Streptococcal dTDP-L-rhamnose biosynthesis enzymes: functional characterization and lead compound identification.

Biosynthesis of the nucleotide sugar precursor dTDP-L-rhamnose is critical for the viability and virulence of many human pathogenic bacteria, including Streptococcus pyogenes (Group A Streptococcus; GAS), Streptococcus mutans and Mycobacterium tuberculosis. Streptococcal pathogens require dTDP-L-rhamnose for the production of structurally similar rhamnose polysaccharides in their cell wall. Via heterologous expression in S. mutans, we confirmed that GAS RmlB and RmlC are critical for dTDP-L-rhamnose biosynthesis through their action as dTDP-glucose-4,6-dehydratase and dTDP-4-keto-6-deoxyglucose-3,5-epimerase enzymes respectively. Complementation with GAS RmlB and RmlC containing specific point mutations corroborated the conservation of previous identified catalytic residues. Bio-layer interferometry was used to identify and confirm inhibitory lead compounds that bind to GAS dTDP-rhamnose biosynthesis enzymes RmlB, RmlC and GacA. One of the identified compounds, Ri03, inhibited growth of GAS, other rhamnose-dependent streptococcal pathogens as well as M. tuberculosis with an IC50 of 120-410 µM. Importantly, we confirmed that Ri03 inhibited dTDP-L-rhamnose formation in a concentration-dependent manner through a biochemical assay with recombinant rhamnose biosynthesis enzymes. We therefore conclude that inhibitors of dTDP-L-rhamnose biosynthesis, such as Ri03, affect streptococcal and mycobacterial viability and can serve as lead compounds for the development of a new class of antibiotics that targets dTDP-rhamnose biosynthesis in pathogenic bacteria.

Tuberculosis bacillary load, an early marker of disease severity: the utility of tuberculosis Molecular Bacterial Load Assay.

In this comparative biomarker study, we analysed 1768 serial sputum samples from 178 patients at 4 sites in Southeast Africa. We show that tuberculosis Molecular Bacterial Load Assay (TB-MBLA) reduces time-to-TB-bacillary-load-result from days/weeks by culture to hours and detects early patient treatment response. By day 14 of treatment, 5% of patients had cleared bacillary load to zero, rising to 58% by 12th week of treatment. Fall in bacillary load correlated with mycobacterial growth indicator tube culture time-to-positivity (Spearmans r=-0.51, 95% CI (-0.56 to -0.46), p<0.0001). Patients with high pretreatment bacillary burdens (above the cohort bacillary load average of 5.5log10eCFU/ml) were less likely to convert-to-negative by 8th week of treatment than those with a low burden (below cohort bacillary load average), p=0.0005, HR 3.1, 95% CI (1.6 to 5.6) irrespective of treatment regimen. TB-MBLA distinguished the bactericidal effect of regimens revealing the moxifloxacin-20 mg rifampicin regimen produced a shorter time to bacillary clearance compared with standard-of-care regimen, p=0.008, HR 2.9, 95% CI (1.3 to 6.7). Our data show that the TB-MBLA could inform clinical decision making in real-time and expedite drug TB clinical trials.

Carprofen elicits pleiotropic mechanisms of bactericidal action with the potential to reverse antimicrobial drug resistance in tuberculosis.

BACKGROUND: The rise of antimicrobial drug resistance in Mycobacterium tuberculosis coupled with the shortage of new antibiotics has elevated TB to a major global health priority. Repurposing drugs developed or used for other conditions has gained special attention in the current scenario of accelerated drug development for several global infectious diseases. In a similar effort, previous studies revealed that carprofen, a non-steroidal anti-inflammatory drug, selectively inhibited the growth of replicating, non-replicating and MDR clinical isolates of M. tuberculosis. OBJECTIVES: We aimed to reveal the whole-cell phenotypic and transcriptomic effects of carprofen in mycobacteria. METHODS: Integrative molecular and microbiological approaches such as resazurin microtitre plate assay, high-throughput spot-culture growth inhibition assay, whole-cell efflux inhibition, biofilm inhibition and microarray analyses were performed. Analogues of carprofen were also synthesized and assessed for their antimycobacterial activity. RESULTS: Carprofen was found to be a bactericidal drug that inhibited mycobacterial drug efflux mechanisms. It also restricted mycobacterial biofilm growth. Transcriptome profiling revealed that carprofen likely acts by targeting respiration through the disruption of membrane potential. The pleiotropic nature of carprofen's anti-TB action may explain why spontaneous drug-resistant mutants could not be isolated in practice. CONCLUSIONS: This immunomodulatory drug and its chemical analogues have the potential to reverse TB antimicrobial drug resistance, offering a swift path to clinical trials of novel TB drug combinations.

