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1.
J Orthop Case Rep ; 14(5): 6-12, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38784864

RESUMEN

Introduction: Multiple spinal epidual abscesses with multifocal systemic abscess and multiple joint septic arthritis present with a large infective burden resulting in sepsis, systemic inflammatory dysregulation, and multi-organ failure. This requires pre-operative resuscitation and surgery of greater complexity, longer operative duration, and blood loss, creating challenges to surgical management. Case Report: A 69-year-old Chinese female presented with multilevel discrete spinal epidural abscesses along the cervical, thoracic, and lumbar spine, alongside concomitant multifocal systemic abscesses and multiple small joint septic arthritis. She received pre-operative resuscitation to restore organ function, reverse acidosis, and coagulopathy, prior tobefore surgical decompression of selected abscesses and joints under a multidisciplinary team. Remaining sites of infection without significant compression were undrained. The patient recovered well with no residual neurological deficits. Conclusion: Multifocal infections in critically ill patients require a multidisciplinary team for preoperative resuscitation, joint surgical planning, and prioritiszing surgical interventions to prevent excessive surgical stress to the patient.

2.
Clin Toxicol (Phila) ; 61(4): 212-222, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37010385

RESUMEN

CONTEXT: The azide anion (N3-) is highly toxic. It exists most commonly as sodium azide, which is used widely and is readily available, raising the potential for occupational incidents and use as a weapon of mass destruction. Azide-poisoned patients present with vomiting, seizures, hypotension, metabolic acidosis, and coma; death can occur. No specific azide antidote exists, with treatment being solely supportive. Azide inhibits mitochondrial cytochrome c oxidase and is likely oxidized to nitric oxide in vivo. Cytochrome c oxidase inhibition depletes intracellular adenosine triphosphate and increases oxidative stress, while increased nitric oxide causes hypotension and exacerbates oxidative damage. Here, we tested whether the cobalamin (vitamin B12) analog cobinamide, a strong and versatile antioxidant that also neutralizes nitric oxide, can reverse azide toxicity in mammalian cells, Drosophila melanogaster, and mice. RESULTS: We found cobinamide bound azide with a moderate affinity (Ka 2.87 × 105 M-1). Yet, cobinamide improved growth, increased intracellular adenosine triphosphate, and reduced apoptosis and malondialdehyde, a marker of oxidative stress, in azide-exposed cells. Cobinamide rescued Drosophila melanogaster and mice from lethal exposure to azide and was more effective than hydroxocobalamin. Azide likely generated nitric oxide in the mice, as evidenced by increased serum nitrite and nitrate, and reduced blood pressure and peripheral body temperature in the animals; the reduced temperature was likely due to reflex vasoconstriction in response to the hypotension. Cobinamide improved recovery of both blood pressure and body temperature. CONCLUSION: We conclude cobinamide likely acted by neutralizing both oxidative stress and nitric oxide, and that it should be given further consideration as an azide antidote.


Asunto(s)
Hipotensión , Vitamina B 12 , Ratones , Animales , Drosophila melanogaster/metabolismo , Azidas/metabolismo , Antídotos/farmacología , Óxido Nítrico , Complejo IV de Transporte de Electrones/metabolismo , Cobamidas , Adenosina Trifosfato , Vitaminas , Mamíferos/metabolismo
3.
Clin Toxicol (Phila) ; 60(5): 615-622, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-34989638

RESUMEN

CONTEXT: Methyl mercaptan (CH3SH) is a colorless, toxic gas with potential for occupational exposure and used as a weapon of mass destruction. Inhalation at high concentrations can result in dyspnea, hypoventilation, seizures, and death. No specific methyl mercaptan antidote exists, highlighting a critical need for such an agent. Here, we investigated the mechanism of CH3SH toxicity, and rescue from CH3SH poisoning by the vitamin B12 analog cobinamide, in mammalian cells. We also developed lethal CH3SH inhalation models in mice and rabbits, and tested the efficacy of intramuscular injection of cobinamide as a CH3SH antidote. RESULTS: We found that cobinamide binds to CH3SH (Kd = 84 µM), and improved growth of cells exposed to CH3SH. CH3SH reduced cellular oxygen consumption and intracellular ATP content and activated the stress protein c-Jun N-terminal kinase (JNK); cobinamide reversed these changes. A single intramuscular injection of cobinamide (20 mg/kg) rescued 6 of 6 mice exposed to a lethal dose of CH3SH gas, while all six saline-treated mice died (p = 0.0013). In rabbits exposed to CH3SH gas, 11 of 12 animals (92%) treated with two intramuscular injections of cobinamide (50 mg/kg each) survived, while only 2 of 12 animals (17%) treated with saline survived (p = 0.001). CONCLUSION: We conclude that cobinamide could potentially serve as a CH3SH antidote.


