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Background: The inclusion of people living with spinal cord injury (SCI) in research has allowed for an informed understanding of priorities of recovery of which bowel dysfunction and bladder dysfunction have been continuously identified. Research has also demonstrated the global disparities in SCI outcomes particularly when comparing high- and low-income countries. Currently, there is a lack of direct comparison between countries when assessing SCI outcomes. Objectives: This is an exploratory study to better understand bowel and bladder dysfunction amongst individuals with SCI in India and Canada. Methods: Data from 33 participants were analyzed. Participants completed an online questionnaire assessing demographic information and the Neurogenic Bowel Dysfunction (NBD) score, Wexner score, Neurogenic Bladder Symptom Score (NBSS), and the Incontinence Quality of Life Instrument (I-QOL). Continuous data were compared using t tests. For not normally distributed data, the independent Mann-Whitney U test was used. Categorical variables were evaluated for association using Fisher's exact or chi-square test, depending on the sample size. Results: Independent Mann-Whitney U test demonstrated that the Canadian participants had poorer bowel function with higher total NBD scores (p = .007) and less frequent bowel movements (p = .036), and they were more likely to experience uneasiness, headaches, and perspiration during bowel movements (p < .001). NBSS results indicated a small but significantly higher proportion of the Indian participants were unsatisfied or unhappy with their bladder function (p = .049). The distribution of Wexner and I-QOL scores were the same across countries. Conclusion: Potential explanations for differences include lifestyle, management, financial resources, patient and caregiver education, and societal pressures, which are all heavily influenced by cultural, geographical, and economic circumstances.
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Calidad de Vida , Traumatismos de la Médula Espinal , Humanos , India , Traumatismos de la Médula Espinal/complicaciones , Traumatismos de la Médula Espinal/fisiopatología , Femenino , Canadá , Masculino , Adulto , Persona de Mediana Edad , Vejiga Urinaria Neurogénica/etiología , Vejiga Urinaria Neurogénica/fisiopatología , Encuestas y Cuestionarios , Intestino Neurogénico/etiología , Intestino Neurogénico/fisiopatología , Anciano , Adulto JovenRESUMEN
Background: The key rehabilitation goal for cervical cord injury is promoting functional hand movement. Patients with mid to low-level cervical spinal cord injury can achieve the useful tenodesis grasp with the assistance of upper extremity orthosis. In this study, a custom molded writing device was fabricated and applied on cervical cord injured patients with the aim of hand rehabilitation. Methods: A total of fourteen individuals with cervical spinal cord injury at C6-C7 level were recruited for the study. They were divided into two groups, where the experimental group was prescribed with the custom molded writing device and the standard-of-care group was prescribed with the traditionally available writing device. The performance of the devices was evaluated using the Quest 2.0 questionnaire and the quality of writing after an intervention time of 4 weeks. Result: The group that used custom molded writing device performed comparatively better when compared to the conventional design. The data showed a significant difference with average QUEST scores of 4.47 ± 0.33 for the group using the wrist-driven writing device and 3.04 ± 0.70 for group using the conventional design. For better understanding of the device's performance, the writing with both the splints was also assessed. Conclusion: A writing device using the tenodesis grasp was fabricated to rehabilitate the writing skills of individuals with cervical spinal cord injuries. The performance of the device provided a favorable result indicating to elaborate the study for future references.
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INTRODUCTION: Internal Jugular Venous (IJV) cannulation or central-line insertion is frequently performed during kyphoscoliosis deformity correction surgery or spine surgery with high risk. This helps monitor central venous pressure and administer medicines when required. Although many complications of IJV cannulation have been reported in the literature, its effect on brachial plexus is not known. The objective of this paper was to report a rare complication of IJV during scoliosis surgery. CASE PRESENTATION: We reported a case of 27-year-old male who was operated for severe kyphoscoliosis correction where preoperatively IJV cannulation was done. Repeated attempts were done during IJV cannula insertion due to altered anatomy. Eventually, cannula insertion was done using ultrasound modality and surgery for correction was done. Postoperatively patient developed right upper extremity weakness and sensory loss although the clinical result of kyphoscoliosis correction was acceptable. EMG-NCV study proved it brachial plexus injury. The patient was treated with intravenous steroid and physiotherapy. The patient recovered completely within 6 months of surgery. CONCLUSION: We reported a case of kyphoscoliosis deformity corrective surgery where IJV cannulation led to brachial plexus injury and was eventually recovered with medications and physiotherapy.
