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1.
iScience ; 27(4): 109527, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38585658

RESUMEN

Hearing loss can lead to long-lasting effects on the central nervous system, and current therapies, such as auditory training and rehabilitation, show mixed success in improving perception and speech comprehension. Vagus nerve stimulation (VNS) is an adjunctive therapy that can be paired with rehabilitation to facilitate behavioral recovery after neural injury. However, VNS for auditory recovery has not been tested after severe hearing loss or significant damage to peripheral receptors. This study investigated the utility of pairing VNS with passive or active auditory rehabilitation in a rat model of noise-induced hearing loss. Although auditory rehabilitation helped rats improve their frequency discrimination, learn novel speech discrimination tasks, and achieve speech-in-noise performance similar to normal hearing controls, VNS did not enhance recovery of speech sound perception. These results highlight the limitations of VNS as an adjunctive therapy for hearing loss rehabilitation and suggest that optimal benefits from neuromodulation may require restored peripheral signaling.

2.
Front Neurosci ; 17: 1248936, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37732302

RESUMEN

Introduction: Repeatedly pairing a tone with vagus nerve stimulation (VNS) alters frequency tuning across the auditory pathway. Pairing VNS with speech sounds selectively enhances the primary auditory cortex response to the paired sounds. It is not yet known how altering the speech sounds paired with VNS alters responses. In this study, we test the hypothesis that the sounds that are presented and paired with VNS will influence the neural plasticity observed following VNS-sound pairing. Methods: To explore the relationship between acoustic experience and neural plasticity, responses were recorded from primary auditory cortex (A1) after VNS was repeatedly paired with the speech sounds 'rad' and 'lad' or paired with only the speech sound 'rad' while 'lad' was an unpaired background sound. Results: Pairing both sounds with VNS increased the response strength and neural discriminability of the paired sounds in the primary auditory cortex. Surprisingly, pairing only 'rad' with VNS did not alter A1 responses. Discussion: These results suggest that the specific acoustic contrasts associated with VNS can powerfully shape neural activity in the auditory pathway. Methods to promote plasticity in the central auditory system represent a new therapeutic avenue to treat auditory processing disorders. Understanding how different sound contrasts and neural activity patterns shape plasticity could have important clinical implications.

3.
J Cereb Blood Flow Metab ; 43(3): 404-418, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36250505

RESUMEN

The impact of aerobic exercise training (AET) on cerebral blood flow (CBF) regulation remains inconclusive. This study investigated the effects of one-year progressive, moderate-to-vigorous AET on CBF, central arterial stiffness, and cognitive performance in cognitively normal older adults. Seventy-three older adults were randomly assigned to AET or stretching-and-toning (SAT, active control) intervention. CBF was measured with 2D duplex ultrasonography. Central arterial stiffness, measured by carotid ß-stiffness index, was assessed with the ultrasonography and applanation tonometry. Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by CBF. A cognitive battery was administered with a focus on memory and executive function. Cardiorespiratory fitness was measured by peak oxygen consumption (V˙O2peak). One-year AET increased V˙O2peak and CBF and decreased CVR and carotid ß-stiffness index. In the AET group, improved V˙O2peak was correlated with increased CBF (r = 0.621, p = 0.001) and decreased CVR (r = -0.412, p = 0.037) and carotid ß-stiffness index (r = -0.478, p = 0.011). Further, increased Woodcock-Johnson recall score was associated with decreased CVR (r = -0.483, p = 0.012) and carotid ß-stiffness index (r = -0.498, p = 0.008) in AET group (not in SAT group). In conclusion, one-year progressive, moderate-to-vigorous aerobic exercise training increased CBF and decreased carotid arterial stiffness and CVR which were associated with improved memory function in cognitively normal older adults.