A comparative study of heterogeneous antibiotic resistance of microbial populations in conventional periprosthetic tissue cultures and sonication fluid cultures of orthopaedics explanted prostheses.

BACKGROUND: "Heterogeneity" describes a phenomenon where subpopulations of seemingly isogenic bacteria exhibit a range of susceptibilities to a particular antibiotic. We aim to investigate the frequency of heterogeneity among microbes isolated from infected prostheses, and its possible correlation with microbial resistance. METHODS: Between May 2014 and June 2019, we investigated 234 patients, at our institution, undergoing revision arthroplasty because of loosening of the prostheses or because of periprosthetic joint infection. All patients had periprosthetic tissue culture, sonication of prosthesis and direct inoculation of Sonication fluid into blood culture bottles. We assessed the presence of heterogeneity among all pathogens isolated from infected prostheses. RESULTS: Using standard non-microbiological criteria to determine periprosthetic joint infection, it was found that 143 patient (61.1%) had aseptic loosening while 91 patients (38.9%) had periprosthetic joint infection. Comparing the two methods, the results of our study showed that the method of sonication was significantly more sensitive than tissue culture [91% (83-96) vs. 43% (33-54); p < 0.005]. In this study, heterogeneity was reported in 15 cases, 16.5% of all infections and 6.4% in the total population. In our study, Staphylococcus epidermidis was the most commonly isolated strain followed by Staphylococcus aureus, at a rate of 35.2% and 19.8%, respectively. Antibiotics in which the microorganisms exhibited heterogeneous bacterial behavior most frequently were Gendamicin (5.3%), Vancomycin (4.9%). CONCLUSION: There is increasing evidence that heterogeneity can lead to therapeutic failure and that the detection of this phenotype is a prerequisite for a proper antibiotic choice to have a successful therapeutic effect.

A novel regulatory factor affecting the transcription of methionine biosynthesis genes in Escherichia coli experiencing sustained nitrogen starvation.

The initial adaptive transcriptional response to nitrogen (N) starvation in Escherichia coli involves large-scale alterations to the transcriptome mediated by the transcriptional activator, NtrC. One of these NtrC-activated genes is yeaG, which encodes a conserved bacterial kinase. Although it is known that YeaG is required for optimal survival under sustained N starvation, the molecular basis by which YeaG benefits N starved E. coli remains elusive. By combining transcriptomics with targeted metabolomics analyses, we demonstrate that the methionine biosynthesis pathway becomes transcriptionally dysregulated in ΔyeaG bacteria experiencing sustained N starvation. It appears the ability of MetJ, the master transcriptional repressor of methionine biosynthesis genes, to effectively repress transcription of genes under its control is compromised in ΔyeaG bacteria under sustained N starvation, resulting in transcriptional derepression of MetJ-regulated genes. Although the aberrant biosynthesis does not appear to be a contributing factor for the compromised viability of ΔyeaG bacteria experiencing sustained N starvation, this study identifies YeaG as a novel regulatory factor in E. coli affecting the transcription of methionine biosynthesis genes under sustained N starvation.

Adjustable loop ACL suspension devices demonstrate less reliability in terms of reproducibility and irreversible displacement.

