Doxycycline as a Potential MMP-1 Inhibitor for the Treatment of Spondylitis Tuberculosis: A Study in Rabbit Model.

Background: Tuberculosis (TB) of the spine is a highly disruptive disease, especially in underdeveloped and developing countries. This condition requires standard TB treatment for 9-18 months, which increases patient risk of drug-resistant TB. Consequently, this raises the concern of adopting additional therapies to shorten the treatment duration, improve the efficacy of anti-TB drugs, and further decrease damage in the affected tissues and organs. Matrix metalloproteinase- (MMP-) 1 is a key regulator of the destruction of the extracellular matrix and associated proteins and is a new potential target for TB treatment research. In the present study, we investigated the effects of doxycycline as an MMP-1 inhibitor in patients with spondylitis TB. Methods: Seventy-two New Zealand white rabbits with spondylitis TB were divided into 12 different groups based on incubation period (2, 4, 6, and 8 weeks) and doxycycline administration (without, 1 mg/kg body weight (BW), and 5 mg/kg BW). We observed the course of infection through the blood concentration changes and immunohistochemical examination of MMP-1, in addition to BTA staining, culture, polymerase chain reaction (PCR), and histopathological examination. Results: Treatment with once daily 5 mg/kg BW doxycycline significantly improved the blood MMP-1 level (p < 0.05) compared with the placebo and 1 mg/kg BW doxycycline. A significantly reduced ongoing infection and a higher healing rate were demonstrated in rabbits with a higher doxycycline dose through BTA staining, culture, PCR, and histopathology. Various degrees of vertebral endplates, vertebral body, and intervertebral disc destruction were observed in 32 rabbits with positive histopathological findings, in addition to positive inflammatory cell infiltration, characterized by numerous lymphocytes, macrophages, and epithelial cells, as well as abundant granulation tissue and necrotic substances proximal to the inoculated vertebral area. Bone and intervertebral disc destructions were more apparent in the untreated rabbits. Conclusion: Our study demonstrated the potential of doxycycline as an adjunctive treatment in spondylitis TB. However, limitations remain regarding the differences in the pathogenesis and virulence of Mycobacterium tuberculosis between rabbit and human systems, sample size, and the dose-dependent effect of doxycycline. Further studies are needed to address these issues.

A holistic approach for severe flexion contracture of bilateral hip, knee, and ankle joints in a neglected patient with prolonged knee-chest positioning on extreme undernourishment: a case report and review of the literature.

BACKGROUND: Flexion contracture in the lower extremity is a common finding in the patient with neuromusculoskeletal disorders. However, severe cases due to prolonged immobilization in knee-chest position are rarely established and remain underreported. This condition is associated with high morbidity and reduced quality of life, especially when it comes to neglected cases with missed injury and late presentation for adequate primary care and rehabilitative program. It remains a difficult challenge to treat, with no established treatment protocol. In addition, other factors related to psychological and socioeconomic conditions may interfere and aggravate the health state of such patients. CASE PRESENTATION: A 19-year-old Javanese man presented with flexion contracture of bilateral hip, knee, and ankle joints due to prolonged immobilization in knee-chest position for almost 2 years following a traffic accident and falling in the bathroom. The condition had persisted for the last 3 years due to irrecoverable condition and lack of awareness. In addition, the patient also presented with paraplegia at level L2-S1, dermatitis neglecta, multiple pressure ulcers, community-acquired pneumonia, and severe malnutrition. Prolonged and sustained passive stretching with serial plastering were performed in the patient. By the time of discharge, patient was able to move and ambulate using wheelchair. Progressive improvement of range of motion and good sitting balance were observed by 3-month follow-up. CONCLUSION: A combination of surgery and rehabilitative care is required in the setting of severe flexion contracture. Passive prolonged stretching showed a better outcome and efficacy in the management of flexion contracture, whether the patient undergoes surgery or not. However, evaluation of residual muscle strength, changes in bone density and characteristic, and the patient's general and comorbid conditions must always be considered when determining the best treatment of choice for each patient to achieve good outcome and result. A holistic approach with comprehensive assessment is important when treating such patients.

Integration of Umbilical Cord Mesenchymal Stem Cell Application in Hydroxyapatite-Based Scaffolds in the Treatment of Vertebral Bone Defect due to Spondylitis Tuberculosis: A Translational Study.