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Fracturas de la Tibia , Humanos , Pierna , Postura , Sedestación , Fracturas de la Tibia/cirugíaRESUMEN
STUDY DESIGN: This was a prospective study. OBJECTIVES: To correlate improvement in motor evoked potential (MEP) during spine surgery with postoperative clinical improvement. MATERIALS AND METHODS: Three hundred fifty-three patients operated for posterior spinal decompression and fixation surgeries were prospectively selected and followed up. Patients who underwent lumbar, dorsal, and cervical surgeries were grouped into-group A, B, and C, respectively. Intraoperative neuromonitoring was done using MEP with free-running electromyography. Improvements in MEP scores were calculated in percentage. Similarly, postoperative improvement in Oswestry disability index (ODI) and visual analog scale (VAS) scores at 3 months were calculated in percentage. Improvements in MEP scores were correlated with clinical improvement using the Spearman ρ test and the r value was calculated to find out the association. RESULTS: Of 353 patients, 319 (250-group A, 38-group B, and 31-group C) were included for the study. VAS and ODI improved significantly from preoperative 8.5±0.8 and 62.9±14.5, to postoperative 2.3±1.1 and 15.9±11.5, respectively, in the entire group. Average preoperative MEP were 127.8±191.0 mV on the right side and 132.3±206.6 mV on the left side, which significantly improved to 163.7±231.2 mV (P=0.0001) and 155.2±219.6 mV (P=0.0001), respectively, showing 157.0% and 178.5% improvement. Correlating MEP improvement with postoperative improvement in ODI showed poor correlation (r=0.088 right and 0.030 left sides). Similarly, correlating MEP improvement with improvement in VAS showed r=0.110 on the right and -0.023 on the left side suggesting poor correlation. Postoperative neurological complications (0.56%) were found in 2 patients in the form of screw malpositioning. CONCLUSIONS: Intraoperative neuromonitoring showed significant improvement during posterior decompression and fixation surgery, and reduction in postoperative neurological complication. The study also exhibited significant postoperative clinical improvement. However, improvement in MEP did not correlate with postoperative clinical improvement suggesting that it has no predictive role.
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Procedimientos Neuroquirúrgicos , Columna Vertebral , Descompresión Quirúrgica , Humanos , Estudios ProspectivosRESUMEN
INTRODUCTION: Treatment of complex upper end tibial fractures has always been a challenge to orthopaedic surgeons. Though the roentgenogram results are satisfactory, the clinical and functional outcomes especially in terms of squatting/cross-leg sitting after long term follow-up are little known. Hence, we have done this study with a primary aim to assess the clinico-radiological and functional outcomes after operative fixation (mostly by locking plates) in complex upper end tibial fractures and a secondary aim to analyze correlation between functional outcome scores/range of motion (ROM) and the ability to squat & sit cross-legged in post-operative period. MATERIALS AND METHODS: This prospective study included a total of 33 patients who were mainly treated with locking plates. In the follow-up, patients were assessed clinico-radiologically and outcome measurements were determined using the Tegner-Lysholm (T-L) Knee Score. Patients were categorized according to their ability to squat/sit cross-legged and a subgroup analysis was performed by comparing mean ROM and T-L score in each group. RESULTS: Majority of patients were in young and adult age group with a male to female ratio of 4.5:1. The average age was 42.39 ±14.64 years. Road traffic accident was the most common mode of injury. Average time interval between injury and surgery was 5.8±4.4 days. All the fractures united by 5-9 months. Mean ROM and T-L score at last follow-up were 120.94°±13.63° and 88.12±7.24 respectively. Average shortening, varus and valgus deformity were 0.43±0.09 cm, 2.12°±0.62° and 1.06°±0.45° respectively. 14 patients (42.42%) were able to squat and 15 (45.45%) were able to sit cross-legged postoperatively. Upon subgroup analysis, difference of mean ROM in those who could squat/sit cross-legged was found statistically significant (p≤0.05), however the difference in mean functional scores was not significant (p≥0.05). CONCLUSION: Complex upper tibial fractures are a difficult entity to deal with. Anatomical locking plates take care of the alignment, articular congruity as well as ligamentous balancing thus giving good mid-term outcomes after ORIF/MIPO. However, applicability of the present functional outcome scores in assessing squatting/cross leg sitting remains doubtful. More weightage needs to be given to these activities to evaluate the outcome in South Asian population.