Asunto(s)
Capacidad Cardiovascular , Ejercicio Físico , Rigidez Vascular , Presión Arterial , Arterias Carótidas/diagnóstico por imagen , Circulación Cerebrovascular/fisiología , Ejercicio Físico/fisiología , Rigidez Vascular/fisiología , Humanos , Adulto
4.
J Intern Med ; 292(5): 788-803, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35713933

RESUMEN

BACKGROUND: Current evidence is inconsistent on the benefits of aerobic exercise training for preventing or attenuating age-related cognitive decline in older adults. OBJECTIVE: To investigate the effects of a 1-year progressive, moderate-to-high intensity aerobic exercise intervention on cognitive function, brain volume, and cortical thickness in sedentary but otherwise healthy older adults. METHODS: We randomized 73 older adults to a 1-year aerobic exercise or stretching-and-toning (active control) program. The primary outcome was a cognitive composite score calculated from eight neuropsychological tests encompassing inductive reasoning, long-term and working memory, executive function, and processing speed. Secondary outcomes were brain volume and cortical thickness assessed by MRI, and cardiorespiratory fitness measured by peak oxygen uptake (VO2 ). RESULTS: One-year aerobic exercise increased peak VO2 by ∼10% (p < 0.001) while it did not change with stretching (p = 0.241). Cognitive composite scores increased in both the aerobic and stretching groups (p < 0.001 for time effect), although no group difference was observed. Total brain volume (p < 0.001) and mean cortical thickness (p = 0.001) decreased in both groups over time, while the reduction in hippocampal volume was smaller in the stretching group compared with the aerobic group (p = 0.040 for interaction). Across all participants, improvement in peak VO2 was positively correlated with increases in cognitive composite score (r = 0.282, p = 0.042) and regional cortical thickness at the inferior parietal lobe (p = 0.016). CONCLUSIONS: One-year aerobic exercise and stretching interventions improved cognitive performance but did not prevent age-related brain volume loss in sedentary healthy older adults. Cardiorespiratory fitness gain was positively correlated with cognitive performance and regional cortical thickness.


Asunto(s)
Disfunción Cognitiva , Ejercicio Físico , Anciano , Cognición , Disfunción Cognitiva/psicología , Terapia por Ejercicio , Humanos , Pruebas Neuropsicológicas , Oxígeno
5.
Neuroscience ; 477: 63-75, 2021 11 21.
Artículo en Inglés | MEDLINE | ID: mdl-34634426

RESUMEN

Intense noise exposure is a leading cause of hearing loss, which results in degraded speech sound discrimination ability, particularly in noisy environments. The development of an animal model of speech discrimination deficits due to noise induced hearing loss (NIHL) would enable testing of potential therapies to improve speech sound processing. Rats can accurately detect and discriminate human speech sounds in the presence of quiet and background noise. Further, it is known that profound hearing loss results in functional deafness in rats. In this study, we generated rats with a range of impairments which model the large range of hearing impairments observed in patients with NIHL. One month after noise exposure, we stratified rats into three distinct deficit groups based on their auditory brainstem response (ABR) thresholds. These groups exhibited markedly different behavioral outcomes across a range of tasks. Rats with moderate hearing loss (30 dB shifts in ABR threshold) were not impaired in speech sound detection or discrimination. Rats with severe hearing loss (55 dB shifts) were impaired at discriminating speech sounds in the presence of background noise. Rats with profound hearing loss (70 dB shifts) were unable to detect and discriminate speech sounds above chance level performance. Across groups, ABR threshold accurately predicted behavioral performance on all tasks. This model of long-term impaired speech discrimination in noise, demonstrated by the severe group, mimics the most common clinical presentation of NIHL and represents a useful tool for developing and improving interventions to target restoration of hearing.


