Niño , Preescolar , Femenino , Humanos , Lactante , Tiempo de Internación , Masculino , Rehabilitación Neurológica , Procedimientos Neuroquirúrgicos/estadística & datos numéricos , Respiración Artificial , Estudios Retrospectivos , Factores de Tiempo , Índices de Gravedad del Trauma
8.
Am Surg ; 85(5): 456-461, 2019 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-31126355

RESUMEN

Estimating the prevalence of harassment, verbal abuse, and discrimination among residents is difficult as events are often under-reported. The purpose of this study was to determine the prevalence of discrimination and abuse among surgical residents using the HITS (Hurt, Insulted, Threatened with harm or Screamed at) screening tool. A multicenter, cross-sectional, survey-based study was conducted at five academic teaching hospitals. Of 310 residents, 76 (24.5%) completed the survey. The HITS screening tool was positive in 3.9 per cent. The most common forms of abuse included sexual harassment (28.9%), discrimination based on gender (15.7%), and discrimination based on ethnicity (7.9%). There was a positive correlation between individuals who reported gender discrimination and racial discrimination (r = 0.778, n = 13, P = 0.002). Individuals who experienced insults were more likely to experience physical threats (r = 0.437, n = 79, P < 0.001) or verbal abuse (r = 0.690, n = 79, P < 0.001). Discrimination and harassment among surgical residents in academic teaching hospitals across the United States is not uncommon. Further research is needed to determine the impact of these findings on resident attrition.


Asunto(s)
Acoso no Sexual/estadística & datos numéricos , Internado y Residencia , Abuso Físico/estadística & datos numéricos , Prejuicio/estadística & datos numéricos , Acoso Sexual/estadística & datos numéricos , Discriminación Social/estadística & datos numéricos , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Prevalencia , Encuestas y Cuestionarios , Estados Unidos
10.
J Trauma Acute Care Surg ; 85(1): 78-84, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29664893

RESUMEN

BACKGROUND: Occupational exposure is an important consideration during emergency department thoracotomy (EDT). While human immunodeficiency virus/hepatitis prevalence in trauma patients (0-16.8%) and occupational exposure rates during operative trauma procedures (1.9-18.0%) have been reported, exposure risk during EDT is unknown. We hypothesized that occupational exposure risk during EDT would be greater than other operative trauma procedures. METHODS: A prospective, observational study at 16 US trauma centers was performed (2015-2016). All bedside EDT resuscitation providers were surveyed with a standardized data collection tool and risk factors analyzed with respect to the primary end point, EDT occupational exposure (percutaneous injury, mucous membrane, open wound, or eye splash). Provider and patient variables and outcomes were evaluated with single and multivariable logistic regression analyses. RESULTS: One thousand three hundred sixty participants (23% attending, 59% trainee, 11% nurse, 7% other) were surveyed after 305 EDTs (gunshot wound, 68%; prehospital cardiopulmonary resuscitation, 57%; emergency department signs of life, 37%), of which 15 patients survived (13 neurologically intact) their hospitalization. Overall, 22 occupational exposures were documented, resulting in an exposure rate of 7.2% (95% confidence interval [CI], 4.7-10.5%) per EDT and 1.6% (95% CI, 1.0-2.4%) per participant. No differences in trauma center level, number of participants, or hours worked were identified. Providers with exposures were primarily trainees (68%) with percutaneous injuries (86%) during the thoracotomy (73%). Full precautions were utilized in only 46% of exposed providers, while multiple variable logistic regression determined that each personal protective equipment item utilized during EDT correlated with a 34% decreased risk of occupational exposure (odds ratio, 0.66; 95% CI, 0.48-0.91; p = 0.010). CONCLUSIONS: Our results suggest that the risk of occupational exposure should not deter providers from performing EDT. Despite the small risk of viral transmission, our data revealed practices that may place health care providers at unnecessary risk of occupational exposure. Regardless of the lifesaving nature of the procedure, improved universal precaution compliance with personal protective equipment is paramount and would further minimize occupational exposure risks during EDT. LEVEL OF EVIDENCE: Therapeutic/care management study, level III.