Asunto(s)
Antídotos , Cobamidas , Animales , Antídotos/uso terapéutico , Chlorocebus aethiops , Humanos , Ratones , Conejos , Compuestos de Sulfhidrilo , Vitamina B 12
4.
Int J Spine Surg ; 13(5): 415-422, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31741830

RESUMEN

BACKGROUND: Lateral access surgery (LAS) for lumbar degenerative spondylolisthesis is a minimally invasive lumbar fusion technique which has been gaining increasing popularity in the recent years. This study aims to identify perioperative factors that influence postoperative satisfaction after LAS for lumbar degenerative spondylolisthesis. METHODS: From August 2010 to November 2014, 52 patients with lumbar degenerative conditions (16 male: 36 female, mean age 64.0 ± 8.7 years) were prospectively recruited and underwent LAS by a single surgeon. All patients were assessed preoperatively and 2 years postoperatively with Numerical Pain Rating Scale (NPRS), Oswestry Disability Index, Short-Form 36 (SF-36) scores, North American Spine Society score for neurogenic symptoms, patient satisfaction, and expectation fulfillment. Cobb angles, global lumbar lordosis, disc heights, adjacent disc heights, fusion, and subsidence were rates assessed. Multiple linear regression performed with satisfaction as dependent variable to identify predictive independent variables. RESULTS: Lower preoperative SF-36 general health scores (P = .03), higher NPRS leg pain scores (P = .04), and longer surgical duration (P = .02) were significant predictors of lower satisfaction (P < .05). NPRS back and leg pain decreased by 80.3 and 83.0%, respectively. Oswestry Disability Index and North American Spine Society score for neurogenic symptoms improved by 76.2 and 75.9%, respectively. Ninety percent of patients reported excellent/good satisfaction. Significant correction and maintenance of Cobb and global lumbar lordosis angles were achieved. There was significant increase in disc heights postoperatively (P = .05) and no significant difference in adjacent disc heights at 2 years (P > .05). Ninety-eight percent of patients achieved Bridwell Fusion Grade 1, and 5.8% had Marchi Grade 3 subsidence. CONCLUSIONS: Lower preoperative SF-36 general health, higher NPRS leg pain, and longer surgical duration are predictors of lower satisfaction in patients undergoing LAS for lumbar degenerative spondylolisthesis. LEVEL OF EVIDENCE: III. CLINICAL RELEVANCE: Identifying preoperative predictors for postoperative clinical outcome can assist clinicians in patient education prior to operation.

5.
Int J Spine Surg ; 13(5): 464-469, 2019 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-31741834

RESUMEN

BACKGROUND: The aim of this study was to identify the rate of unsuspected malignancy in vertebral compression fractures (VCFs) treated with percutaneous vertebral augmentation procedures (PVAPs). METHODS: From 2004-2015, 410 patients with VCFs underwent PVAPs with biopsy in a single tertiary hospital. All patients had preoperative magnetic resonance imaging (MRI) read by consultant radiologists and reviewed by the performing surgeon prior to PVAPs. All procedures were performed by fellowship-trained spine surgeons. A patient was considered to have an unsuspected malignancy if preoperative MRI was negative for malignancy but histology from the operative biopsy was positive. RESULTS: A total of 44 of 45 patients (97.8%) were identified to have malignancy on preoperative MRI. One patient had a negative MRI but positive biopsy (myeloma). This patient also had a positive myeloma panel. A total of 41 of 44 patients with suspicious MRI preoperatively had a history of malignancy with histology consistent with metastatic spread from the known primary. Two patients had a new diagnosis of malignancy (1 breast carcinoma, 1 metastatic cancer likely of breast or gastrointestinal origin). Younger patients were more likely to have a VCF due to malignancy (odds ratio, 28.33 in age < 60 years). CONCLUSIONS: Almost 98% of patients with malignancy (44 of 45 patients) could be successfully identified with a preoperative MRI. The addition of a myeloma panel to MRI identified all patients with malignancies prior to PVAP in our study. We recommend MRI and myeloma panel for all patients with VCFs to be treated with PVAPs. For patients who undergo a PVAP, routine biopsy should be performed.