Asunto(s)
Pérdida Auditiva Provocada por Ruido , Percepción del Habla , Animales , Umbral Auditivo , Potenciales Evocados Auditivos del Tronco Encefálico , Audición , Humanos , Ruido/efectos adversos , Ratas
6.
Surg Neurol Int ; 12: 271, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34221602

RESUMEN

BACKGROUND: COVID-19 has had a significant impact on the economy, health care, and society as a whole. To prevent the spread of infection, local governments across the United States issued mandatory lockdowns and stay-at-home orders. In the surgical world, elective cases ceased to help "flatten the curve" and prevent the infection from spreading to hospital staff and patients. We explored the effect of the cancellation of these procedures on trainee operative experience at our high-volume, multihospital neurosurgical practice. METHODS: Our department cancelled all elective cases starting March 16, 2020, and resumed elective surgical and endovascular procedures on May 11, 2020. We retrospectively reviewed case volumes for 54 days prelockdown and 54 days postlockdown to evaluate the extent of the decrease in surgical volume at our institution. Procedure data were collected and then divided into cranial, spine, functional, peripheral nerve, pediatrics, and endovascular categories. RESULTS: Mean total cases per day in the prelockdown group were 12.26 ± 7.7, whereas in the postlockdown group, this dropped to 7.78 ± 5.5 (P = 0.01). In the spine category, mean cases per day in the prelockdown group were 3.13 ± 2.63; in the postlockdown group, this dropped to 0.96 ± 1.36 (P < 0.001). In the functional category, mean cases per day in the prelockdown group were 1.31 ± 1.51, whereas in the postlockdown group, this dropped to 0.11 ± 0.42 (P < 0.001). For cranial (P = 0.245), peripheral nerve (P = 0.16), pediatrics (P = 0.34), and endovascular (P = 0.48) cases, the volumes dropped but were not statistically significant decreases. CONCLUSION: The impact of this outbreak on operative training does appear to be significant based solely on statistics. Although the drop in case volumes during this time can be accounted for by the pandemic, it is important to understand that this is a multifactorial effect. Further studies are needed for these results to be generalizable and to fully understand the effect this pandemic has had on trainee operative experience.

7.
Stereotact Funct Neurosurg ; 99(4): 322-328, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33657550

RESUMEN

This manuscript introduces the latest generation of a patient-mounted platform designed for segmental injections of therapeutics direct into the spinal cord parenchyma. It emphasizes its importance and it presents the rationale for developing this delivery methodology. It compares the newest with the previous generations, detailing how the modifications can streamline transportation, assembly, sterilization, and utilization of the platform by different surgeons. Finally, the illustrations depict the main alterations, as well as a cadaveric assessment of the device prototype in the cervical and thoracolumbar regions.


Asunto(s)
Médula Espinal , Humanos , Inyecciones Espinales , Médula Espinal/cirugía
8.
World Neurosurg ; 144: e750-e765, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32949803

RESUMEN

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is the surgical method of choice to treat the canonical symptoms of Parkinson disease, occasionally surgical sites become infected or the hardware erodes, necessitating explantation. Usual practice is to remove and reimplant replacement leads after tissue healing, leaving patients without the clinical benefits of DBS for several months, and at risk for DBS withdrawal in some, and some patients are no longer good surgical candidates for reimplantation. Radiofrequency ablation through the DBS lead is an option for these patients. METHODS: We performed a retrospective chart review of all patients who underwent radiofrequency ablation of the STN or GPi through indwelling DBS leads performed before hardware removal at our institution. We generated patient-specific anatomic models to determine lesion locations and volumes. RESULTS: Six patients underwent radiofrequency ablation of the STN (n = 4) and GPi (n = 2) through indwelling DBS leads. All 6 of these patients initially showed comparable motor symptom relief to that experienced with DBS before lesioning, with 4 patients sustaining meaningful long-term (≥2 years) improvement. Better outcomes were achieved in those patients with a higher percentage of the planned target lesioned. CONCLUSIONS: Radiofrequency ablation through indwelling DBS leads before explantation could be considered a viable alternative to subsequent reimplantation or stereotactic lesion in patients with Parkinson disease in whom hardware explantation is necessary, if the patient achieved substantive symptom relief with DBS. This approach avoids symptom exacerbation while awaiting revision surgery.


