Treatment strategy and clinical outcomes of surgically managed hip periprosthetic fractures: analysis from a high-volume centre.

BACKGROUND: Hip periprosthetic fractures (PPF) after total hip arthroplasty (THA) are becoming increasingly prevalent. Their management is secondary to the fracture type and the stability of the implant. This study aimed to provide the outcomes of operatively managed PPF from a high-volume centre to help guide future decision making. METHODS: This was a retrospective study of prospectively collected data from January 2008 to January 2021. Patient demographics, implant specific details, and fixation strategy were collected. Complications including infection, reoperation, re-fracture, re-revision, were collected. Short-term mortality was evaluated at 3 months and 1 year. P-values <0.05 were considered significant. RESULTS: 282 surgically managed PPF were identified. Vancouver B2 were predominant in 52% of the cases. Revision alone and revision with additional fixation were the most frequent strategies in 168 cases (60%). Complications requiring reoperation occurred in 20% of the cases, with infection as the most frequent (8.5%). Mortality rate was 7.8% at 3 months and 15.7% at 1 year, with significantly lower rates in B2 type. B2 fractures treated with cemented stems had a significantly lower 1-year mortality than distal fit revisions. CONCLUSIONS: PPF is associated with a high complication rate. Revision alone and revision with additional fixation remain the preferred method in B2/B3 type fractures, however, cemented revision can yield similar outcomes with lower short-term mortality. Considering the high-risk elderly and frail category of patients, a multidisciplinary team is necessary to improve outcomes and reduce mortality.

The Clinical Frailty Scale is a Strong Predictor of 1-Year Mortality in Surgically Managed Hip Periprosthetic Fracture: An Analysis From a High-Volume Institution.

BACKGROUND: Hip periprosthetic fractures (PPFs) after primary total hip arthroplasty are increasing with the number of primary implants and aging population. Mortality has been reported up to 34% at 1-year. The aim of this study was to evaluate the association of Clinical Frailty Scale (CFS) and 1-year mortality, complication rate, and length of stay (LOS) in surgically managed hip PPFs. METHODS: This was a retrospective study of prospectively collected data from January 2008 to January 2021. A total of 282 surgically managed hip PPFs were identified. Mean age was 79 years (range, 42 to 106). Preoperative scores were analyzed through linear regression to identify significant association with mortality, complication and LOS. Receiver operating characteristic curve and Area Under the Curve (AUC) were generated to evaluate the quality of the models and the discriminatory ability of each clinical score. Significance was considered at P values < .05. RESULTS: Mortality was 7.8% at 3-months and 15.7% at 1-year. Complication rate requiring surgery was 19.5% and mean LOS was 8.9 ± 7 days. The CFS was significantly associated with 3-month (odds ratio 2.23, P < .001) and 1-year mortality (odds ratio 2.01, P < .001). The receiver operating characteristic curve test for 1-year mortality showed a greater AUC for the CFS when compared with American Society for Anesthesiologists score and age-adjusted Charlson Comorbidity Index (AUC 0.80 versus 0.68 versus 0.72, respectively). CONCLUSIONS: Frailty is a syndrome with increased risk of mortality after surgically managed PPF. The CFS can be easily assessed at the time of admission and could be considered as a strong and reliable predictor of 1-year mortality with a greater AUC than the conventionally used American Society for Anesthesiologists score.

What are the Outcomes of Secondary Patella Resurfacing for Dissatisfaction Following Primary Knee Arthroplasty? A Systematic Review and Meta-Analysis of 604 Knees.

BACKGROUND: Secondary patella resurfacing is often performed for dissatisfaction following primary knee arthroplasty where the native patella was retained. The purpose of this meta-analysis was to evaluate outcomes of secondary patella resurfacing. METHODS: The systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies reporting on patients who underwent secondary patella resurfacing after previous primary knee arthroplasty with retention of the native patella were considered eligible. The risk of bias was assessed using the Methodological Index for Non-Randomized studies tool. A random-effects model and the inverse-variance weighting method was used for meta-analysis. There were sixteen retrospective studies including 604 knees (594 patients) with a mean follow up of 42 months (range, 2 to 197). RESULTS: An overall improvement in patient-reported outcomes (PROMs) was achieved in 53% of cases from pooled data available for 293 knees [95% Confidence Interval (CI) (0.44, 0.62), I2=68% - moderate heterogeneity]. The pooled proportion of patients satisfied with the procedure was 59% [95% CI (48, 68), I2 = 70% - moderate heterogeneity] in a sample size of 415. There was a minimal rate (2%) of complication incidence when performing secondary patella resurfacing and a pooled rate of revision surgery of 10%. CONCLUSIONS: An improvement in pain, satisfaction, and PROMs was achieved in slightly more than half of the patients following secondary patella resurfacing. However, studies lacked standardized objective selection criteria for the procedure and the available data was predominantly retrospective, with high heterogeneity and variation in outcome reporting.

