Wound drain in lumbar arthrodesis for degenerative disease: an experimental, multicenter, randomized controlled trial.

INTRODUCTION: Drains for surgical wound management are frequently used in spine surgery. They are often used to decrease the incidence of postoperative hematoma and decrease wound tension. No conclusive evidence in the literature supports using drains to avoid complications in degenerative lumbar spine surgery. PURPOSE: We aimed to evaluate wound drains in patients with lumbar arthrodesis for degenerative disorders based on clinical outcomes, complications, hematocrit, and length of stay. STUDY DESIGN: A multicenter randomized prospective controlled clinical trial. PATIENT SAMPLE: We enrolled surgical candidates for posterior lumbar decompression and fusion surgery for degenerative disorders from October 2019 to August 2021. Patients were randomized into the drain or nondrain group at nine hospitals. The inclusion criteria were as follows: patients aged 40 to 80 years with lumbar and radicular pain, lumbar degenerative disorder, and primary surgery up to three levels. The exclusion criteria were bleeding abnormalities, bleeding >2,500 mL and dural tears. OUTCOME MEASURES: Preoperative data including Oswestry disability index (ODI), SF-36, lumbar and lower extremity visual analog scale (VAS), body mass index (BMI), hematocrit, and temperature were recorded. Surgical parameters, including surgical time, complications, estimated blood loss (EBL), postoperative temperature and hematocrit (days 1 and 4), dressing saturation, and length of hospital stay (LOS), were registered. METHODS: The two groups were assessed preoperatively, perioperatively and at the 1-month follow-up. A REDCap database was used for registration. Data analysis was performed using classical statistics. RESULTS: One hundred one patients were enrolled using the Redcap database, and 93 patients were evaluated at the final follow-up. Forty-five patients were randomized to the drain group, and 48 were randomized to the nondrain group. The preoperative characteristics were equivalent in both groups: demographic aspects, pain, ODI, SF-36, BMI, hematocrit, and spine pathology. Surgical time, EBL and complications were similar, with no difference between the groups. No difference was found between BMI and complications. No difference was observed in dressing saturation or postoperative temperature between the groups. The postoperative day 4 hematocrit was higher in the nondrain group [36.4% (32-39)] than in the drain group [34% (29.7-37.6)] without statistically differences (p=.054). The LOS was higher in the drain group [4 (3-5) days] than in the nondrain group [3 (2-4) days] (p=.007). The quality-of-life score, SF-36, was higher in the nondrain group [67.9 (53.6-79.2)] than in the drain group [56.7 (49.1-66)] (p=.043). CONCLUSIONS: Nondrain patients presented shorter LOS and better outcomes, with similar complication rates. No difference was found between BMI and complications. Based on this study, in patients undergoing primary posterior spinal decompression and fusion up to three levels for degenerative lumbar disorders, we do not recommend the use of postoperative drains.

Dianhydrogalactitol Overcomes Multiple Temozolomide Resistance Mechanisms in Glioblastoma.

Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major obstacles in GBM treatment. Identifying and overcoming the mechanisms of therapy resistance is instrumental to develop novel therapeutic approaches for patients with GBM. To determine the major drivers of temozolomide (TMZ) sensitivity, we performed shRNA screenings in GBM lines with different O6-methylguanine-DNA methyl-transferase (MGMT) status. We then evaluated dianhydrogalactitol (Val-083), a small alkylating molecule that induces interstrand DNA crosslinking, as a potential treatment to bypass TMZ-resistance mechanisms. We found that loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms driving TMZ resistance in vitro Treatment of established GBM cells and tumorsphere lines with Val-083 induces DNA damage and cell-cycle arrest in G2-M phase, independently of MGMT or MMR status, thus circumventing conventional resistance mechanisms to TMZ. Combination of TMZ and Val-083 shows a synergic cytotoxic effect in tumor cells in vitro, ex vivo, and in vivo We propose this combinatorial treatment as a potential approach for patients with GBM.

Dolor lumbar: revisión y evidencia de tratamiento / Low back pain: review and evidence of treatment

El dolor lumbar corresponde a uno de los síntomas más prevalentes en la humanidad, siendo la segunda causa más frecuente de atención médica a nivel mundial. Existen diversos enfoques de diagnóstico y tratamiento para dolor lumbar, entre ellos la temporalidad del síntoma, el trabajo de diagnóstico sindromático, los síntomas de alarma, también llamados "banderas rojas", que pueden hacer sospechar patologías de mayor gravedad o urgencia. El estudio etiológico puede ser necesario en casos agudos con estas banderas rojas y en casos crónicos. Este estudio se realiza principalmente con imágenes (radiografías, tomografía computada, resonancia magnética, SPECT/CT) y ocasionalmente con exámenes de laboratorio. La mayor parte de los tratamientos están enfocados en el manejo conservador, principalmente el ejercicio físico guiado y asociado a fármacos analgésicos. Existen terapias alternativas tales como la acupuntura, el tai-chi, entre otros, algunas de ellas han mostrado ser un buen complemento al manejo del dolor lumbar. El enfoque multidisciplinario es la tendencia más actual de manejo, esto incluye el trabajo e intervención de diversos profesionales abordando el problema de forma integral, incluyendo el manejo psicoterapéutico. Intervenciones como las infiltraciones de columna han demostrado reducir el dolor por tiempos cortos, siendo útiles como puente para realizar un tratamiento apropiado. La cirugía solo se reserva para casos refractarios, siendo controversiales los resultados existentes en la literatura.