Asunto(s)
Estimulación Encefálica Profunda , Procedimientos Neuroquirúrgicos/métodos , Enfermedad de Parkinson/cirugía , Ablación por Radiofrecuencia/métodos , Anciano , Encéfalo/diagnóstico por imagen , Femenino , Globo Pálido/cirugía , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico por imagen , Estudios Retrospectivos , Núcleo Subtalámico/cirugía , Resultado del Tratamiento
9.
J Cereb Blood Flow Metab ; 40(3): 600-610, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-30764704

RESUMEN

Age is the strongest risk factor for cerebrovascular disease; however, age-related changes in cerebrovascular function are still not well understood. The objective of this study was to measure cerebral vasomotor reactivity (CVMR) during hypo- and hypercapnia across the adult lifespan. One hundred fifty-three healthy participants (21-80 years) underwent measurements of cerebral blood flow velocity (CBFV) via transcranial Doppler, mean arterial pressure (MAP) via plethysmograph, and end-tidal CO2 (EtCO2) via capnography during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia). Cerebrovascular conductance (CVCi) and resistance (CVRi) indices were calculated from the ratios of CBFV and MAP. CVMRs were assessed by the slopes of CBFV and CVCi in response to changes in EtCO2. The baseline CBFV and CVCi decreased and CVRi increased with age. Advanced age was associated with progressive declines in CVMR during hypocapnia indicating reduced cerebral vasoconstriction, but increases in CVMR during hypercapnia indicating increased vasodilation. A negative correlation between hypo- and hypercapnic CVMRs was observed across all subjects (CBFV%/ EtCO2: r = -0.419, CVCi%/ EtCO2: r = -0.442, P < 0.0001). Collectively, these findings suggest that aging is associated with decreases in CBFV, increases in cerebrovascular resistance, reduced vasoconstriction during hypocapnia, but increased vasodilatory responsiveness during hypercapnia.


Asunto(s)
Envejecimiento , Presión Sanguínea , Circulación Cerebrovascular , Hipercapnia , Hipocapnia , Ultrasonografía Doppler Transcraneal , Resistencia Vascular , Vasoconstricción , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Hipercapnia/diagnóstico por imagen , Hipercapnia/fisiopatología , Hipocapnia/diagnóstico por imagen , Hipocapnia/fisiopatología , Masculino , Persona de Mediana Edad
10.
Foot Ankle Surg ; 26(6): 676-680, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-31515200

RESUMEN

BACKGROUND: The aim of this project was to analyse whether a CT influences surgical planning in ankle fracture involving the posterior malleolus. METHODS: Twenty consecutive patients with fractures involving the posterior malleolus were retrospectively selected and had their plain radiographs and CT scan anonymised. Initially, radiographs alone were presented to nine trauma surgeons to formulate a surgical plan individually. After a minimum of 6 weeks, the same process was repeated with CT scans available. RESULTS: The surgical approach for ankle fracture fixation changed in 32.7% of cases following CT scan review. A CT scan altered the decision to stabilise the posterior malleolus in 25.6% and the decision of whether to stabilise the syndesmosis in 16.6% of cases. CONCLUSIONS: This study demonstrates that a pre-operative CT scan changes the surgical approach in 32.7% of cases and therefore we recommend use of CT scanning in this subset of ankle injuries.