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Fracturas de la Tibia , Adulto , Femenino , Fijación Interna de Fracturas , Humanos , Pierna , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Rango del Movimiento Articular , Sedestación , Fracturas de la Tibia/diagnóstico por imagen , Fracturas de la Tibia/cirugía , Resultado del TratamientoRESUMEN
INTRODUCTION: Back pain is a common ailment affecting individuals around the globe. Animal models to understand the back pain mechanism, treatment modalities, and spinal cord injury are widely researched topics worldwide. Despite the presence of several animal models on disc degeneration and Spinal Cord Injury, there is a lack of a comprehensive review. MATERIAL AND METHOD: A methodological narrative literature review was carried out for the study. A total of 1273 publications were found, out of which 763 were related to spine surgery in animals. The literature with full-text availability was selected for the review. Scale for the Assessment of Narrative Review Articles (SANRA) guidelines was used to assess the studies. Only English language publications were included which were listed on PubMed. A total of 113 studies were shortlisted (1976-2019) after internal validation scoring. RESULT: The animal models for spine surgery ranged from rodents to primates. These are used to study the mechanisms of back pain as well as spinal cord injuries. The models could either be created surgically or through various means like use of electric cautery, chemicals or trauma. Genetic spine models have also been documented in which the injuries are created by genetic alterations and knock outs. Though the dorsal approach is the most common, the literature also mentions the anterior and lateral approach for spine surgery animal experiments. CONCLUSION: There are no single perfect animal models to represent and study human models. The selection is based on the application and the methodology. Careful selection is needed to give optimum and appropriate results.
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Low back pain is often the direct result of degeneration of the intervertebral disc. A wide range of therapeutics including anti-catabolic, pro-anabolic factors and chemo-attractants that can stimulate resident cells and recruit endogenous progenitors are under consideration. The avascular nature and the dense matrix of this tissue make it challenging for systemically administered drugs to reach their target cells inside the nucleus pulposus (NP), the central gelatinous region of the intervertebral disc (IVD). Therefore, local intra-discal injection of therapeutic drugs directly into the NP is a clinically relevant delivery approach, however, suffers from rapid and wide diffusion outside the injection site resulting in short lived benefits while causing systemic toxicity. NP has a high negative fixed charge density due to the presence of negatively charged aggrecan glycosaminoglycans that provide swelling pressures, compressive stiffness and hydration to the tissue. This negative fixed charge density can also be used for enhancing intra-NP residence time of therapeutic drugs. Here we design positively charged Avidin grafted branched Dextran nanostructures that utilize long-range binding effects of electrostatic interactions to bind with the intra-NP negatively charged groups. The binding is strong enough to enable a month-long retention of cationic nanostructures within the NP following intra-discal administration, yet weak and reversible to allow movement to reach cells dispersed throughout the tissue. The branched carrier has multiple sites for drug conjugation and can reduce the need for multiple injections of high drug doses and minimize associated side-effects, paving the way for effective clinical translation of potential therapeutics for treatment of low back pain and disc degeneration.