Low back pain is one of the most prevalent symptoms in humanity, being the second most common cause of medical attention worldwide. There are various approaches to diagnosis and treatment for low back pain, including the temporality of the symptom, the work of syndromatic diagnosis, the alarm symptoms, also called "red flags", that can make suspect pathologies of greater severity or emergency. The etiological study may be necessary in acute cases with these "red flags" and in chronic cases. This study is mainly done with images (X-rays, CT scan, MRI, SPECT/CT) and occasionally with laboratory tests. Most of the treatments are focused on conservative management, mainly guided physical exercise associated with analgesic drugs. There are alternative therapies such as acupuncture, tai-chi, among others, some of them have proven to be a good complement to the management of low back pain. The multidisciplinary approach is the most current management trend, this includes the work and intervention of various professionals addressing the problem in an integral way, including psychotherapeutic management. Interventions such as spinal infiltrations have been shown to reduce pain for short times, being useful as a bridge for proper treatment. Surgery is only reserved for refractory cases, the results existing in the literature being controversial.

MGMT genomic rearrangements contribute to chemotherapy resistance in gliomas.

Temozolomide (TMZ) is an oral alkylating agent used for the treatment of glioblastoma and is now becoming a chemotherapeutic option in patients diagnosed with high-risk low-grade gliomas. The O-6-methylguanine-DNA methyltransferase (MGMT) is responsible for the direct repair of the main TMZ-induced toxic DNA adduct, the O6-Methylguanine lesion. MGMT promoter hypermethylation is currently the only known biomarker for TMZ response in glioblastoma patients. Here we show that a subset of recurrent gliomas carries MGMT genomic rearrangements that lead to MGMT overexpression, independently from changes in its promoter methylation. By leveraging the CRISPR/Cas9 technology we generated some of these MGMT rearrangements in glioma cells and demonstrated that the MGMT genomic rearrangements contribute to TMZ resistance both in vitro and in vivo. Lastly, we showed that such fusions can be detected in tumor-derived exosomes and could potentially represent an early detection marker of tumor recurrence in a subset of patients treated with TMZ.

Role of MSK1 in the Induction of NF-κB by the Chemokine CX3CL1 in Microglial Cells.

Microglial cells are essential mediators of neuroinflammatory processes involved in several pathologies. Moreover, the chemokine fractalkine (CX3CL1) is essential in the crosstalk between neurons and microglia. However, the exact roles of CX3CL1, CX3CL1 receptor (CX3CR1) and microglia signalling are not fully understood in neuroinflammation. In addition, the findings reported on this subject are controversial. In this work, we investigated whether CX3CL1 induced pro-inflammatory signalling activation through NF-κB pathway. We were able to show that CX3CL1 activates the pro-inflammatory pathway mediated by the transcription factor NF-κB as an early response in microglial cells. On the other side, CX3CR1-deficient microglia showed impaired NF-κB axis. Phospho-kinase assay proteome profiles indicated that CX3CL1 induced several kinases such as MAPK's (ERK and JNK), SRC-family tyrosine kinases (YES, FGR, LCK and LYN) and most interesting and also related to NF-κB, the mitogen- and stress-activated kinase-1 (MSK1). Knockdown of MSK1 with short interfering RNAs decreased partially MSK1 protein levels (about 50%), enough to decrease the mRNA levels of Il-1ß, Tnf-α and iNos triggered by stimulation with CX3CL1. These results indicate the relevance of CX3CL1 in the activation of the pro-inflammatory NF-κB signalling pathway through MSK1 in microglial cells.

Role of Microvesicles in the Spread of Herpes Simplex Virus 1 in Oligodendrocytic Cells.

Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establishes latent infections in the neurons of sensory ganglia. In some cases, the virus spreads into the central nervous system, causing encephalitis or meningitis. Cells infected with several different types of viruses may secrete microvesicles (MVs) containing viral proteins and RNAs. In some instances, extracellular microvesicles harboring infectious virus have been found. Here we describe the features of shedding microvesicles released by the human oligodendroglial HOG cell line infected with HSV-1 and their participation in the viral cycle. Using transmission electron microscopy, we detected for the first time microvesicles containing HSV-1 virions. Interestingly, the Chinese hamster ovary (CHO) cell line, which is resistant to infection by free HSV-1 virions, was susceptible to HSV-1 infection after being exposed to virus-containing microvesicles. Therefore, our results indicate for the first time that MVs released by infected cells contain virions, are endocytosed by naive cells, and lead to a productive infection. Furthermore, infection of CHO cells was not completely neutralized when virus-containing microvesicles were preincubated with neutralizing anti-HSV-1 antibodies. The lack of complete neutralization and the ability of MVs to infect nectin-1/HVEM-negative CHO-K1 cells suggest a novel way for HSV-1 to spread to and enter target cells. Taken together, our results suggest that HSV-1 could spread through microvesicles to expand its tropism and that microvesicles could shield the virus from neutralizing antibodies as a possible mechanism to escape the host immune response.IMPORTANCE Herpes simplex virus 1 (HSV-1) is a neurotropic pathogen that can infect many types of cells and establishes latent infections in neurons. Extracellular vesicles are a heterogeneous group of membrane vesicles secreted by most cell types. Microvesicles, which are extracellular vesicles which derive from the shedding of the plasma membrane, isolated from the supernatant of HSV-1-infected HOG cells were analyzed to find out whether they were involved in the viral cycle. The importance of our investigation lies in the detection, for the first time, of microvesicles containing HSV-1 virions. In addition, virus-containing microvesicles were endocytosed into CHO-K1 cells and were able to actively infect these otherwise nonpermissive cells. Finally, the infection of CHO cells with these virus-containing microvesicles was not completely neutralized by anti-HSV-1 antibodies, suggesting that these extracellular vesicles might shield the virus from neutralizing antibodies as a possible mechanism of immune evasion.

Sciatic nerve regeneration in rats by a nerve conduit engineering with a membrane derived from natural latex.

PURPOSE: To evaluate the capacity of natural latex membrane to accelerate and improve the regeneration quality of the of rat sciatic nerves. METHODS: Forty male adult Wistar rats were used, anesthetized and operated to cut the sciatic nerve and receive an autograft or a conduit made with a membrane derived from natural latex (Hevea brasiliensis). Four or eight weeks after surgery, to investigate motor nerve recovery, we analyzed the neurological function by walking pattern (footprints analysis and computerized treadmill), electrophysiological evaluation and histological analysis of regenerated nerve (autologous nerve graft or tissue cables between the nerve stumps), and anterior tibial and gastrocnemius muscles. RESULTS: All functional and morphological analysis showed that the rats transplanted with latex conduit had a better neurological recovery than those operated with autologous nerve: quality of footprints, performance on treadmill (p<0.01), electrophysiological response (p<0.05), and quality of histological aspects on neural regeneration. CONCLUSION: The data reported showed behavioral and functional recovery in rats implanted with latex conduit for sciatic nerve repair, supporting a complete morphological and physiological regeneration of the nerve.

Sciatic nerve regeneration in rats by a nerve conduit engineering with a membrane derived from natural latex / Regeneração do nervo ciático em ratos através de um conduto confeccionado com uma membrana de látex natural

PURPOSE: To evaluate the capacity of natural latex membrane to accelerate and improve the regeneration quality of the of rat sciatic nerves. METHODS: Forty male adult Wistar rats were used, anesthetized and operated to cut the sciatic nerve and receive an autograft or a conduit made with a membrane derived from natural latex (Hevea brasiliensis). Four or eight weeks after surgery, to investigate motor nerve recovery, we analyzed the neurological function by walking pattern (footprints analysis and computerized treadmill), electrophysiological evaluation and histological analysis of regenerated nerve (autologous nerve graft or tissue cables between the nerve stumps), and anterior tibial and gastrocnemius muscles. RESULTS: All functional and morphological analysis showed that the rats transplanted with latex conduit had a better neurological recovery than those operated with autologous nerve: quality of footprints, performance on treadmill (p<0.01), electrophysiological response (p<0.05), and quality of histological aspects on neural regeneration. CONCLUSION: The data reported showed behavioral and functional recovery in rats implanted with latex conduit for sciatic nerve repair, supporting a complete morphological and physiological regeneration of the nerve.

OBJETIVO: Avaliar a capacidade de uma membrana de látex natural em acelerar e melhorar a qualidade da regeneração do nervo ciático seccionado de ratos. MÉTODOS: Foram utilizados 40 ratos machos adultos da linhagem Wistar, anestesiados e operados com autoenxerto ou com interposição de um tubo confeccionado com uma membrana derivada do latex natural (Havea brasiliensis). Quatro ou oito semanas após a cirurgia, para investigar a recuperação motora do nervo, foram analisadas a função neurológica através do padrão da marcha (análise das pegadas e esteira computadorizada), avaliação eletrofisiológica e análise histológica do nervo regenerado (enxerto de nervo autólogo ou formação de nervo novo entre os cotos nervosos) e músculos gastrocnêmio e tibial anterior. RESULTADOS: Todas as análises morfológicas e funcionais demonstraram que os ratos transplantados com o conduto de látex tiveram recuperação melhor do que aqueles operados com nervo autólogo: qualidade das pegadas impressas, desempenho em esteira (p<0,01), resposta eletrofisiológica (p<0,05), e qualidade histológica da regeneração nervosa. CONCLUSÃO: Os dados apresentados demonstraram recuperação comportamental e funcional nos ratos implantados com o conduto de látex para a reparação do nervo ciático por meio de uma completa regeneração morfológica e fisiológica do nervo.