PURPOSE: The aim of this study was to perform a comprehensive biomechanical examination of frequently applied femoral cortical suspension devices, comparing the properties of both fixed and adjustable fixation mechanisms. It was hypothesized that adjustable loop devices demonstrate less consistent fixation properties with increased variability compared to fixed loop devices. METHODS: Nine frequently applied fixation button types were tested, six adjustable and three rigid loop devices. Six samples of each device type were purchased. Each device was installed in a servo-hydraulic mechanical testing machine, running a 2000 cycle loading protocol at force increments between 50 and 500 N. Irreversible displacement in mm was measured for all of the tested samples of each implant. Ultimately, maximum load to failure was applied and measured in Nm. An irreversible displacement of 3 mm was considered failure of the implant. RESULTS: Three of the six adjustable devices (GraftMax™, TightRope® ToggleLoc™) demonstrated a median displacement above the threshold of clinical failure before completion of the cycles. All adjustable loop devices showed a wide intragroup variation in terms of irreversible displacement, compared to fixed-loop devices. Fixed-loop devices provided consistent reproducible results with narrow ranges and significantly lower irreversible displacement (p < 0.05), the maximum being 1.4 mm. All devices withstood an ultimate force of more than 500 N. CONCLUSION: Adjustable loop devices still show biomechanical inferiority and demonstrate heterogeneity of fixation properties with wide- and less-reproducible displacement ranges resultant to the mechanism of adjustment, denoting less reliability. However, three adjustable devices (RIGIDLOOP™ Adjustable, Ultrabutton ◊, ProCinch™) demonstrate fixation capacities within the margins of clinical acceptance. RIGIDLOOP™ Adjustable provides the most comparable fixation properties to fixed loop devices.

Collagen application reduces complication rates of mid-substance ACL tears treated with dynamic intraligamentary stabilization.

PURPOSE: Dynamic intraligamentary stabilization was recently proposed as an option for the treatment of acute ACL ruptures. The aim of this study was to investigate the feasibility of the procedure in mid-substance ACL ruptures and examine whether the additional application of a bilayer collagen I/III membrane would provide for a superior outcome. METHODS: The study group consisted of patients presenting with a mid-substance ACL rupture undergoing dynamic intraligamentary stabilization using the Ligamys™ device along with application of a collagen I/III membrane to the surface of the ACL (group A, n = 23). The control group comprised a matched series of patients presenting with a mid-substance ACL rupture also treated by dynamic intraligamentary stabilization Ligamys™ repair, however, without additional collagen application (group B, n = 33). Patients were evaluated preoperatively and at 24-month follow-up for stability as well as Tegner and Lysholm scores. Knee laxity was measured as a difference in anterior translation (ΔAP) and pivot shift. Any events occurring during the follow-up period of 24 months were documented. Logistic regression of complications was performed, and adjustment undertaken where necessary. RESULTS: A high total complication rate of 78.8 % was noted in group B, compared to group A (8.7 %) (p = 0.002). The addition of a collagen membrane was the only independent prognostic factor associated with reduced complications (OR 8.0, CI 2.0-32.2, p = 0.003, for collagen-free treatment). In group B, 6 patients suffered a re-rupture with subsequent instability requiring secondary hamstring reconstruction surgery, and 11 developed extension loss requiring arthroscopic debridement, whilst in group A, 2 patients required arthroscopic debridement for loss of exension, with no further encountered complication. Median Lysholm score was significantly higher in group A compared to group B (median 100 range 93-100 vs median 95 range 60-100, p = 0.03) at final follow-up. CONCLUSIONS: A high complication rate following ACL Ligamys™ repair of mid-substance ruptures was noted. Application of a collagen membrane to the surface of the ACL resulted in a reduced incidence of extension deficit and re-ruptures. The results indicate that solitary ACL Ligamys™ repair does not present an appropriate treatment modality for mid-substance ACL ruptures. Collage application proved to provide healing benefits with superior clinical outcome after ACL repair. LEVEL OF EVIDENCE: Case control study, Level III.

Outcome measures in clinical ACL studies: an analysis of highly cited level I trials.