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Avidina/administración & dosificación , Dextranos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Disco Intervertebral/efectos de los fármacos , Nanoestructuras/administración & dosificación , Animales , Avidina/farmacología , Bovinos , Dextranos/farmacología , Glicosaminoglicanos , Semivida , Inyecciones , Degeneración del Disco Intervertebral/tratamiento farmacológico , Dolor de la Región Lumbar/tratamiento farmacológico , Núcleo Pulposo/efectos de los fármacos , Núcleo Pulposo/metabolismo , Electricidad EstáticaRESUMEN
STUDY DESIGN: Nonrandomized, prospective, and case-controlled study. PURPOSE: To evaluate the efficacy and cost-effectiveness of topically applied tranexamic acid (TXA) during different phases of spine surgery. OVERVIEW OF LITERATURE: Perioperative blood loss is the leading cause of postoperative anemia associated with prolonged stays in hospital and long recovery times. The direct and indirect costs involved pose a significant economic challenge in developing countries. There is no consensus for topical use of tranexamic acid in spine surgery. METHODS: Patients requiring a single-level TLIF were divided into two groups. In the TXA group (n=75), the wound surface was soaked with TXA (1 g in 100 mL saline solution) for 3 minutes after exposure, after decompression, and before wound closure, and in the control group (n=175) using only saline. Intraoperative blood loss drain volume was recorded on each of the first 2 days immediately after surgery. An estimated cost analysis was made on the basis of the length of hospital stay and the blood transfusion. RESULTS: IBL for the control group was 783.33±332.71 mL and for intervention group 410.57±189.72 mL (p<0.001). The operative time for control group was 3.24±0.38 hours and for intervention group 2.99±0.79 hours (p<0.695). Hemovac drainage on days 1 and 2 for control group was 167.10±53.83 mL and 99.33±37.5 mL, respectively, and for intervention group 107.03±44.37 mL and 53.38±21.99 mL, respectively (p<0.001). The length of stay was significantly shorter in the intervention group (4.8±1.1 days) compared to control group (7.0±2.3 days). The cost of treatment in the intervention group was US dollar (USD) 4,552.57±1,222.6 compared with that in the control group USD 6,529.9±1,505.04. CONCLUSIONS: Topical TXA is a viable, cost-effective method of decreasing perioperative blood loss in major spine surgery with fewer overall complications than other methods. Further studies are required to find the ideal dosage and timing.
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INTRODUCTION: Hip joint fracture-dislocations are rare injuries and usually result from high energy trauma. Femoral head fractures account for only 7-16% of all hip fracture-dislocations. There is always a controversy regarding optimal surgical treatment modality and approach for the treatment of Pipkin type IV fractures. In a 60 years old individual, various reports favor primary hip arthroplasty as compared to open reduction and internal fixation (ORIF). The posterior approach is preferred because it provides adequate exposure of the acetabular fracture and an opportunity for simultaneous repair of the femoral head and acetabular fractures. Another benefit is that anterior vascular supply to the femoral head and abductor function can be preserved. CASE REPORT: In this case report, we present a neglected 15 days old rare injury (Pipkin type IV femoral head fracture) in a 60 years old male patient that was given a trial of hip preservation surgery by ORIF through posterior (Kocher-Langenbeck) approach. CONCLUSION: A neglected case of Pipkin type IV injury with chances of avascular necrosis and arthritis can be given a trial of hip preservation surgery because in an Indian scenario sitting cross legged and squatting are indispensable activities of daily lifestyle and appropriate surgical technique, adequate exposure, anatomic reduction, and stable internal fixation of the fractures are critical to achieve satisfactory clinical results.
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Introduction: Despite adequate inpatient rehabilitation, a number of spinal cord injury (SCI) individuals suffer from difficulties at home and in their local environments. This is mainly prevalent in low-middle-income countries (LMIC) due to a lack of qualified personal caregivers. This issue could be addressed with the help of telehealth technology, which may be used in LMICs without economic concerns. Case presentations: A 44-year-old male with C3 AIS C SCI and a 35-year-old female with T12 AIS A SCI were discharged after successful rehabilitation from a tertiary care spinal center. The patients demonstrated gradual loss in their independence, which was evident by monitoring their home activities biweekly for 4 weeks via a combination of telephone calls, live video chat, and WhatsApp. Subsequently after 4 weeks of consistent guidance, pre-post scores after teletherapy were analyzed for the self-care and mobility subcomponents of the self-reported SCIM III. Discussion: After consistent supervised guidance via telehealth, self-care scores improved in the C3 AIS C case from 3 to 15 and in the T12 AIS A case from 4 to 15, while mobility scores respectively improved from 14 to 27 and 4 to 16. Identification of individual competencies, performance, and capacity in activities of daily living and participation, self-assessment, caregiver training, and home integration contributed toward successful community integration. This case series documents the benefits of using telehealth and home goal planning in the aftercare of SCI individuals, in order to improve quality of life in their local environment.