Popliteal tendon impingement as a cause of pain following total knee arthroplasty: a systematic review.

INTRODUCTION: Popliteal tendon impingement (PTI) is an under-recognized cause of persistent pain following total knee arthroplasty (TKA). The purpose of the systematic review was to summarize and outline successful strategies in the diagnosis and management of PTI. METHODS: A systematic review following the PRISMA guidelines was performed for four databases: MEDLINE (Pubmed), Ovid EMBASE, Web of Science, and Cochrane Database. It was registered in the International Prospective Register for Systematic Reviews and Meta-analysis (PROSPERO) under the registration number: CRD42023398723. The risk of bias assessment was performed using the criteria of the methodological index for non-randomized studies (MINORS). RESULTS: A total of 8 studies were included. There were 2 retrospective case series and 6 case reports. The follow-up ranged from 6 to 30 months. Two studies described PTI as an intraoperative phenomenon during TKA with "snapping"; whilst 6 studies described indications and outcomes for arthroscopic tenotomy for PTI following TKA. In making the diagnosis, there was concurrence that the posterolateral pain should be focal and that dynamic ultrasonography and diagnostic injection play an important role. Two specific clinical tests have been described. There was no consistency regarding the need for imaging. There were no reports of instability following popliteal tendon tenotomy or other complications. CONCLUSION: PTI should be suspected as a cause for persistent focal pain at the posterolateral knee following TKA. The diagnosis can be suspected on imaging and should be confirmed with dynamic ultrasonography and an ultrasound-guided diagnostic injection. An arthroscopic complete tenotomy of the tendon can reliably alleviate pain and relies on correct diagnosis. There is no evidence for clinically relevant negative biomechanical consequences following tenotomy. LEVEL OF EVIDENCE: Systematic Review of Level IV and V studies.

Pregnancy, Hip Pain, and Total Hip Replacement.

➤ Young women who are 15 to 45 years of age and undergo total hip replacements are at increased risk for revision compared with women >75 years of age.➤ Among women of childbearing age with a total hip replacement, 12% to 17% will later have at least 1 pregnancy.➤ Young women who undergo total hip replacement do not have an increased risk of pregnancy complications.➤ Of the 60% of women who experienced pain with a total hip replacement during pregnancy, 21% had persisting pain, and 4% reported the pain as severe.➤ Women who have a total hip replacement and later experience pregnancy and childbirth have no increased risk of pregnancy complications or increased revision rates; there was no effect of the mode of delivery on revision rates or complications including fracture, dislocation, or loosening, according to the limited studies available.

Structure of the d-Cycloserine-Resistant Variant D322N of Alanine Racemase from Mycobacterium tuberculosis.

Alanine racemase (Alr) is a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the racemization of l-alanine to d-alanine. Alr is one of the two targets of the broad-spectrum antibiotic d-cycloserine (DCS), a structural analogue of d-alanine. Despite being an essential component of regimens used to treat multi- and extensively drug-resistant tuberculosis for almost seven decades, resistance to DCS has not been observed in patients. We previously demonstrated that DCS evades resistance due to an ultralow rate of emergence of mutations. Yet, we identified a single polymorphism (converting Asp322 to Asn) in the alr gene, which arose in 8 out of 11 independent variants identified and that confers resistance. Here, we present the crystal structure of the Alr variant D322N in both the free and DCS-inactivated forms and the characterization of its DCS inactivation mechanism by UV-visible and fluorescence spectroscopy. Comparison of these results with those obtained with wild-type Alr reveals the structural basis of the 240-fold reduced inhibition observed in Alr D322N.

Metal-on-Metal Hips: Ten-Year Clinical and Radiographic Outcomes of the ADEPT Metal-on-Metal Hip Resurfacing and Modular Total Hip Arthroplasty.