BACKGROUND: Vertebral bone defect represents one of the most commonly found skeletal problems in the spine. Progressive increase of vertebral involvement of skeletal tuberculosis (TB) is reported as the main cause, especially in developed countries. Conventional spinal fusion using bone graft has been associated with donor-site morbidity and complications. We reported the utilization of umbilical cord mesenchymal stem cells (UC-MSCs) combined with hydroxyapatite (HA) based scaffolds in treating vertebral bone defect due to spondylitis tuberculosis. MATERIALS AND METHODS: Three patients with tuberculous spondylitis in the thoracic, thoracolumbar, or lumbar region with vertebral body collapse of more than 50 percent were included. The patient underwent a 2-stage surgical procedure, consisting of debridement, decompression, and posterior stabilization in the first stage followed by anterior fusion using the lumbotomy approach at the second stage. Twenty million UC-MSCs combined with HA granules in 2 cc of saline were transplanted to fill the vertebral bone defect. Postoperative alkaline phosphatase level, quality of life, and radiological healing were evaluated at one-month, three-month, and six-month follow-up. RESULTS: The initial mean ALP level at one-month follow-up was 48.33 ± 8.50 U/L. This value increased at the three-month follow-up but decreased at the six-month follow-up time, 97 ± 8.19 U/L and 90.33 ± 4.16 U/L, respectively. Bone formation of 50-75% of the defect site with minimal fracture line was found. Increased bone formation comprising 75-100% of the total bone area was reported six months postoperation. A total score of the SF-36 questionnaire showed better progression in all 8 domains during the follow-up with the mean total score at six months of 2912.5 ± 116.67 from all patients. CONCLUSION: Umbilical cord mesenchymal stem cells combined with hydroxyapatite-based scaffold utilization represent a prospective alternative therapy for bone formation and regeneration of vertebral bone defect due to spondylitis tuberculosis. Further clinical investigations are needed to evaluate this new alternative.

The Effect of Mesenchymal Stem Cell-Enriched Scaffolds on MMP-8 and TGF-ß Levels of Vertebrae Postlaminoplasty in Rabbit Model.

INTRODUCTION: Some laminoplasty procedures still have restenosis because of bony-bridging failure of the laminar hinge. The present study aimed to determine the effect of mesenchymal stem cell (MSC)-enriched scaffolds on vertebral regeneration after laminoplasty on the basis of the number of osteoblasts, matrix metalloproteinase-8 (MMP-8), and transforming growth factor-beta (TGF-ß) levels. METHODS: Laminoplasty procedure using the Hirabayashi technique was conducted at the lumbar level in 32 rabbits that were divided into four and three groups of the control (C) and treatment groups, respectively, with different types of laminoplasty spacer (T1, autograft; T2, scaffold; and T3, scaffold with MSCs). Histopathological studies were conducted to calculate the number of osteoblasts and enzyme-linked immunosorbent assay tests to detect MMP-8 and TGF-ß 4 weeks after the surgery. RESULTS: The results showed a significant decrease in MMP-8 level in the T3 group compared with that in the control group (p < 0.05). A significant difference exists between the average number of newly formed osteoblasts in the control group compared with that in the T3 group (p < 0.05) with a higher mean blood TGF-ß level of all experimental groups compared with that of the control group (p = 0.58). CONCLUSION: The significant decrease in MMP-8 levels, increase in TGF-ß levels, and increased number of osteoblasts on MSC-seeded polylactic acid scaffolds could be useful to support the laminoplasty procedure to prevent restenosis because it was biocompatible and promoted the bone healing process.

Significance of the Association between Disc Degeneration Changes on Imaging and Low Back Pain: A Review Article.

Low back pain (LBP) is a major health issue resulting in a huge economic burden on the community. It not only increases the medical costs directly, but also raises the disability and loss of productivity in the general population. Symptoms include local pain over the spinal area, pain radiating to the lower leg, stiffness, and muscle tension. LBP is strongly linked with intervertebral disc degeneration that is further associated with the disruption of the complex anatomy of nucleus pulposus, annulus fibrosus, and adjacent supporting structures of the spine. Change in the shape and intensity of nucleus pulposus, decreased disc height, disc herniation, vertebral endplate changes, presence of osteophyte, and posterior high intensity zones are degenerative changes found in imaging studies. Every feature is considered while grading the severity score. Modic changes, DEBIT (disc extension beyond interspace) score, and Pfirrmann criteria are some of the scoring criteria used for evaluating disc degeneration severity. Moreover, the total number and contiguous pattern of affected discs play a crucial role in symptom generation of back pain. Many studies have reported asymptomatic patients. Thus, the correlation between degeneration severity found in imaging study and symptom severity of LBP remain unclear. This review discusses and summarizes the available literature on the significance of the association between the severity of degenerative changes found in imaging study with the presence and intensity of LBP.