Asunto(s)
Fracturas de Tobillo/diagnóstico por imagen , Fracturas de Tobillo/cirugía , Toma de Decisiones Clínicas , Cuidados Preoperatorios , Cirujanos , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Anciano , Fracturas de Tobillo/clasificación , Femenino , Fijación de Fractura , Humanos , Masculino , Persona de Mediana Edad , Pautas de la Práctica en Medicina , Radiografía , Estudios Retrospectivos , Adulto Joven
11.
Neurol Clin ; 38(1): 201-214, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31761059

RESUMEN

Deep brain stimulation is the most advanced and effective neuromodulation therapy for Parkinson disease, essential tremor, and generalized dystonia. This article discusses how imaging improves surgical techniques and outcomes and widens possibilities in translational neuroscience in Parkinson disease, essential tremor, generalized dystonia, and epilepsy. In movement disorders diffusion tensor imaging allows anatomic segment of cortical areas and different functional subregions within deep-seated targets to understand the side effects of stimulation and gain more data to describe the therapeutic mechanism of action. The introduction of visualization of white matter tracks increases the safety of neurosurgical techniques in functional neurosurgery and neuro-oncology.


Asunto(s)
Estimulación Encefálica Profunda/métodos , Trastornos del Movimiento/diagnóstico por imagen , Trastornos del Movimiento/terapia , Neuroimagen/métodos , Técnicas Estereotáxicas , Imagen de Difusión Tensora/métodos , Distonía/diagnóstico por imagen , Distonía/terapia , Epilepsia/diagnóstico por imagen , Epilepsia/terapia , Temblor Esencial/diagnóstico por imagen , Temblor Esencial/terapia , Humanos , Procedimientos Neuroquirúrgicos/métodos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/terapia
12.
Neurosurg Clin N Am ; 30(2): 137-146, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30898266

RESUMEN

Parkinson disease (PD) is the second most common neurodegenerative disorder and affects more than 1 million individuals in the United States. Deep brain stimulation (DBS) is one form of treatment of PD. DBS treatment is still evolving due to technological innovations that shape how this therapy is used.


Asunto(s)
Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Humanos , Microelectrodos , Resultado del Tratamiento
13.
J Orthop ; 16(1): 91-96, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30662246

RESUMEN

OBJECTIVES: We aimed to report outcomes of Bicondylar Tibial Plateau (BTP) fractures treated using Ilizarov fixation, and identify risk factors for developing post-traumatic radiographic osteoarthritis (ROA). METHODS: Retrospective study of 80 BTP fractures managed with Ilizarov fixation. RESULTS: All fractures united, with only 3 cases of deep infection. ROA was evident in 12.5% at average 13 months post-injury. Increased tibial articular-widening associated with risk of developing ROA (p = 0.02). CONCLUSION: Ilizarov fixation is safe and reliable in the management of BTP fractures. Restoration of tibial articular-width at fixation associated with reduced risk of developing radiographic OA.

14.
J Cereb Blood Flow Metab ; 39(5): 926-936, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-29219028

RESUMEN

Ambulatory blood pressure (ABP) reflects the end-organ vascular stress in daily life; however, its influence on brain neuronal fiber integrity and cerebral blood flow (CBF) remains unclear. The objective of this study was to determine the associations among ABP, white matter (WM) neuronal fiber integrity, and CBF in older adults. We tested 144 participants via ABP monitoring and diffusion tensor imaging. The total level and pulsatile indices of CBF were measured by phase-contrast MRI and transcranial Doppler, respectively. Neuropsychological assessment was conducted in 72 participants. Among ambulatory and office BP measures, elevated 24-h pulse pressure (PP) was associated with the greatest number of WM skeleton voxels with decreased fractional anisotropy (FA) and increased mean diffusivity (MD). Furthermore, these associations remained significant after adjusting for age, antihypertensive use, aortic stiffness, WM lesion volume, and office PP. Radial diffusivity (RD) was elevated in the regions with decreased FA, while axial diffusivity was unaltered. The reduction in diastolic index explained a significant proportion of the individual variability in FA, MD, and RD. Executive function performance was correlated with WM fiber integrity. These findings suggest that elevated ambulatory PP may deteriorate brain neuronal fiber integrity via reduction in diastolic index.