6.
Spine (Phila Pa 1976) ; 44(12): 839-847, 2019 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-30540718

RESUMEN

STUDY DESIGN: Retrospective study using prospectively collected registry data. OBJECTIVE: The authors examine the influence of preoperative mental health on outcomes after anterior cervical discectomy and fusion (ACDF) and determine the impact of ACDF on postoperative mental health. SUMMARY OF BACKGROUND DATA: While studies have reported a negative correlation between preoperative mental health and outcomes following lumbar spine surgery, the influence on outcomes following cervical spine surgery remains relatively understudied. METHODS: Prospectively collected registry data of 104 patients who underwent single-level ACDF for cervical spondylotic myelopathy were reviewed. Patients were dichotomized into top and bottom halves based on preoperative SF-36 MCS (Mental Component Summary) using a cutoff of 48. Outcomes assessed were visual analogue scale for neck pain, arm pain, AAOS Neck Pain and Disability, Neurogenic Symptoms, Neck Disability Index, Short-Form 36, Japanese Orthopaedic Association myelopathy score, return to work, return to function, satisfaction and expectation fulfilment up to 2 years postoperatively. RESULTS: The preoperative MCS was 37.5 ±â€Š8.1 and 57.4 ±â€Š6.3 in the Low and High MCS groups respectively (P < 0.001). The Low MCS group had poorer preoperative scores (P < 0.05). There was no significant difference in length of stay or comorbidities (P > 0.05). The High MCS group had less neck pain (P = 0.002) and showed a trend towards lower Neck Disability Index (P = 0.062) at 2 years. The Low MCS group demonstrated greater improvement in Japanese Orthopaedic Association (P = 0.007) and similar improvement in other scores (P > 0.05). There was no significant difference in proportion that achieved minimal clinically important difference for each score (P > 0.05). Both groups had similar rates of return to work, return to function, expectation fulfilment, and satisfaction (P > 0.05). Lower preoperative MCS was predictive of greater improvement in MCS (r = -0.477, P < 0.001). CONCLUSION: Despite relatively greater pain and disability at 2 years, patients with poor baseline mental health experienced similar improvement in clinical outcomes, return to work, and satisfaction rates. LEVEL OF EVIDENCE: 3.


Asunto(s)
Vértebras Cervicales/cirugía , Discectomía/tendencias , Salud Mental/tendencias , Medición de Resultados Informados por el Paciente , Satisfacción del Paciente , Reinserción al Trabajo/tendencias , Fusión Vertebral/tendencias , Adulto , Anciano , Vértebras Cervicales/diagnóstico por imagen , Discectomía/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor de Cuello/diagnóstico por imagen , Dolor de Cuello/psicología , Dolor de Cuello/cirugía , Dimensión del Dolor/métodos , Dimensión del Dolor/psicología , Dimensión del Dolor/tendencias , Estudios Prospectivos , Sistema de Registros , Estudios Retrospectivos , Reinserción al Trabajo/psicología , Enfermedades de la Médula Espinal/diagnóstico por imagen , Enfermedades de la Médula Espinal/psicología , Enfermedades de la Médula Espinal/cirugía , Fusión Vertebral/psicología , Factores de Tiempo , Resultado del Tratamiento
7.
Spine (Phila Pa 1976) ; 43(7): 477-483, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-28858183