PURPOSE: Clinical research in the area of anterior cruciate ligament (ACL) injury has shown substantial growth during the last decade. This was accompanied by the establishment of a wide range of outcome measures used to address the demands of clinical studies. The aim of this study was to evaluate outcome measures reported by highly cited level I trials in ACL research and identify factors influencing citation metrics. METHODS: The database of the Institute for Scientific Information (ISI) was utilized to screen journals under the subject categories "Orthopaedics", "Sports Sciences", "Radiology" and "General medicine" for the 50 most cited level I ACL trials based on predefined inclusion criteria. Metadata, citation metrics and outcome measures were extracted for each article. Frequencies of reported outcome measures were calculated, and a multiple linear regression model applied to identify factors influencing citation metrics. RESULTS: Two independent outcome measures demonstrated an influence on acquisition of citations including: 1-report of the pivot-shift test and 2-inclusion of the Knee Injury and Osteoarthritis Outcome (KOOS) score. Furthermore, highly cited ACL trials frequently reported KT-1000 measures of anterior translation, range of motion (ROM), graft failure, Lysholm, Tegner and subjective International Knee Documentation (IKDC) scores. CONCLUSION: This analysis reflects on the outcome measures utilized in highly cited level I trials impacting the field of ACL research. It also identifies factors likely to influence acquisition of citations. This is of both clinical and academic relevance when choosing appropriate measures for post-operative outcome evaluation after ACL surgery. LEVEL OF EVIDENCE: I.

Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.

BACKGROUND: New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. METHODS AND RESULTS: Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). CONCLUSIONS: This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb mRNA profiles 0-2 weeks into chemotherapy predict the efficacy of treatment 6 weeks later. These observations advocate assaying dynamic bacterial phenotypes through drug therapy as biomarkers for treatment success.

Repurposing drugs for treatment of tuberculosis: a role for non-steroidal anti-inflammatory drugs.

INTRODUCTION: The number of cases of drug-resistant Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), has risen rapidly in recent years. This has led to the resurgence in repurposing existing drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), for anti-TB treatment. SOURCES OF DATA: Evidence from novel drug screening in vitro, in vivo, pharmacokinetic/pharmacodynamics analyses and clinical trials has been used for the preparation of this systematic review of the potential of NSAIDs for use as an adjunct in new TB chemotherapies. AREAS OF AGREEMENT: Certain NSAIDs have demonstrated inhibitory properties towards actively replicating, dormant and drug-resistant clinical isolates of M. tuberculosis cells. AREAS OF CONTROVERSY: NSAIDs are a diverse class of drugs, which have reported off-target activities, and their endogenous antimicrobial mechanism(s) of action is still unclear. GROWING POINTS: It is essential that clinical trials of NSAIDs continue, in order to assess their suitability for addition to the current TB treatment regimen. Repurposing molecules such as NSAIDs is a vital, low-risk strategy to combat the trend of rapidly increasing antibiotic resistance.

Tetrahydroisoquinolines affect the whole-cell phenotype of Mycobacterium tuberculosis by inhibiting the ATP-dependent MurE ligase.

OBJECTIVES: (S)-Leucoxine, isolated from the Colombian Lauraceae tree Rhodostemonodaphne crenaticupula Madriñan, was found to inhibit the growth of Mycobacterium tuberculosis H37Rv. A biomimetic approach for the chemical synthesis of a wide array of 1-substituted tetrahydroisoquinolines was undertaken with the aim of elucidating a common pharmacophore for these compounds with novel mode(s) of anti-TB action. METHODS: Biomimetic Pictet-Spengler or Bischler-Napieralski synthetic routes were employed followed by an evaluation of the biological activity of the synthesized compounds. RESULTS: In this work, the synthesized tetrahydroisoquinolines were found to inhibit the growth of M. tuberculosis H37Rv and affect its whole-cell phenotype as well as the activity of the ATP-dependent MurE ligase, a key enzyme involved in the early stage of cell wall peptidoglycan biosynthesis. CONCLUSIONS: As the correlation between the MIC and the half-inhibitory enzymatic concentration was not particularly strong, there is a credible possibility that these compounds have pleiotropic mechanism(s) of action in M. tuberculosis.