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Calidad de Vida , Traumatismos de la Médula Espinal/rehabilitación , Telerrehabilitación/métodos , Adulto , Femenino , Humanos , India , MasculinoRESUMEN
BACKGROUND: A noninvasive approach for basilar invagination (BI) and moreover, cervical traction to reduce odontoid invagination, has not been thoroughly described in the literature. We report a case of BI with Arnold-Chiari malformation in which preoperative reduction using Gardner well cervical traction was attempted and the patient developed central hypoventilation syndrome. CASE DESCRIPTION: A 15-year-old boy presented with a 6-month history of progressive cervical myelopathy signs and symptoms, modified Japanese orthopedic association score 12 of 18. Radiology showed type A BI with occipitalization of atlas and a posterior arch defect of axis. A preoperative closed cervical traction followed by occipitocervical fusion via a posterior-only approach was planned. The patient developed 3 episodes of apnea on sleeping when on traction. Labeled as central hypoventilation, he was operated by foramen magnum decompression and occipitocervical fusion. CONCLUSIONS: Cervical traction followed by posterior fixation is an effective way to manage basilar invagination with Arnold-Chiari malformation and assimilated C1. However, patients should be monitored closely for respiratory dysfunction.
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Malformación de Arnold-Chiari/cirugía , Articulación Atlantooccipital/cirugía , Apnea Central del Sueño/etiología , Enfermedades de la Columna Vertebral/cirugía , Tracción/efectos adversos , Adolescente , Malformación de Arnold-Chiari/complicaciones , Malformación de Arnold-Chiari/diagnóstico por imagen , Articulación Atlantooccipital/diagnóstico por imagen , Descompresión Quirúrgica/métodos , Humanos , Masculino , Enfermedades de la Columna Vertebral/complicaciones , Enfermedades de la Columna Vertebral/diagnóstico por imagen , Fusión Vertebral/métodosRESUMEN
STUDY DESIGN: Retrospective study. PURPOSE: Missing cottonoids during and after spinal surgery is a persistent problem and account for the most commonly retained surgical instruments (RSIs) noticed during a final cottonoid count. The aim of this study was to enumerate risk factors and describe the sequence to look out for misplaced cottonoids during spinal surgery and provide an algorithm for resolving the problem. OVERVIEW OF LITERATURE: There are only a few case reports on RSIs among various surgical branches. The data is inconclusive and there is little evidence in the literature that relates to spinal surgery. METHODS: This retrospective study was conducted at Indian Spinal Injuries Centre. The data was collected from hospital records ranging from January 2013 to December 2017. The surgical cases in which cottonoid counts were inconsistent during or after the procedure were included in the study. The case files along with operating theater records were thoroughly screened for selecting those in which there was confirmed evidence of such an event. RESULTS: There were 7,059 spinal surgeries performed during the study period. Fifteen cases of miscounts were recorded with an incidence of one in every 471 cases. Cottonoids were most commonly lost under the shoes of the surgeon or assistants. In two instances, cottonoids were found in the surgical field and trapped in the interbody cage site. Based on these locations, a systematic search algorithm was created. CONCLUSIONS: This study enumerates RSI risk factors in spinal surgical procedures and describes steps that can be followed to account for any missing cottonoids. The incidence of missing cottonoids can be decreased using a goal-oriented approach and ensuring that surgical teams work in collaboration.