BACKGROUND: The aim of this study is to update the 10-year follow-up survivorship and metal ions levels of a cohort of metal-on-metal (MoM) hip resurfacing (HR) and large-diameter-head (LDH) total hip arthroplasty (THA). METHODS: The study is a retrospective analysis of prospectively collected data that compared the outcomes of 24 MoM HR (21 patients) and 15 (11 patients) modular LHD MoM THA at >10 years follow-up. Baseline characteristics as well as intraoperative and postoperative information were collected, including complications, revisions, clinical and radiographic outcomes, and serum metal ions level (Cobalt, Chromium). Metal ion levels were compared using a two-tailed unpaired t-test and Wilcoxon signed-rank test (jamovi v2.3.3.0, Sydney, NSW, AU). RESULTS: No significant differences were detected in gender, BMI, and ASA score between the two groups. Patients in the modular THA group were significantly older (57 years vs. 46 years; p < 0.05). The HR overall survivorship was 91.7% (22 of 24 hips) with survivorship from implant failure and/or aseptic loosening and/or metal debris related 100% of problems. The modular THA overall survivorship was 86.7% (13 of 15 hips) with survivorship from implant aseptic loosening and metal ions complications of 93.4% (14 of 15 hips). No significant difference was noted when comparing clinical outcomes. Metal ions were significantly lower in the HR group (Co 25.8 nmol/L vs. 89 nmol/L; p < 0.001-Cr 33.5 nmol/L vs. 55.2 nmol/L; p = 0.026). CONCLUSION: Both implants reported excellent and comparable clinical outcomes at >10 years follow-up. The Adept HR reported remarkable survivorship, in line with the registry data, proving once again its reliability in young active males. The modular LDH THA, despite being discontinued, presented higher reliability and a lower failure rate when compared with similar withdrawn MoM implants. Trunnionosis did not appear to be a significant problem in this particular modular design.

Implementation of a clinical pathway for osteoporosis management within an Orthopaedic Fracture Clinic.

BACKGROUND: A fracture liaison service (FLS) is a multidisciplinary system approach to reducing subsequent fracture risk in patients with a recent fragility fracture. This study investigated the utility of an alternate model delivered by orthopaedic surgeons in increasing the investigation and treatment of osteoporosis within an orthopaedic fracture clinic in a tertiary hospital. METHOD: We established a pathway of treatment (FLS) for women ≥50 years old with a minimal trauma fracture (MTF) in the orthopaedic fracture clinic using existing clinic resources to identify patients. All female patients ≥50 years old with upper limb MTFs during the study period were included and compared with historical controls prior to the intervention. The intervention and control groups were compared to assess the capacity of the new model of care to identify suitable patients and deliver best practice care. RESULTS: After the intervention the cumulative rate of osteoporosis screening increased from 52/173 to 201/318 (P < 0.001). Among the patients who were screened for osteoporosis the treatment rate increased from 25/52 to 126/201 (P < 0.001). The intervention resulted in a significant reduction in patients who were not screened after MTF from 87/173 to 40/318 (P < 0.001). CONCLUSION: We have developed a low-cost pathway developed by the orthogeriatric team integrated into an orthopaedic fracture clinic that leads to increased screening and treatment of osteoporosis. This model was implemented in a tertiary hospital with an integrated inpatient orthogeriatric service and highly engaged orthopaedic surgeons and may not be applicable in other settings.

Repeat two-stage revision for knee prosthetic joint infection results in very high failure rates.

INTRODUCTION: Two stage revision total knee arthroplasty (TKA) is the gold standard for treatment and eradication of knee prosthetic joint infections (PJI), but the literature is limited on the outcomes of repeat two-stage TKA after PJI recurrence. This study presents the outcomes of repeat two-stage revision TKA and investigates potential factors contributing to success or failure, aiming to assist counselling and decision-making. METHODS: A retrospective study was undertaken investigating all two-stage revision TKA performed at one institution between 2005 and 2020. Twenty cases underwent repeat two-stage revision TKA. Patient outcomes and factors contributing to treatment success or failure were investigated. PJI was diagnosed according to MSIS criteria. RESULTS: Of the 20 cases, 14 were classified as failed treatment (70%) due to a failure to eradicate infection, further surgical intervention or death. In this cohort, there were no statistically significant differences between the groups regarding factors contributing to treatment success or failure. In the success group, patient reported functional outcomes were variable. CONCLUSION: This study demonstrates that patients undergoing a repeat two-stage TKA have very poor outcomes. This study did not identify any factors that predicted failure. Patients need to be counselled regarding poor outcomes with repeat two-stage TKA, and other treatment options such as early amputation or lifelong suppression should be considered.

Obesity, Comorbidities, and Prior Operations Additively Increase Failure in 2-Stage Revision Total Knee Arthroplasty for Prosthetic Joint Infection.