ProTides of N-(3-(5-(2'-deoxyuridine))prop-2-ynyl)octanamide as potential anti-tubercular and anti-viral agents.

The flavin-dependent thymidylate synthase X (ThyX), rare in eukaryotes and completely absent in humans, is crucial in the metabolism of thymidine (a DNA precursor) in many microorganisms including several human pathogens. Conserved in mycobacteria, including Mycobacterium leprae, and Mycobacterium tuberculosis, it represents a prospective anti-mycobacterial therapeutic target. In a M. tuberculosis ThyX-enzyme inhibition assay, N-(3-(5-(2'-deoxyuridine-5'-phosphate))prop-2-ynyl)octanamide was reported to be the most potent and selective 5-substituted 2'-deoxyuridine monophosphate analogue. In this study, we masked the two charges at the phosphate moiety of this compound using our ProTide technology in order to increase its lipophilicity and then allow permeation through the complex mycobacterial cell wall. A series of N-(3-(5-(2'-deoxyuridine))prop-2-ynyl)octanamide phosphoroamidates were chemically synthesized and their biological activity as potential anti-tuberculars was evaluated. In addition to mycobacteria, several DNA viruses depend on ThyX for their DNA biosynthesis, thus these prodrugs were also screened for their antiviral properties.

The Use of TNF-α Inhibitors in Active Ankylosing Spondylitis Treatment.

Ankylosing spondylitis (AS) is a challenging disease, characterized by chronic inflammation and structural damage primarily affecting the axial skeleton, while extra-articular manifestations may also appear. This results in the deterioration of patients' quality of life. Over the past few decades, tumor necrosis factor-α (TNF-α) inhibitors have revolutionized the management of AS, offering substantial relief from symptoms and improving patient outcomes. The aim of this review is to assess the efficacy of TNF-α inhibitors in patients with active AS. A search was performed in the PubMed database using the following keywords: ("TNF alpha inhibitors" OR "anti TNF-a" OR "TNF-a inhibitors" OR "anti TNF-alpha" OR "Etanercept " OR "Golimumab" OR "Infliximab" OR "Certolizumab pegol" OR "Adalimumab") AND "ankylosing spondylitis". The search was completed in February 2024, and 35 studies were included in this review following PRISMA guidelines. The findings reveal evidence supporting the efficacy of TNF-α inhibitors in reducing inflammation, preventing structural damage, and enhancing overall well-being in AS patients. Overall, TNF-α inhibitors have emerged as a cornerstone in the therapeutic algorithm against AS with a very satisfactory safety profile.

Sagittal Balance Parameters and Proximal Junctional Kyphosis in Adolescent Idiopathic Scoliosis.

Background: To review and evaluate multiple preoperative and postoperative sagittal parameters and their association with the risk of developing proximal junctional kyphosis (PJK) in patients with adolescent idiopathic scoliosis (AIS) who undergo correction surgery. Methods: A systematic search was performed in December 2022 in PubMed, Embase and the Cochrane Library to retrieve all the studies relevant to our research. After the study selection and data extraction following PRISMA guidelines, RevMan 5.3 was used for statistical analysis. All the analyzed factors were evaluated by using odds ratios and weighted mean differences with 95% confidence intervals. Moreover, the meta-analysis of proportions via MedCalc was used for analyzing quantitative data from the studies. Results: A total of 22 studies were included in our meta-analysis. All the available values of sagittal parameters were evaluated. Among all the potential risk factors, higher preoperative thoracic kyphosis (Test for overall effect Z = 11.79, p < 0.00001), higher preoperative sagittal vertical axis (SVA) (test for overall effect Z = 11.19, p < 0.00001), greater thoracic kyphosis change post-op. compared to pre-op. (test for overall effect Z = 6.02, p < 0.00001), increased postoperative lumbar lordosis (test for overall effect Z = 3.65, p = 0.0003), higher post-op. SVA (test for overall effect Z = 24.93, p < 0.00001) and a larger pelvic incidence/lumbar lordosis (PI/LL) mismatch (test for overall effect Z = 20.50, p < 0.00001) were found to be the risk factors for PJK after AIS surgery. Moreover, a decreased rod contour angle (RCA) (test for overall effect Z = 3.79, p < 0.0002) and higher proximal junctional angle-rod contour angle (PJA-RCA) (test for overall effect Z = 39.18, p < 0.00001) play a significant role in the risk of developing PJK after AIS correction. Conclusions: Sagittal balance is of great importance when considering the surgical correction of AIS. Many factors in our meta-analysis were found to increase the incidence for PJK such as higher preoperative thoracic kyphosis and pre-op. SVA. Furthermore, increased thoracic kyphosis change, increased post-operative lumbar lordosis, SVA and PI/LL mismatch are also factors that influence the possibility of post-op. PJK. Lastly, RCA and PJA-RCA are two important factors that need attention during AIS, as over-contouring of the rod could lead to PJK in AIS patients.