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In the current clinical scenario, restenosis following the primary surgical procedure for lumbar canal stenosis is being frequently noticed. A number of studies have evaluated the reoperation rates following different surgical procedures for lumbar canal stenosis. However, a dilemma still exists about the surgical procedures, associated comorbidities and reoperation rates. In this study, we have reviewed the existing literature for lumbar canal stenosis surgery and their reoperation rates. A PubMed search for all papers stating "reoperation after spinal stenosis," "revision surgery after spinal stenosis," and "reoperations and lumbar canal stenosis" were explored. A total of 440 publications were found, of which 23 publications were shortlisted. The existing literature on reoperation rates after surgery for lumbar canal stenosis was reviewed and analyzed. From the literature search, 29680 patients who underwent surgeries for spinal stenosis have been included in the review. 11.65% ± 4.25% of them underwent reoperations following the primary procedure with a followup period of 6.80 ± 3.90 years. Fenestration surgeries showed an average reoperation rate of 7.58% ± 5.29% in 8.28 ± 6.26 years followup as compared to laminectomy alone (12.70% ± 7.49%, 6.50 ± 2.12 years followup). Laminectomy with or without fusion showed a reoperation rate of 11.22% ± 4.25% in 6.00 ± 2.60 years followup period. The comparative results of these studies were however not significant. The causes of reoperation were multifactorial ranging from the type of procedure performed, associated comorbidities or smoking. Statistical data do not indicate the superiority of any particular type of surgery, which reduces the rate of reoperation. The causes for reoperation are inadequate decompression or instability. The literature does not give statistics for these complications in the papers. Smoking is an independent risk factor for revision surgery. Diabetes reduces the time interval between the initial surgery and the revision surgery. This review highlights the causes of reoperations in various lumbar stenosis surgeries, associated comorbidities and expected outcome.
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To date, there is no periadventitial drug delivery method available in the clinic to prevent restenotic failure of open vascular reconstructions. Resveratrol is a promising anti-restenotic natural drug but subject to low bioavailability when systemically administered. In order to reconcile these two prominent issues, we tested effects of periadventitial delivery of resveratrol on all three major pro-restenotic pathologies including intimal hyperplasia (IH), endothelium impairment, and vessel shrinkage. In a rat carotid injury model, periadventitial delivery of resveratrol either via Pluronic gel (2-week), or polymer sheath (3-month), effectively reduced IH without causing endothelium impairment and vessel shrinkage. In an in vitro model, primary smooth muscle cells (SMCs) were stimulated with elevated transforming growth factor (TGFß) and its signaling protein Smad3, known contributors to IH. TGFß/Smad3 up-regulated Kruppel-like factor (KLF5) protein, and SMC de-differentiation which was reversed by KLF5 siRNA. Furthermore, TGFß/Smad3-stimulated KLF5 production and SMC de-differentiation were blocked by resveratrol via its inhibition of the Akt-mTOR pathway. Concordantly, resveratrol attenuated Akt phosphorylation in injured arteries. Taken together, periadventitial delivery of resveratrol produces durable inhibition of all three pro-restenotic pathologies - a rare feat among existing anti-restenotic methods. Our study suggests a potential anti-restenotic modality of resveratrol application suitable for open surgery.
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Diferenciación Celular/efectos de los fármacos , Reestenosis Coronaria/prevención & control , Regulación de la Expresión Génica/efectos de los fármacos , Músculo Liso Vascular/citología , Proteína smad3/metabolismo , Estilbenos/farmacología , Factor de Crecimiento Transformador beta/metabolismo , Animales , Antioxidantes/farmacología , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Reestenosis Coronaria/metabolismo , Reestenosis Coronaria/patología , Masculino , Músculo Liso Vascular/efectos de los fármacos , Músculo Liso Vascular/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Resveratrol , Transducción de Señal/efectos de los fármacosRESUMEN
Pheohyphomycosis is an uncommon infection and its association in spondylodiscitis has not yet been reported. The purpose of this case report is to describe a rare case of Pheohyphomycotic spondylodiscitis and methods to diagnose and manage the patient with less invasive techniques. A 29-year-old male patient presented to the outpatient department with complaints of gradually increasing low back pain with bilateral lower limbs radicular pain since one and a half years. He had associated fever, weight loss, voice changes, and dry, scaly, erythematous skin with elevated ESR. The patient had been taking anti-Koch's therapy since 1 year with little relief in pain and no radiological improvement. Percutaneous pedicle biopsy of L4 vertebra was taken under local anaesthesia and confirmed Pheohyphomycosis which was treated with antifungal medications. The patient showed sequential improvement with long term antifungal treatment. He was eventually able to walk independently without support.