RESUMEN

STUDY DESIGN: Retrospective matched pair cohort study using prospectively collected registry data. OBJECTIVES: The aim of this study was to determine whether patients with DM have poorer patient-reported outcomes and poorer fusion rates after undergoing a single-level anterior cervical discectomy and fusion (ACDF) for cervical myelopathy. SUMMARY OF BACKGROUND DATA: ACDF remains the most common procedure in the treatment of cervical spondylotic myelopathy (CSM); however, there is a paucity of literature with regards to patient-reported outcome measures (PROMs), health-related quality-of-life (HRQOL) scores, and fusion rates post-ACDF in diabetic patients with CSM. METHODS: From 2002 to 2012, 29 diabetic patients were matched with 29 nondiabetic controls. Patient demographics, perioperative data, and validated spine-specific scores including the Numerical Pain Rating Scale on Neck Pain and Upper Limb Pain, American Academy of Orthopaedic Surgeons (AAOS) neck pain and disability scores, AAOS Neurogenic Symptoms Score, Neck Disability Index, Japanese Orthopaedic Association Cervical Myelopathy Score, and Short Form 36 Physical/Mental Component Summaries were recorded. Fusion rates based on Bridwell grading were assessed at 2 years. RESULTS: After matching, there were no significant preoperative differences in patient demographics, clinical outcomes, PROMs or HRQoL measures between the DM and control group (P > 0.05). There was no difference in either length of hospital stay (P = 0.92) or length of surgery (P = 0.92) between the two groups. At 2 years postoperatively, there were no significant differences between validated spine-specific scores, PROMs, HRQoL scores, satisfaction rates, or fulfilment of expectations between the two groups. Significant poorer Bridwell fusion grades were noted in the DM group at 2 years postoperatively (P < 0.05). Subgroup analysis within the DM group demonstrated that glycated hemoglobin levels had no impact on functional outcomes, fulfilment of expectations, or patient satisfaction at 2 years (P > 0.05). CONCLUSION: Despite poorer fusion outcomes following single-level ACDF for symptomatic CSM, there was no significant difference in validated spine outcome scores, PROMs, HRQoL measures, or satisfaction levels when compared to nondiabetic controls at short-term follow-up. LEVEL OF EVIDENCE: 3.


Asunto(s)
Vértebras Cervicales/cirugía , Discectomía , Dolor de Cuello/cirugía , Calidad de Vida , Enfermedades de la Médula Espinal/cirugía , Adulto , Anciano , Discectomía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Estudios Retrospectivos , Fusión Vertebral/métodos , Resultado del Tratamiento
8.
Mol Cell Biol ; 37(20)2017 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-28739856

RESUMEN

CKS proteins are small (9-kDa) polypeptides that bind to a subset of the cyclin-dependent kinases. The two paralogs expressed in mammals, Cks1 and Cks2, share an overlapping function that is essential for early development. However, both proteins are frequently overexpressed in human malignancy. It has been shown that CKS protein overexpression overrides the replication stress checkpoint, promoting continued origin firing. This finding has led to the proposal that CKS protein-dependent checkpoint override allows premalignant cells to evade oncogene stress barriers, providing a causal link to oncogenesis. Here, we provide mechanistic insight into how overexpression of CKS proteins promotes override of the replication stress checkpoint. We show that CKS proteins greatly enhance the ability of Cdk2 to phosphorylate the key replication initiation protein treslin in vitro Furthermore, stimulation of treslin phosphorylation does not occur by the canonical adapter mechanism demonstrated for other substrates, as cyclin-dependent kinase (CDK) binding-defective mutants are capable of stimulating treslin phosphorylation. This effect is recapitulated in vivo, where silencing of Cks1 and Cks2 decreases treslin phosphorylation, and overexpression of wild-type or CDK binding-defective Cks2 prevents checkpoint-dependent dephosphorylation of treslin. Finally, we provide evidence that the role of CKS protein-dependent checkpoint override involves recovery from checkpoint-mediated arrest of DNA replication.


Asunto(s)
Quinasas CDC2-CDC28/metabolismo , Proteínas Portadoras/metabolismo , Puntos de Control del Ciclo Celular/fisiología , Proteínas de Ciclo Celular/metabolismo , Replicación del ADN/fisiología , Proteínas de Ciclo Celular/genética , Daño del ADN/fisiología , Humanos , Fosforilación
9.
Oncotarget ; 8(70): 114911-114923, 2017 Dec 29.
Artículo en Inglés | MEDLINE | ID: mdl-29383129

RESUMEN

The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.