Asunto(s)
Envejecimiento , Presión Sanguínea , Encéfalo/diagnóstico por imagen , Circulación Cerebrovascular , Anciano , Anciano de 80 o más Años , Monitoreo Ambulatorio de la Presión Arterial , Encéfalo/irrigación sanguínea , Encéfalo/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/fisiopatología , Imagen de Difusión Tensora , Función Ejecutiva , Humanos , Persona de Mediana Edad , Rigidez Vascular , Sustancia Blanca/irrigación sanguínea , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/fisiopatología
15.
J Neurosurg ; : 1-12, 2018 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-30554176

RESUMEN

OBJECTIVEDeep brain stimulation (DBS) is an effective procedure in improving motor symptoms for patients with advanced Parkinson's disease (PD) through the use of high-frequency stimulation. Although one of the most commonly used target sites for DBS, sensorimotor regions of the globus pallidus interna (GPi) have yet to be thoroughly described with advanced neuroimaging analysis in vivo for human subjects. Furthermore, many imaging studies to date have been performed in a research setting and bring into question the feasibility of their applications in a clinical setting, such as for surgical planning. This study compares two different tractography methods applied to clinically feasible acquisition sequences in identifying sensorimotor regions of the GPi and the subthalamic nucleus (STN) in patients with advanced PD selected to undergo DBS.METHODSSeven patients with refractory PD selected for DBS were examined by MRI. Diffusion images were acquired with an average acquisition time of 15 minutes. Probabilistic and deterministic tractography methods were applied to each diffusion-weighted data set using FSL and MRtrix, respectively. Fiber assignment was performed using combined sensorimotor areas as initiation seeds and the STN and GPi, separately, as inclusion masks. Corticospinal tracts were excluded by setting the cerebral peduncles as exclusion masks. Variability between proposed techniques was shown using center of gravity (CoG) coordinates.RESULTSDeterministic and probabilistic corticopallidal and corticosubthalamic pathways were successfully reconstructed for all subjects across all target sites (bilaterally). Both techniques displayed large connections between the sensorimotor cortex with the posterolateral aspect of the ipsilateral GPi and the posterosuperolateral aspect of the ipsilateral STN. The average variability was 2.67 mm, with the probabilistic method identifying the CoG consistently more posterior and more lateral than the deterministic method.CONCLUSIONSSuccessful delineation of the sensorimotor regions in both the GPi and STN is achievable within a clinically reasonable timeframe. The techniques described in this paper may enhance presurgical planning with increased accuracy and improvement of patient outcomes in patients undergoing DBS. The variability found between tracking techniques warrants the use of the probabilistic tractography method over the deterministic method for presurgical planning. Probabilistic tractography was found to have an advantage over deterministic tractography in its sensitivity, in accurately describing previously described tracts, and in its ability to detect a larger number of fibers.

16.
Strategies Trauma Limb Reconstr ; 13(3): 129-135, 2018 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-30203142

RESUMEN

This retrospective case series evaluates the technique of transverse debridement, acute shortening and subsequent distraction histogenesis in the management of open tibial fractures with bone and soft tissue loss, thereby avoiding the need for a soft tissue flap to cover the wound. Thirty-one patients with Gustilo grade III open tibial fractures between 2001 and 2011 were initially managed with transverse wound extensions, debridement and shortening to provide bony apposition and allowing primary wound closure without tension, or coverage with mobilization of soft tissue and split skin graft. Temporary monolateral external fixation was used to allow soft tissues resuscitation, followed by Ilizarov frame for definitive fracture stabilization. Leg length discrepancy was corrected by corticotomy and distraction histogenesis. Union was evaluated radiologically and clinically. Patients' mean age was 37.3 years (18.3-59.3). Mean bone defect was 3.2 cm (1-8 cm). Mean time to union was 40.1 weeks (12.6-80.7 weeks), and median frame index was 75 days/cm. Median lengthening index (time in frame after corticotomy for lengthening) was 63 days/cm. Mean clinic follow-up was 79 weeks (23-174). Six patients had a total of seven complications. Four patients re-fractured after frame removal, one of whom required a second frame. Two patients required a second frame for correction of residual deformity, and one patient developed a stiff non-union which united following a second frame. There were no cases of deep infection. Acute shortening followed by distraction histogenesis is a safe method for the acute treatment of open tibial fractures with bone and soft tissue loss. This method also avoids the cost, logistical issues and morbidity associated with the use of local or free-tissue transfer flaps and has a low rate of serious complications despite the injury severity.