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BACKGROUND: Three major processes, constrictive vessel remodeling, intimal hyperplasia (IH), and retarded re-endothelialization, contribute to restenosis after vascular reconstructions. Clinically used drugs inhibit IH but delay re-endothelialization and also cause constrictive remodeling. Here we have examined halofuginone, an herbal derivative, for its beneficial effects on vessel remodeling and differential inhibition of IH versus re-endothelialization. METHODS AND RESULTS: Two weeks after perivascular application to balloon-injured rat common carotid arteries, halofuginone versus vehicle (n=6 animals) enlarged luminal area 2.14-fold by increasing vessel size (adaptive remodeling; 123%), reducing IH (74.3%) without inhibiting re-endothelialization. Consistent with its positive effect on vessel expansion, halofuginone reduced collagen type 1 (but not type 3) production in injured arteries as well as that from adventitial fibroblasts in vitro. In support of its differential effects on IH versus re-endothelialization, halofuginone produced greater inhibition of vascular smooth muscle cell versus endothelial cell proliferation at concentrations ≈50 nmol/L. Furthermore, halofuginone at 50 nmol/L effectively blocked Smad3 phosphorylation in smooth muscle cells, which is known to promote smooth muscle cell proliferation, migration, and IH, but halofuginone had no effect on phospho-Smad3 in endothelial cells. CONCLUSIONS: Periadventitial delivery of halofuginone dramatically increased lumen patency via adaptive remodeling and selective inhibition of IH without affecting endothelium recovery. Halofuginone is the first reported small molecule that has favorable effects on all 3 major processes involved in restenosis.
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Inhibidores de la Angiogénesis/administración & dosificación , Angioplastia de Balón , Arterias Carótidas/efectos de los fármacos , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Endotelio Vascular/efectos de los fármacos , Fibroblastos/efectos de los fármacos , Hiperplasia/prevención & control , Miocitos del Músculo Liso/efectos de los fármacos , Piperidinas/administración & dosificación , Complicaciones Posoperatorias/prevención & control , Quinazolinonas/administración & dosificación , Adaptación Biológica/efectos de los fármacos , Inhibidores de la Angiogénesis/efectos adversos , Animales , Arterias Carótidas/patología , Arterias Carótidas/cirugía , Traumatismos de las Arterias Carótidas/cirugía , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Colágeno Tipo I/metabolismo , Endotelio Vascular/patología , Fibroblastos/patología , Humanos , Hiperplasia/etiología , Masculino , Modelos Animales , Miocitos del Músculo Liso/patología , Especificidad de Órganos , Piperidinas/efectos adversos , Quinazolinonas/efectos adversos , Ratas , Ratas Sprague-Dawley , Proteína smad3/metabolismo , Remodelación Vascular/efectos de los fármacosRESUMEN
Intimal hyperplasia produces restenosis (re-narrowing) of the vessel lumen following vascular intervention. Drugs that inhibit intimal hyperplasia have been developed, however there is currently no clinical method of perivascular drug-delivery to prevent restenosis following open surgical procedures. Here we report a poly(ε-caprolactone) (PCL) sheath that is highly effective in preventing intimal hyperplasia through perivascular delivery of rapamycin. We first screened a series of bioresorbable polymers, i.e., poly(lactide-co-glycolide) (PLGA), poly(lactic acid) (PLLA), PCL, and their blends, to identify desired release kinetics and sheath physical properties. Both PLGA and PLLA sheaths produced minimal (<30%) rapamycin release within 50days in PBS buffer. In contrast, PCL sheaths exhibited more rapid and near-linear release kinetics, as well as durable integrity (>90days) as evidenced in both scanning electron microscopy and subcutaneous embedding experiments. Moreover, a PCL sheath deployed around balloon-injured rat carotid arteries was associated with a minimum rate of thrombosis compared to PLGA and PLLA. Morphometric analysis and immunohistochemistry revealed that rapamycin-loaded perivascular PCL sheaths produced pronounced (85%) inhibition of intimal hyperplasia (0.15±0.05 vs 1.01±0.16), without impairment of the luminal endothelium, the vessel's anti-thrombotic layer. Our data collectively show that a rapamycin-loaded PCL delivery system produces substantial mitigation of neointima, likely due to its favorable physical properties leading to a stable yet flexible perivascular sheath and steady and prolonged release kinetics. Thus, a PCL sheath may provide useful scaffolding for devising effective perivascular drug delivery particularly suited for preventing restenosis following open vascular surgery.