10.
11.
J Cancer Educ ; 31(2): 292-300, 2016 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25971431

RESUMEN

Operating since 1994, the UCSD Moores Cancer Center's Asian Grocery Store-Based Cancer Education Program (the Program) is a proven and sustainable strategy for disseminating cancer and poison control information to Asian and Pacific Islander (API) communities. This paper describes the process taken to identify health topics that can be readily addressed within the Program's infrastructure and reports results of the pilot testing of the educational module that was developed by following that process. The development of each new module is guided by the Health Belief Model and the Tipping Point Model. The process starts with the selection of a health topic demonstrating pressing need and treatment options in the API community. Then, using the Pareto principle, reasonably modifiable risk factors are chosen to be addressed in the module. "Sticky messaging" for the modifiable risk factors is developed to package the health information as memorable and transmissible calls-to-action. Finally, grocery store outreaches were used to pilot test the new module to assess its effectiveness at facilitating health care information to API community members. By adhering to the steps described in this paper, the authors were able to: (1) select liver cancer as a pressing API health issue that could be positively impacted by the Program; (2) identify reasonably modifiable risk factors for the chosen health issue; (3) generate compelling call-to-action messages to decrease risk of exposure; and (4) demonstrate the cultural and linguistic alignment of the liver cancer control module. The development and testing of new health education modules follow a methodical process guided by scientific principles. Understanding and employing the elements of an existing evidence-based and sustainable health education program can increase the likelihood of success in addressing the health needs of the API community.


Asunto(s)
Servicios de Alimentación/organización & administración , Educación en Salud , Conocimientos, Actitudes y Práctica en Salud , Neoplasias/prevención & control , Educación del Paciente como Asunto , Asiático , Humanos , Proyectos Piloto
12.
J Spinal Disord Tech ; 28(6): E328-35, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23563354

RESUMEN

STUDY DESIGN: We conducted a retrospective analysis of a prospectively collected database in a tertiary hospital over 10 years. OBJECTIVE: Treatment for vertebral compression fractures remains an area of controversy with respect to timing and type of surgical management. We analyzed the clinical outcomes and radiographic measurements of 4 different modalities of treatment for these fractures. SUMMARY OF BACKGROUND DATA: From 2001 to 2011, we analyzed a total of 363 patients after failure of 30 days of conservative management. These patients were then further managed either conservatively or with vertebroplasty, balloon kyphoplasty, or sky bone expander. Outcomes were assessed by using self-report measures: Visual Analog Score; functional measures: Oswestry Disability Index and Short-Form 36; and physiological measures: preoperative and postoperative radiographs. METHODS: The outcome measures were assessed for 6 months for those treated conservatively and up till 2 years for those treated surgically. Radiographic measurements of the spine were correlated with the clinical outcomes. RESULTS: A total of 62 patients (12.1%) were treated conservatively, 148 (40.8%) with vertebroplasty, 97 (26.7%) with balloon kyphoplasty, and 56 (15.4%) with sky bone expander. We found significant improvements in Visual Analog Score, Oswestry Disability Index, and Short-Form-36 scores for all groups after 1-month follow-up (P<0.05), with the surgical groups demonstrating a greater improvement in pain scores after the first postoperative day (P<0.0001) when compared with the conservative group. The improvements in outcomes in those treated surgically were sustained for up to 2 years with no significant difference (P>0.05) among the surgical groups. We also found significant improvement (P<0.005) in anterior vertebral and kyphotic wedge angle after surgical intervention. CONCLUSIONS: We have shown that early surgical intervention allows for quicker pain relief compared with conservative treatment, with similar improvements in anterior vertebral height and kyphotic wedge angle between all 3 groups of surgical management.