BACKGROUND: Prosthetic joint infection (PJI) of the knee carries significant morbidity, mortality, and economic cost. We hypothesize that obese and poor medical hosts will have a significant and additive increase in failure rate undergoing 2-stage revision total knee arthroplasty for PJI. METHODS: All 2-stage revision total knee arthroplasty procedures for PJI performed at one institution were identified between 2005 and 2020. In total, 144 patients were included and defined as success or failure based on published criteria regarding infection eradication, further intervention, or mortality. The American Society of Anesthesiologists score and the Charlson Comorbidity Index were utilized to assess host grade. Patient, surgical, and microbiologic variables were investigated with univariable and multivariable analysis to explore association with risk of failure. RESULTS: In the cohort, 32.4% of patients failed with mean follow-up of 5.1 years. In multivariable analysis, the number of major operations requiring arthrotomy and implantation of new material between the primary and first stage, host grade, and elevated body mass index were the major contributors to failure. Combining these factors, with body mass index >30 and 2 or more major operations, the failure rate increased to 76.5% and 71.4% respectively for American Society of Anesthesiologists score 3 (P ≤ .001) and Charlson Comorbidity Index ≥2 (P ≤ .001). CONCLUSION: In this cohort, multiple major operations between the primary and first stage, host grade, and obesity were the major contributors to failure. When combining these factors, patients had an additive increase in failure rate. Treatments such as amputation or less invasive options and suppression should be discussed and considered in these patients.

Restoring Tumour Selectivity of the Bioreductive Prodrug PR-104 by Developing an Analogue Resistant to Aerobic Metabolism by Human Aldo-Keto Reductase 1C3.

PR-104 is a phosphate ester pre-prodrug that is converted in vivo to its cognate alcohol, PR-104A, a latent alkylator which forms potent cytotoxins upon bioreduction. Hypoxia selectivity results from one-electron nitro reduction of PR-104A, in which cytochrome P450 oxidoreductase (POR) plays an important role. However, PR-104A also undergoes 'off-target' two-electron reduction by human aldo-keto reductase 1C3 (AKR1C3), resulting in activation in oxygenated tissues. AKR1C3 expression in human myeloid progenitor cells probably accounts for the dose-limiting myelotoxicity of PR-104 documented in clinical trials, resulting in human PR-104A plasma exposure levels 3.4- to 9.6-fold lower than can be achieved in murine models. Structure-based design to eliminate AKR1C3 activation thus represents a strategy for restoring the therapeutic window of this class of agent in humans. Here, we identified SN29176, a PR-104A analogue resistant to human AKR1C3 activation. SN29176 retains hypoxia selectivity in vitro with aerobic/hypoxic IC50 ratios of 9 to 145, remains a substrate for POR and triggers γH2AX induction and cell cycle arrest in a comparable manner to PR-104A. SN35141, the soluble phosphate pre-prodrug of SN29176, exhibited superior hypoxic tumour log cell kill (>4.0) to PR-104 (2.5-3.7) in vivo at doses predicted to be achievable in humans. Orthologues of human AKR1C3 from mouse, rat and dog were incapable of reducing PR-104A, thus identifying an underlying cause for the discrepancy in PR-104 tolerance in pre-clinical models versus humans. In contrast, the macaque AKR1C3 gene orthologue was able to metabolise PR-104A, indicating that this species may be suitable for evaluating the toxicokinetics of PR-104 analogues for clinical development. We confirmed that SN29176 was not a substrate for AKR1C3 orthologues across all four pre-clinical species, demonstrating that this prodrug analogue class is suitable for further development. Based on these findings, a prodrug candidate was subsequently identified for clinical trials.

Role of post-translational modifications in the acquisition of drug resistance in Mycobacterium tuberculosis.

Tuberculosis (TB) is one of the primary causes of deaths due to infectious diseases. The current TB regimen is long and complex, failing of which leads to relapse and/or the emergence of drug resistance. There is a critical need to understand the mechanisms of resistance development. With increasing drug pressure, Mycobacterium tuberculosis (Mtb) activates various pathways to counter drug-related toxicity. Signaling modules steer the evolution of Mtb to a variant that can survive, persist, adapt, and emerge as a form that is resistant to one or more drugs. Recent studies reveal that about 1/3rd of the annotated Mtb proteome is modified post-translationally, with a large number of these proteins being essential for mycobacterial survival. Post-translational modifications (PTMs) such as phosphorylation, acetylation, and pupylation play a salient role in mycobacterial virulence, pathogenesis, and metabolism. The role of many other PTMs is still emerging. Understanding the signaling pathways and PTMs may assist clinical strategies and drug development for Mtb. In this review, we explore the contribution of PTMs to mycobacterial physiology, describe the related cellular processes, and discuss how these processes are linked to drug resistance. A significant number of drug targets, InhA, RpoB, EmbR, and KatG, are modified at multiple residues via PTMs. A better understanding of drug-resistance regulons and associated PTMs will aid in developing effective drugs against TB.