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Fármacos Cardiovasculares/administración & dosificación , Traumatismos de las Arterias Carótidas/tratamiento farmacológico , Estenosis Carotídea/prevención & control , Portadores de Fármacos , Neointima , Poliésteres/química , Sirolimus/administración & dosificación , Animales , Fármacos Cardiovasculares/química , Traumatismos de las Arterias Carótidas/patología , Estenosis Carotídea/patología , Proliferación Celular/efectos de los fármacos , Química Farmacéutica , Preparaciones de Acción Retardada , Modelos Animales de Enfermedad , Hiperplasia , Cinética , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Sirolimus/química , Solubilidad , Tecnología Farmacéutica/métodosRESUMEN
Intimal hyperplasia is the cause of the recurrent occlusive vascular disease (restenosis). Drugs currently used to treat restenosis effectively inhibit smooth muscle cell (SMC) proliferation, but also inhibit the growth of the protective luminal endothelial cell (EC) lining, leading to thrombosis. To identify compounds that selectively inhibit SMC versus EC proliferation, we have developed a high-throughput screening (HTS) format using human cells and have employed this to screen a multiple compound collection (NIH Clinical Collection). We developed an automated, accurate proliferation assay in 96-well plates using human aortic SMCs and ECs. Using this HTS format we screened a 447-drug NIH Clinical Library. We identified 11 compounds that inhibited SMC proliferation greater than 50%, among which idarubicin exhibited a unique feature of preferentially inhibiting SMC versus EC proliferation. Concentration-response analysis revealed this differential effect most evident over an â¼10 nM-5 µM window. In vivo testing of idarubicin in a rat carotid injury model at 14 days revealed an 80% reduction of intimal hyperplasia and a 45% increase of lumen size with no significant effect on re-endothelialization. Taken together, we have established a HTS assay of human vascular cell proliferation, and identified idarubicin as a selective inhibitor of SMC versus EC proliferation both in vitro and in vivo. Screening of larger and more diverse compound libraries may lead to the discovery of next-generation therapeutics that can inhibit intima hyperplasia without impairing re-endothelialization.
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Proliferación Celular/efectos de los fármacos , Idarrubicina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Túnica Íntima/efectos de los fármacos , Animales , Células Cultivadas , Células Endoteliales/efectos de los fármacos , Ensayos Analíticos de Alto Rendimiento/métodos , Humanos , Hiperplasia/tratamiento farmacológico , Masculino , Miocitos del Músculo Liso/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Restenosis, or arterial lumen re-narrowing, occurs in 30-50% of the patients undergoing angioplasty. Adaptive remodeling is the compensatory enlargement of the vessel size, and has been reported to prevent the deleterious effects of restenosis. Our previous studies have shown that elevated transforming growth factor (TGF-ß) and its signaling protein Smad3 in the media layer induce adaptive remodeling of angioplastied rat carotid artery accompanying an increase of total collagen in the adventitia. In order to gain insights into a possible role of collagen in Smad3-induced adaptive remodeling, here we have investigated a mechanism of cell-cell communication between medial smooth muscle cells (SMCs) and adventitial fibroblasts in regulating the secretion of two major collagen subtypes. We have identified a preferential collagen-3 versus collagen-1 secretion by adventitial fibroblasts following stimulation by the conditioned medium from the TGF-ß1-treated/Smad3-expressing medial smooth muscle cells (SMCs), which contained higher levels of CTGF and IGF2 as compared to control medium. Treating the TGF-ß/Smad3-stimulated SMCs with an siRNA to either CTGF or IGF2 reversed the effect of conditioned media on preferential collagen-3 secretion from fibroblasts. Moreover, recombinant CTGF and IGF2 together stimulated adventitial fibroblasts to preferentially secrete collagen-3 versus collagen-1. This is the first study to identify a preferential secretion of collagen-3 versus collagen-1 from adventitial fibroblasts as a result of TGF-ß/Smad3 stimulation of medial SMCs, and that CTGF and IGF2 function together to mediate this signaling communication between the two cell types.