Correction: Characterisation of ATP-Dependent Mur Ligases Involved in the Biogenesis of Cell Wall Peptidoglycan in Mycobacterium tuberculosis.

[This corrects the article DOI: 10.1371/journal.pone.0060143.].

Electrical Stimulation and Motor Function Rehabilitation in Spinal Cord Injury: A Systematic Review.

Spinal cord injury (SCI) often leads to devastating motor impairments, significantly affecting the quality of life of affected individuals. Over the last decades, spinal cord electrical stimulation seems to have encouraging effects on the motor recovery of impacted patients. This review aimed to identify clinical trials focused on motor function recovery through the application of epidural electrical stimulation, transcutaneous electrical stimulation, and functional electrical stimulation. Several clinical trials met these criteria, focusing on the impact of the aforementioned interventions on walking, standing, swimming, trunk stability, and upper extremity functionality, particularly grasp. After a thorough PubMed online database research, 37 clinical trials were included in this review, with a total of 192 patients. Many of them appeared to have an improvement in function, either clinically assessed or recorded through electromyography. This review outlines the various ways electrical stimulation techniques can aid in the motor recovery of SCI patients. It stresses the ongoing need for medical research to refine these techniques and ultimately enhance rehabilitation results in clinical settings.

Antimycobacterials from lovage root (Ligusticum officinale Koch).

The n-hexane extract of Lovage root was found to significantly inhibit the growth of both Mycobacterium smegmatis mc²155 and Mycobacterium bovis BCG, and therefore a bioassay-guided isolation strategy was undertaken. (Z)-Ligustilide, (Z)-3-butylidenephthalide, (E)-3-butylidenephthalide, 3-butylphthalide, α-prethapsenol, falcarindiol, levistolide A, psoralen and bergapten were isolated by chromatographic techniques, characterized by NMR spectroscopy and MS, and evaluated for their growth inhibition activity against Mycobacterium tuberculosis H37Rv using the whole-cell phenotypic spot culture growth inhibition assay (SPOTi). Cytotoxicity against RAW 264.7 murine macrophage cells was employed for assessing their degree of selectivity. Falcarindiol was the most potent compound with a minimum inhibitory concentration (MIC) value of 20 mg/L against the virulent H37Rv strain; however, it was found to be cytotoxic with a half-growth inhibitory concentration (GIC50) in the same order of magnitude (SI < 1). Interestingly the sesquiterpene alcohol α-prethapsenol was found to inhibit the growth of the pathogenic mycobacteria with an MIC value of 60 mg/L, being more specific towards mycobacteria than mammalian cells (SI ~ 2). Colony forming unit analysis at different concentrations of this phytochemical showed mycobacteriostatic mode of action.

Anterior crucial ligament rupture: self-healing through dynamic intraligamentary stabilization technique.