17.
Nat Commun ; 9(1): 1645, 2018 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-29695780

RESUMEN

Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK-875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-Å crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Gαq-coupled partial agonist, compound 1 is a dual Gαq and Gαs-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), γ-linolenic acid, can be computationally modeled in this site. Both γ-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site.


Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Incretinas/metabolismo , Secreción de Insulina , Receptores Acoplados a Proteínas G/agonistas , Sitio Alostérico/genética , Animales , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/metabolismo , Sinergismo Farmacológico , Células HEK293 , Humanos , Hipoglucemiantes/uso terapéutico , Insulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Simulación del Acoplamiento Molecular , Mutagénesis Sitio-Dirigida , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico , Ácido gammalinolénico/metabolismo
18.
Pain Med ; 19(4): 699-707, 2018 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-29244102

RESUMEN

Study Design: Observational study using insurance claims. Objective: To quantify opioid usage leading up to spinal cord stimulation (SCS) and the potential impact on outcomes of SCS. Setting: SCS is an interventional therapy that often follows opioid usage in the care continuum for chronic pain. Methods: This study identified SCS patients using the Truven Health MarketScan databases from January 2010 to December 2014. The index event was the first occurrence of a permanent SCS implant. Indicators of opioid usage at implant were daily morphine equivalent dose (MED), number of unique pain drug classes, and diagnosis code for opioid abuse. System explant was used as a measure of ineffective SCS therapy. Multivariate logistic regression was used to analyze the effect of pre-implant medications on explants. Results: A total of 5,476 patients (56 ± 14 years; 60% female) were included. SCS system removal occurred in 390 patients (7.1%) in the year after implant. Number of drug classes (odds ratio [OR] = 1.11, P = 0.007) and MED level (5-90 vs < 5 mg/d: OR = 1.32, P = 0.043; ≥90 vs < 5 mg/d: OR = 1.57, P = 0.005) were independently predictive of system explant. Over the year before implant, MED increased in 54% (stayed the same in 21%, decreased in 25%) of patients who continued with SCS and increased in 53% (stayed the same in 20%, decreased in 27%) of explant patients (P = 0.772). Over the year after implant, significantly more patients with continued SCS had an MED decrease (47%) or stayed the same (23%) than before (P < 0.001). Conclusions: Chronic pain patients receive escalating opioid dosage prior to SCS implant, and high-dose opioid usage is associated with an increased risk of explant. Neuromodulation can stabilize or decrease opioid usage. Earlier consideration of SCS before escalated opioid usage has the potential to improve outcomes in complex chronic pain.


Asunto(s)
Analgésicos Opioides/uso terapéutico , Dolor Crónico/terapia , Estimulación de la Médula Espinal , Resultado del Tratamiento , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos
19.
Injury ; 48(7): 1613-1615, 2017 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-28545726