Asunto(s)
Servicio de Urgencia en Hospital/estadística & datos numéricos , Exposición Profesional/estadística & datos numéricos , Toracotomía/efectos adversos , Adulto , Femenino , Personal de Salud/estadística & datos numéricos , Encuestas Epidemiológicas , Humanos , Masculino , Estudios Prospectivos , Factores de Riesgo , Toracotomía/estadística & datos numéricos , Centros Traumatológicos/estadística & datos numéricos , Estados Unidos
12.
J Trauma Acute Care Surg ; 83(1): 25-29, 2017 07.
Artículo en Inglés | MEDLINE | ID: mdl-28452877

RESUMEN

With a relative shortage of type AB plasma, many centers have converted to type A plasma for resuscitation of patients whose blood type is unknown. The goal of this study is to determine outcomes for trauma patients who received incompatible plasma transfusions as part of a massive transfusion protocol (MTP). METHODS: As part of an Eastern Association for the Surgery of Trauma multi-institutional trial, registry and blood bank data were collected from eight trauma centers for trauma patients (age, ≥ 15 years) receiving emergency release plasma transfusions as part of MTPs from January 2012 to August 2016. Incompatible type A plasma was defined as transfusion to patient blood type B or type AB. RESULTS: Of the 1,536 patients identified, 92% received compatible plasma transfusions and 8% received incompatible type A plasma. Patient characteristics were similar except for greater penetrating injuries (48% vs 36%; p = 0.01) in the incompatible group. In the incompatible group, patients were transfused more plasma units at 4 hours (median, 9 vs. 5; p < 0.001) and overall for stay (11 vs. 9; p = 0.03). No hemolytic transfusion reactions were reported. Two transfusion-related acute lung injury events were reported in the compatible group. Between incompatible and compatible groups, there was no difference in the rates of acute respiratory distress syndrome (6% vs. 8%; p = 0.589), thromboembolic events (9% vs. 7%; p = 0.464), sepsis (6% vs. 8%; p = 0.589), or acute renal failure (8% vs. 8%, p = 0.860). Mortality at 6 (17% vs. 15%, p = 0.775) and 24 hours (25% vs. 23%, p = 0.544) and at 28 days or discharge (38% vs. 35%, p = 0.486) were similar between groups. Multivariate regression demonstrated that Injury Severity Score, older age and more red blood cell transfusion at 4 hours were independently associated with death at 28 days or discharge; Injury Severity Score and more red blood cell transfusion at 4 hours were predictors for morbidity. Incompatible transfusion was not an independent determinant of mortality or morbidity. CONCLUSION: Transfusion of type A plasma to patients with blood groups B and AB as part of a MTP does not appear to be associated with significant increases in morbidity or mortality. LEVEL OF EVIDENCE: Therapeutic study, level IV.


Asunto(s)
Transfusión de Componentes Sanguíneos/métodos , Incompatibilidad de Grupos Sanguíneos , Hemorragia/terapia , Plasma , Resucitación/métodos , Heridas y Lesiones/terapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hemorragia/mortalidad , Humanos , Puntaje de Gravedad del Traumatismo , Masculino , Persona de Mediana Edad , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Centros Traumatológicos , Resultado del Tratamiento , Estados Unidos , Heridas y Lesiones/mortalidad
13.
Semin Pediatr Surg ; 26(1): 36-42, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28302283

RESUMEN

Pediatric thoracic trauma is relatively uncommon but results in disproportionately high levels of morbidity and mortality when compared with other traumatic injuries. These injuries are often more devastating due to differences in children׳s anatomy and physiology relative to adult patients. A high index of suspicion is of utmost importance at the time of presentation because many significant thoracic injuries will have no external signs of injury. With proper recognition and management of these injuries, there is an associated improved long-term outcome. This article reviews the current literature and discusses the initial evaluation, current management practices, and future directions in pediatric thoracic trauma.


Asunto(s)
Traumatismos Torácicos , Niño , Humanos , Traumatismos Torácicos/diagnóstico , Traumatismos Torácicos/epidemiología , Traumatismos Torácicos/terapia , Pared Torácica/anatomía & histología , Pared Torácica/fisiología
14.
J Neurosci Res ; 94(11): 1007-17, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27638585