Asunto(s)
Fracturas por Compresión/diagnóstico por imagen , Fracturas por Compresión/cirugía , Procedimientos Ortopédicos/métodos , Fracturas Osteoporóticas/diagnóstico por imagen , Fracturas Osteoporóticas/cirugía , Anciano , Anciano de 80 o más Años , Evaluación de la Discapacidad , Femenino , Humanos , Cifoplastia/efectos adversos , Cifoplastia/métodos , Cifosis/diagnóstico por imagen , Cifosis/cirugía , Masculino , Procedimientos Ortopédicos/efectos adversos , Dimensión del Dolor , Radiografía , Autoinforme , Fracturas de la Columna Vertebral , Columna Vertebral/diagnóstico por imagen , Dispositivos de Expansión Tisular , Resultado del Tratamiento , Vertebroplastia/efectos adversos , Vertebroplastia/métodos
13.
J Cancer Educ ; 30(1): 26-30, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24969319

RESUMEN

The Asian Grocery Store-Based Cancer Education Program (the Program) is a proven strategy for promoting early breast cancer detection among Asian American women. The authors sought to test whether the same public health model can become an effective strategy for increasing the Asian community's awareness of the California Smokers' Helpline (the Helpline) and thereby, potentially decreasing this community's use of tobacco products. The new module, mainly staffed by four well-trained, volunteer undergraduates, explained the risks of first- and second-hand tobacco exposure and how to access the Helpline's services. A brochure, provided in English, Chinese, Korean, and Vietnamese (the Helpline's available Asian languages), was used to guide the bicultural, bilingual students' tobacco-related discussions with shoppers. The students' repeated presence at the nine partnering Asian grocery stores served as reminders of the Helpline's availability. In its first year of operation, the student trainers reached 1,052 men and 1,419 women with tobacco cessation messages. Equally important, the participating grocery stores' managers did not object to students telling their customers to quit using the tobacco products sold in their stores. The results suggest that the Program's tobacco cessation module is a viable, community-specific, public health strategy. It is also a strategy with the potential for applications to reduce other health threats.


Asunto(s)
Educación en Salud , Servicios de Salud/provisión & distribución , Difusión de la Información , Cese del Hábito de Fumar/etnología , Cese del Hábito de Fumar/estadística & datos numéricos , Asiático , California/etnología , Femenino , Humanos , Masculino , Nativos de Hawái y Otras Islas del Pacífico , Proyectos Piloto
14.
Cell ; 156(3): 413-27, 2014 Jan 30.
Artículo en Inglés | MEDLINE | ID: mdl-24485452

RESUMEN

The response to DNA damage, which regulates nuclear processes such as DNA repair, transcription, and cell cycle, has been studied thoroughly. However, the cytoplasmic response to DNA damage is poorly understood. Here, we demonstrate that DNA damage triggers dramatic reorganization of the Golgi, resulting in its dispersal throughout the cytoplasm. We further show that DNA-damage-induced Golgi dispersal requires GOLPH3/MYO18A/F-actin and the DNA damage protein kinase, DNA-PK. In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA-damaging agents. Identification of the DNA-damage-induced Golgi response reveals an unexpected pathway through DNA-PK, GOLPH3, and MYO18A that regulates cell survival following DNA damage.


Asunto(s)
Daño del ADN , Proteína Quinasa Activada por ADN/metabolismo , Aparato de Golgi/metabolismo , Proteínas de la Membrana/metabolismo , Miosinas/metabolismo , Secuencia de Aminoácidos , Animales , Línea Celular , Supervivencia Celular , Células Cultivadas , Humanos , Proteínas de la Membrana/química , Ratones , Datos de Secuencia Molecular , Fosforilación , Ratas , Alineación de Secuencia
15.
Mol Cell ; 50(5): 699-710, 2013 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-23685072

RESUMEN

Oncogene-induced senescence is an important tumor-suppressing defense mechanism. However, relatively little is known about the signaling pathway mediating the senescence response. Here, we demonstrate that a multifunctional acetyltransferase, Tip60, plays an essential role in oncogenic ras-induced senescence. Further investigation reveals a cascade of posttranslational modifications involving p38, Tip60, and PRAK, three proteins that are essential for ras-induced senescence. Upon activation by ras, p38 induces the acetyltransferase activity of Tip60 through phosphorylation of Thr158; activated Tip60 in turn directly interacts with and induces the protein kinase activity of PRAK through acetylation of K364 in a manner that depends on phosphorylation of both Tip60 and PRAK by p38. These posttranslational modifications are critical for the prosenescent function of Tip60 and PRAK, respectively. These results have defined a signaling pathway that mediates oncogene-induced senescence, and identified posttranslational modifications that regulate the enzymatic activity and biological functions of Tip60 and PRAK.