PURPOSE: Surgery involving arthroscopic reconstruction of the injured ligament is the gold standard treatment for torn anterior cruciate ligament (ACL). Recent studies support the hypothesis of biological self-healing of ruptured ACL. The aim of the study is to evaluate, in an animal model, the efficacy of a new technique, dynamic intraligamentary stabilization that utilizes biological self-healing for repair of acute ACL ruptures. METHODS: The ACL in 11 adult female white alpine sheep was transected and in 8 sheep reconstructed by dynamic intraligamentary stabilization. To enhance the healing potential, microfracturing and collagen were used in all animals. The contralateral, non-operated knees served as controls. At 3 months postkilling, all animals were submitted to magnetic resonance imaging and biomechanical and histological evaluation. RESULTS: No surgery-related complications were observed. Postoperatively, all animals regularly used the operated leg with full weight bearing and no lameness. At the time of killing, all animals exhibited radiological and histological healing of the transacted ACL. Biomechanical tests confirmed successful restoration of anteroposterior translation in the dynamic intraligamentary stabilization knees. Histological examination revealed dense scar tissue at the ends of the transected ligaments exhibiting hypercellularity and hypervascularization. CONCLUSION: The dynamic intraligamentary stabilization technique successfully induced self-healing of ruptured ACL in a sheep model. Knee joints remained stable during the healing period allowing free range of motion and full weight bearing, and no signs of osteoarthritis or other intraarticular damage in the follow up were observed.

The cement prosthesis-like spacer: an intermediate halt on the road to healing.

BACKGROUND: Periprosthetic infections remain a devastating problem in the field of joint arthroplasty. In the following study, the results of a two-stage treatment protocol for chronic periprosthetic infections using an intraoperatively molded cement prosthesis-like spacer (CPLS) are presented. METHODS: Seventy-five patients with chronically infected knee prosthesis received a two-stage revision procedure with the newly developed CPLS between June 2006 and June 2011. Based on the microorganism involved, patients were grouped into either easy to treat (ETT) or difficult to treat (DTT) and treated accordingly. Range of motion (ROM) and the knee society score (KSS) were utilized for functional assessment. RESULTS: Mean duration of the CPLS implant in the DTT group was 3.6 months (range 3-5 months) and in the ETT group 1.3 months (range 0.7-2.5 months). Reinfection rates of the final prosthesis were 9.6% in the ETT and 8.3% in the DTT group with no significant difference between both groups regarding ROM or KSS (P = 0.87, 0.64, resp.). CONCLUSION: The results show that ETT patients do not necessitate the same treatment protocol as DTT patients to achieve the same goal, emphasizing the need to differentiate between therapeutic regimes. We also highlight the feasibility of CLPS in two-stage protocols.

Rehabilitation Prognostic Factors following Hip Fractures Associated with Patient's Pre-Fracture Mobility and Functional Ability: A Prospective Observation Study.

Low physical function is associated with poor outcomes in the elderly population suffering from hip fractures. The present study aims to evaluate the prognostic tools for predicting patient recovery after hip fractures and investigate the correlation between the pre-fracture motor and functional statuses. A prospective study was performed, including 80 patients suffering from hip fractures. Patient history, previous falls, the type of fracture and overall survival were evaluated. Patient-reported outcome measures (SF-36, EQ-5D/VAS, Charlson Comorbidity Index (CCI), Short Physical Performance Battery (SPPB), Timed Up and Go (TUG) and Harris Hip Score (HHS)) were monitored before hospital discharge at 6 weeks, and 3, 6 and 12 months postoperatively. Overall, 55% of patients experienced at least one fall, and 46% of them used crutches before the fracture. The average CCI score was 6.9. The SPPB score improved from 1.4 ± 1.3 (1 week) to 4.4 ± 2.1 (48 weeks). A one-year age increase, female sex, and prior history of falls lead to 0.1-, 0.92-, 0.56-fold lower SPPB scores, respectively, at 12 months. The HHS recorded the greatest improvement between 6 and 12 weeks (52.1 ± 14.6), whereas the TUG score continued to improve significantly from 139.1 ± 52.6 s (6 weeks) to 66.4 ± 54 s (48 weeks). The SPPB and performance test can be routinely used as a prognostic tool.