RESUMEN

Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a debilitating and always fatal pediatric neurodegenerative disease caused by a mutation in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC). In the absence of GALC, progressive loss of myelin and accumulation of a neurotoxic substrate lead to incapacitating loss of motor and cognitive function and death, typically by 2 years of age. Currently, there is no cure. Recent convincing evidence of the therapeutic potential of combining gene and cell therapies in the murine model of GLD has accelerated the requirement for validated markers of disease to evaluate therapeutic efficacy. Here we demonstrate clinically relevant and quantifiable measures of central (CNS) and peripheral (PNS) nervous system disease progression in the naturally occurring canine model of GLD. As measured by brainstem auditory-evoked response testing, GLD dogs demonstrated a significant increase in I-V interpeak latency and hearing threshold at all time points. Motor nerve conduction velocities (NCVs) in GLD dogs were significantly lower than normal by 12-16 weeks of age, and sensory NCV was significantly lower than normal by 8-12 weeks of age, serving as a sensitive indicator of peripheral nerve dysfunction. Post-mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and the PNS. Additionally, cerebrospinal fluid psychosine concentrations were significantly elevated in GLD dogs, demonstrating potential as a biochemical marker of disease. These data demonstrate that CNS and PNS disease progression can be quantified over time in the canine model of GLD with tools identical to those used to assess human patients. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Potenciales Evocados Auditivos del Tronco Encefálico/genética , Leucodistrofia de Células Globoides/complicaciones , Leucodistrofia de Células Globoides/genética , Enfermedades del Sistema Nervioso , Animales , Modelos Animales de Enfermedad , Perros , Estimulación Eléctrica , Femenino , Galactosilceramidasa/genética , Humanos , Leucodistrofia de Células Globoides/diagnóstico por imagen , Leucodistrofia de Células Globoides/veterinaria , Imagen por Resonancia Magnética , Masculino , Mutación Missense/genética , Sistema Nervioso/diagnóstico por imagen , Sistema Nervioso/patología , Sistema Nervioso/fisiopatología , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/terapia , Conducción Nerviosa/genética , Psicosina/líquido cefalorraquídeo
15.
Mol Genet Metab ; 119(1-2): 124-30, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27386755

RESUMEN

High fidelity animal models of human disease are essential for preclinical evaluation of novel gene and protein therapeutics. However, these studies can be complicated by exaggerated immune responses against the human transgene. Here we demonstrate that dogs with a genetic deficiency of the enzyme α-l-iduronidase (IDUA), a model of the lysosomal storage disease mucopolysaccharidosis type I (MPS I), can be rendered immunologically tolerant to human IDUA through neonatal exposure to the enzyme. Using MPS I dogs tolerized to human IDUA as neonates, we evaluated intrathecal delivery of an adeno-associated virus serotype 9 vector expressing human IDUA as a therapy for the central nervous system manifestations of MPS I. These studies established the efficacy of the human vector in the canine model, and allowed for estimation of the minimum effective dose, providing key information for the design of first-in-human trials. This approach can facilitate evaluation of human therapeutics in relevant animal models, and may also have clinical applications for the prevention of immune responses to gene and protein replacement therapies.


Asunto(s)
Terapia de Reemplazo Enzimático , Iduronidasa/genética , Enfermedades por Almacenamiento Lisosomal/terapia , Mucopolisacaridosis I/terapia , Animales , Modelos Animales de Enfermedad , Perros , Terapia Genética , Vectores Genéticos , Glicosaminoglicanos/metabolismo , Humanos , Iduronidasa/deficiencia , Iduronidasa/uso terapéutico , Enfermedades por Almacenamiento Lisosomal/genética , Enfermedades por Almacenamiento Lisosomal/patología , Mucopolisacaridosis I/genética , Mucopolisacaridosis I/patología , Transgenes
16.
Am J Surg ; 208(6): 1083-90; discussion 1089-90, 2014 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-25440492

RESUMEN

BACKGROUND: Over the last 10 years, the paradigm of damage control resuscitation (DCR) has been associated with improved patient outcomes. This study investigates the outcomes of both closed and open pelvic ring fractures at a single institution before and after the formal implementation of DCR principles. METHODS: A retrospective chart review was performed in an urban level I trauma center of all patients who sustained open or closed pelvic ring fractures between 2002 and 2012. RESULTS: Two thousand two hundred forty-seven patients presented with pelvic fractures between 2002 and 2012. Overall mortality was 10% (n = 212). Only 8% of all patients with closed fractures required DCR compared with 28% of patients with open fractures. There was no difference in mortality when comparing DCR and pre-DCR cohorts for either open or closed pelvic fractures. CONCLUSIONS: Interestingly, although DCR seems to lead to more efficient initial resuscitations, further improvements in patient mortality were not realized with formal implementation of DCR principles.


Asunto(s)
Fracturas Óseas/mortalidad , Huesos Pélvicos/lesiones , Resucitación/métodos , Adulto , Transfusión Sanguínea , Causas de Muerte , Femenino , Fracturas Óseas/terapia , Georgia , Humanos , Masculino , Estudios Retrospectivos , Factores de Riesgo , Centros Traumatológicos , Índices de Gravedad del Trauma , Resultado del Tratamiento
17.
Mol Genet Metab ; 109(4): 390-6, 2013 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-23746554