Asunto(s)
Senescencia Celular/genética , Genes ras , Histona Acetiltransferasas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Acetilación , Línea Celular , Histona Acetiltransferasas/genética , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Lisina Acetiltransferasa 5 , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Transducción de Señal , Treonina/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/genética
16.
Spine (Phila Pa 1976) ; 38(10): 846-50, 2013 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-23222569

RESUMEN

STUDY DESIGN: This is a prospective study. OBJECTIVE: A 2-year outcome of erectile dysfunction (ED) in patients younger than 50 years with fracture-unrelated lumbar spine disease requiring surgical decompression for ED is evaluated. Risk factors for ED were also evaluated. SUMMARY OF BACKGROUND DATA: There is no literature documenting 2-year follow-up of ED status in young patients with atraumatic lumbar spine disease. METHODS: All male patients younger than 50 years who underwent lumbar spine surgery between June 2006 and November 2007 without risk factors for ED were included. Patient demographics, neurological dysfunction, visual analogue scale (VAS) for back and leg pain, Oswestry Disability Index, North American Spine Society score for neurogenic symptoms, and the international index of erectile function-5 scores were recorded preoperatively and at 2 years. Patients who did not complete a 2-year follow-up were excluded. RESULTS.: A total of 75 patients were eligible for the study. Nineteen patients did not complete a 2-year follow-up giving a response rate of 75%. There were 56 patients in the study with a mean age of 38.4 (SD, 7.2; range, 20-49). The most common diagnosis was prolapsed intervertebral disc (77%) for which patients underwent discectomy. Preoperatively, 21 of 56 (37.5%) patients had ED. Despite significant improvement in mean VAS scores for back pain and leg pain, Oswestry Disability Index, and North American Spine Society score for neurogenic symptoms at 2 years (P < 0.01), the mean international index of erectile function-5 scores remained stable. Patients with ED at 2 years had greater back pain (mean VAS score 3.4) compared with patients without back pain (mean VAS score, 1.6; P ≤ 0.01). CONCLUSION: Despite excellent outcome in most spine scores postoperatively after lumbar spine surgery, one has to be less optimistic about any improvement in the ED status of patients after surgery. ED is still a problem 2 years after surgery. Back pain reduction may have a significant role in dealing with ED at 2 years postoperatively. LEVEL OF EVIDENCE: 2.


Asunto(s)
Descompresión Quirúrgica/efectos adversos , Disfunción Eréctil/etiología , Vértebras Lumbares/cirugía , Enfermedades de la Columna Vertebral/cirugía , Adulto , Dolor de Espalda/etiología , Evaluación de la Discapacidad , Discectomía/efectos adversos , Humanos , Desplazamiento del Disco Intervertebral/etiología , Pierna/fisiopatología , Masculino , Persona de Mediana Edad , Dolor/etiología , Dolor/fisiopatología , Dimensión del Dolor , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Factores de Riesgo , Factores de Tiempo , Adulto Joven
17.
Spine (Phila Pa 1976) ; 37(9): 797-801, 2012 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-21912318