RESUMEN

OBJECTIVES: To review the outcomes of patients treated with the Ilizarov method for an isolated, closed, simple diaphyseal, Tibial fracture at our institution over the last decade. METHODS: The Ilizarov frame database was used to identify 76 skeletally mature patients who sustained an isolated, closed, extra-articular, simple, diaphyseal Tibial fracture; the injury also known as a "nail-able Tibial fracture." RESULTS: The average age of the patient was 38 (17-70). All 76 patients progressed to union. The average time until union was 148 (55-398) days. The coronal and sagittal alignment was 3° (0-17°) and 4° (0-14°) respectively. No patient suffered from compartment syndrome. No patient developed septic arthritis. No patient had documented anterior knee pain or secondary knee specialist input post frame removal. On average, there were 9(4-29) follow up appointments and 10(5-26) radiographs post frame application. There is a 59% chance of a patient having a difficulty post frame application. The malunion rate was 5%. Persisting pinsite infection post frame removal occurred in 5 patients (6.5%). Drilling of the pinsite sequestrum resolved the infection in four of these patients, giving a deep infection rate of 1.3%. CONCLUSIONS: The Ilizarov method has a role to play in the treatment of simple closed Tibial shaft fractures in patients who need to kneel. Patient education is a priority however; the patient must be made aware of the difficulty rate associated with the Ilizarov method when compared to the complication profile of alternative treatments.


Asunto(s)
Fijadores Externos , Fracturas Cerradas/cirugía , Técnica de Ilizarov , Fracturas de la Tibia/cirugía , Adolescente , Adulto , Anciano , Remoción de Dispositivos , Fijadores Externos/efectos adversos , Femenino , Estudios de Seguimiento , Curación de Fractura/fisiología , Fracturas Cerradas/fisiopatología , Humanos , Técnica de Ilizarov/efectos adversos , Masculino , Persona de Mediana Edad , Osteomielitis/tratamiento farmacológico , Osteomielitis/prevención & control , Osteomielitis/cirugía , Educación del Paciente como Asunto , Factores de Riesgo , Infección de la Herida Quirúrgica/tratamiento farmacológico , Infección de la Herida Quirúrgica/prevención & control , Infección de la Herida Quirúrgica/cirugía , Resultado del Tratamiento , Adulto Joven
20.
Spine (Phila Pa 1976) ; 42 Suppl 14: S35-S40, 2017 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-28441315

RESUMEN

STUDY DESIGN: Topic overview. OBJECTIVE: To describe the varied etiologies resulting in chronic spinal pain and review the current available evidence for treatments. SUMMARY OF BACKGROUND DATA: Chronic pain conditions, especially those that affect the axial back and radiate to the extremities, affect a large population. This results in pronounced disability and a high socioeconomic burden. Our understanding of the underlying mechanisms for chronic pain is limited. This prevents a comprehensive diagnostic approach. Evidence from high-level clinical trials supporting treatments for chronic spinal pain is also limited. METHODS: Articles were identified through PubMed searches or already known to the author. The literature was reviewed and summarized, indicating the strength of evidence available for many treatment modalities. RESULTS: There are very few studies published that evaluate behavioral modifications for chronic spinal pain and only one long-term study investigating chronic pharmacological treatments. The data on the success of spinal surgeries to relieve chronic spinal pain suggest an unacceptably high failure rate. The best evidence (Level I) currently available suggests that spinal cord stimulation is a safe, effective, and durable treatment for chronic spinal pain. Recent clinical data support further investigation of new innovations and earlier therapeutic consideration of currently employed approaches. CONCLUSION: Currently, physicians are limited in the practice of evidence-based medicine regarding chronic spinal pain treatments due to both the paucity of data available and an inconsistent diagnostic nomenclature. The introduction of new neurostimulation modalities is promising but requires better characterization through ongoing prospective clinical investigation. LEVEL OF EVIDENCE: 5.


Asunto(s)
Dolor de Espalda/diagnóstico , Dolor de Espalda/terapia , Dolor Crónico/diagnóstico , Dolor Crónico/terapia , Estimulación de la Médula Espinal/métodos , Dolor de Espalda/clasificación , Dolor Crónico/clasificación , Medicina Basada en la Evidencia/métodos , Medicina Basada en la Evidencia/tendencias , Humanos , Estudios Prospectivos , Estimulación de la Médula Espinal/tendencias
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