RESUMEN

Cobalamin malabsorption accompanied by selective proteinuria is an autosomal recessive disorder known as Imerslund-Gräsbeck syndrome in humans and was previously described in dogs due to amnionless (AMN) mutations. The resultant vitamin B12 deficiency causes dyshematopoiesis, lethargy, failure to thrive, and life-threatening metabolic disruption in the juvenile period. We studied 3 kindreds of border collies with cobalamin malabsorption and mapped the disease locus in affected dogs to a 2.9Mb region of homozygosity on canine chromosome 2. The region included CUBN, the locus encoding cubilin, a peripheral membrane protein that in concert with AMN forms the functional intrinsic factor-cobalamin receptor expressed in ileum and a multi-ligand receptor in renal proximal tubules. Cobalamin malabsorption and proteinuria comprising CUBN ligands were demonstrated by radiolabeled cobalamin uptake studies and SDS-PAGE, respectively. CUBN mRNA and protein expression were reduced ~10 fold and ~20 fold, respectively, in both ileum and kidney of affected dogs. DNA sequencing demonstrated a single base deletion in exon 53 predicting a translational frameshift and early termination codon likely triggering nonsense mediated mRNA decay. The mutant allele segregated with the disease in the border collie kindred. The border collie disorder indicates that a CUBN mutation far C-terminal from the intrinsic factor-cobalamin binding site can abrogate receptor expression and cause Imerslund-Gräsbeck syndrome.


Asunto(s)
Síndromes de Malabsorción/genética , Proteinuria/genética , Receptores de Superficie Celular/genética , Deficiencia de Vitamina B 12/genética , Vitamina B 12/metabolismo , Anemia Megaloblástica , Animales , Perros , Exones , Femenino , Mutación del Sistema de Lectura , Regulación de la Expresión Génica , Humanos , Íleon/metabolismo , Riñón/metabolismo , Síndromes de Malabsorción/etiología , Síndromes de Malabsorción/metabolismo , Masculino , Unión Proteica , Proteinuria/etiología , Proteinuria/metabolismo , Estabilidad del ARN/genética , Receptores de Superficie Celular/metabolismo , Vitamina B 12/genética , Deficiencia de Vitamina B 12/etiología , Deficiencia de Vitamina B 12/metabolismo
18.
Arch Gen Psychiatry ; 69(1): 89-97, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-21893641

RESUMEN

CONTEXT: The serotonin transporter (SLC6A4) has been associated with several stress-related syndromes including posttraumatic stress disorder (PTSD). The ability to detect meaningful associations is largely dependent on reliable measures of preexisting trauma. OBJECTIVE: To study the association of genetic variants within SLC6A4 with acute and posttraumatic stress symptoms in a civilian cohort with known levels of preexisting trauma and PTSD symptoms collected prior to a shared index traumatic event. DESIGN: Ongoing longitudinal study. SETTING: On February 14, 2008, a lone gunman shot multiple people on the campus of Northern Illinois University in DeKalb, Illinois, killing 5 and wounding 21. As part of an ongoing longitudinal study on that campus, a cohort of female undergraduate students, interviewed prior to the shooting, completed follow-up trauma-related measures including PTSD symptom severity (follow-up survey was launched 17 days postshooting; n = 691). To obtain DNA, salivary samples were collected from a subset of the original study population based on willingness to participate (n = 276). PARTICIPANTS: Two hundred four undergraduate women. MAIN OUTCOME MEASURES: SLC6A4 polymorphisms STin2, 5-HTTLPR, and rs25531 were genotyped in 235 individuals. RESULTS: We found that although the STin2 variant and 5-HTTLPR alone did not associate with increased PTSD symptoms, rs25531 and the 5-HTTLPR multimarker genotype (combined 5-HTTLPR and rs25531) were associated with significantly increased acute stress disorder symptoms at 2 to 4 weeks postshooting (n = 161; P < .05). This association remained significant when controlling for race and for level of shooting exposure (n = 123; P < .007). The association was most robust with the 5-HTTLPR multimarker genotype and avoidance symptoms (P = .003). CONCLUSION: These data suggest that differential function of the serotonin transporter may mediate differential response to a severe trauma. When examined in a relatively homogenous sample with shared trauma and known prior levels of child and adult trauma, the 5-HTTLPR multimarker genotype may serve as a useful predictor of risk for PTSD-related symptoms in the weeks and months following the trauma.


Asunto(s)
Interacción Gen-Ambiente , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Trastornos por Estrés Postraumático/genética , Trastornos de Estrés Traumático Agudo/genética , Adolescente , Adulto , Femenino , Predisposición Genética a la Enfermedad , Humanos , Illinois , Acontecimientos que Cambian la Vida , Estudios Longitudinales , Persona de Mediana Edad , Polimorfismo Genético , Estudios Prospectivos , Trastornos por Estrés Postraumático/diagnóstico , Trastornos de Estrés Traumático Agudo/diagnóstico , Universidades , Adulto Joven
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