RESUMEN

STUDY DESIGN: This is a prospective study. OBJECTIVE: The prevalence of erectile dysfunction (ED) in patients younger than 50 years with fracture-unrelated lumbar spine disease requiring surgical decompression without other risk factors for ED is evaluated. SUMMARY OF BACKGROUND DATA: There is little literature documenting ED in young patients with atraumatic lumbar spine disease. METHODS: All male patients younger than 50 years who underwent lumbar spine surgery during June 2006 to November 2007 without risk factors for ED were included. Patient demographics, neurological dysfunction, visual analogue scale (VAS) for back and leg pain, Oswestry Disability Index (ODI), North American Spine Society score for neurogenic symptoms (NS), and the International Index of Erectile function (IIEF-5) scores were recorded preoperatively, at 1, 3, and 6 months. RESULTS: There were 61 patients with mean age 38.4 years (SD = 7.0; range, 20-49). Most of patients had (43 or 70.5%) prolapsed intervertebral disc with discectomy being the commonest operation. Mean VAS scores, ODI, and NS improved significantly postoperatively. However, the mean IIEF-5 scores did not. Preoperatively, there was no correlation between ED and VAS scores on back pain (P = 0.70), leg pain (P = 0.91), ODI (P = 0.93), or NS (P = 0.51). At 6 months, patients with NS > 70 had an increased risk of ED (P = 0.03). Eighty percent of patients with NS > 70 had ED compared with 30% of patients with NS ≤ 70. There was, however, no correlation between ED with ODI (P = 0.38) and VAS scores on back pain (P = 0.20) or leg pain (P = 0.08) at 6 months. CONCLUSION: The incidence of ED in patients younger than 50 years with nonfracture-related lumbar spine disease undergoing surgery without risk factors was 34.3%. Despite improvement in VAS, ODI, and NS scores postoperatively, ED did not improve. Patients with NS > 70 postoperatively were more likely to have ED reflecting possible permanent nerve damage from lumbar spine pathology.


Asunto(s)
Disfunción Eréctil/etiología , Vértebras Lumbares/cirugía , Procedimientos Ortopédicos/efectos adversos , Enfermedades de la Columna Vertebral/cirugía , Adulto , Factores de Edad , Dolor de Espalda/etiología , Distribución de Chi-Cuadrado , Descompresión Quirúrgica/efectos adversos , Evaluación de la Discapacidad , Discectomía/efectos adversos , Humanos , Incidencia , Laminectomía/efectos adversos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Dimensión del Dolor , Estudios Prospectivos , Medición de Riesgo , Factores de Riesgo , Singapur , Enfermedades de la Columna Vertebral/complicaciones , Enfermedades de la Columna Vertebral/diagnóstico , Fusión Vertebral/efectos adversos , Encuestas y Cuestionarios , Factores de Tiempo , Resultado del Tratamiento , Adulto Joven
18.
J Orthop Surg (Hong Kong) ; 19(2): 135-40, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21857032

RESUMEN

PURPOSE: To evaluate the outcomes, fusion rates, complications, and adjacent segment degeneration associated with transforaminal lumbar interbody fusion (TLIF). METHODS: 32 men and 80 women aged 15 to 85 (mean, 57) years underwent 141 fusions (84 one-level, 27 2-level, and one 3-level) and were followed up for 24 to 76 (mean, 33) months. 92% of the patients had degenerative lumbar disease, 15 of whom had had previous lumbar surgery. Radiographic and clinical outcomes were assessed at 2 years. The short-form 36 (SF-36) health survey, visual analogue scale (VAS) for pain, and the modified North American Spine Society (NASS) Low Back Pain Outcome Instrument were used. RESULTS: Of the 141 levels fused, 110 (78%) were fused with remodelling and trabeculae (grade I), and 31 (22%) had intact grafts but were not fully incorporated (grade II). No patient had pseudoarthroses (grade III or IV). For one-level fusions, poorer radiological fusion grades correlated with higher VAS scores for pain (p<0.01). All components of the SF-36, the VAS scores for pain, and the NASS scores improved significantly after TLIF (p<0.01), except for general health in the SF-36 (p=0.59). Improvement from postoperative 6 months to 2 years was not significant, except for physical function (p<0.01) and role function (physical) [p=0.01] in the SF-36. Two years after TLIF, 50% of the patients reported returning to full function, whereas 72% were satisfied. 26 (23%) of the patients had adjacent segment degeneration, but only 4 of them were symptomatic. CONCLUSION: TLIF is a safe and effective treatment for degenerative lumbar diseases.


Asunto(s)
Degeneración del Disco Intervertebral/cirugía , Fusión Vertebral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Indicadores de Salud , Humanos , Vértebras Lumbares , Masculino , Persona de Mediana Edad , Dimensión del Dolor , Complicaciones Posoperatorias/epidemiología , Fusión Vertebral/efectos adversos , Espondilolistesis/cirugía , Resultado del Tratamiento , Adulto Joven
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