Development and Optimization of Chromosomally-Integrated Fluorescent Mycobacterium tuberculosis Reporter Constructs.

Mycobacterium tuberculosis resides in the lungs in various lesion types with unique microenvironmental conditions. This diversity is in line with heterogeneous disease progression and divergent drug efficiency. Fluorescent reporter strains can be used to decipher the micromilieu and to guide future treatment regimens. Current reporters using replicating plasmids, however, are not suitable for long-term mouse infections or studies in non-human primates. Using a combination of recombinant DNA and protein optimization techniques, we have developed reporter strains based on integrative plasmids, which exhibit stimulus-response characteristics and fluorescence intensities comparable to those based on replicating plasmids. We successfully applied the concepts by constructing a multi-color reporter strain able to detect simultaneous changes in environmental pH, Mg2+ concentrations, and protein expression levels.

D-Cycloserine destruction by alanine racemase and the limit of irreversible inhibition.

The broad-spectrum antibiotic D-cycloserine (DCS) is a key component of regimens used to treat multi- and extensively drug-resistant tuberculosis. DCS, a structural analog of D-alanine, binds to and inactivates two essential enzymes involved in peptidoglycan biosynthesis, alanine racemase (Alr) and D-Ala:D-Ala ligase. Inactivation of Alr is thought to proceed via a mechanism-based irreversible route, forming an adduct with the pyridoxal 5'-phosphate cofactor, leading to bacterial death. Inconsistent with this hypothesis, Mycobacterium tuberculosis Alr activity can be detected after exposure to clinically relevant DCS concentrations. To address this paradox, we investigated the chemical mechanism of Alr inhibition by DCS. Inhibition of M. tuberculosis Alr and other Alrs is reversible, mechanistically revealed by a previously unidentified DCS-adduct hydrolysis. Dissociation and subsequent rearrangement to a stable substituted oxime explains Alr reactivation in the cellular milieu. This knowledge provides a novel route for discovery of improved Alr inhibitors against M. tuberculosis and other bacteria.

Comparative fitness analysis of D-cycloserine resistant mutants reveals both fitness-neutral and high-fitness cost genotypes.

Drug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated why Mycobacterium tuberculosis fails to become resistant to D-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primary D-cycloserine resistance conferring mutations.

2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure-Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization.

Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

Preoperative planning for redirective, periacetabular osteotomies.

Redirective, periacetabular osteotomies (PAO) represent a group of surgical procedures for treatment of developmental dysplasia of the hip (DDH) in skeletally mature and immature patients. The ultimate goal of all procedures is to reduce symptoms, improve function and delay or prevent progression of osteoarthritis. During the last two decades, the understanding of the underlying pathomechanisms has continuously evolved. This is mainly attributable to the development of the femoroacetabular impingement concept that has increased the awareness of the underlying three-dimensional complexity associated with DDH. With increasing knowledge about the pathobiomechanics of dysplastic hips, diagnostic tools have improved allowing for sophisticated preoperative analyses of the morphological and pathobiomechanical features, and early recognition of degenerative changes, which may alter the long-term outcome. As redirective, PAO are technically demanding procedures, preoperative planning is crucial to avoid intraoperative obstacles and to sufficiently address the patient-specific deformity. Although conventional radiography has been used for decades, it has not lost its primary role in the diagnostic work-up of patients with DDH. Furthermore, an increasing number of modern imaging techniques exists allowing for assessment of early cartilage degeneration (biochemical magnetic resonance imaging) as well as 3D planning and computer-based virtual treatment simulation of PAO. This article reviews the literature with regard to the current concepts of imaging of DDH, preoperative planning and treatment recommendations for redirective, PAO.

The bacillary and macrophage response to hypoxia in tuberculosis and the consequences for T cell antigen recognition.

Mycobacterium tuberculosis is a facultative anaerobe and its characteristic pathological hallmark, the granuloma, exhibits hypoxia in humans and in most experimental models. Thus the host and bacillary adaptation to hypoxia is of central importance in understanding pathogenesis and thereby to derive new drug treatments and vaccines.

Glutamate Racemase Is the Primary Target of ß-Chloro-d-Alanine in Mycobacterium tuberculosis.

The increasing global prevalence of drug resistance among many leading human pathogens necessitates both the development of antibiotics with novel mechanisms of action and a better understanding of the physiological activities of preexisting clinically effective drugs. Inhibition of peptidoglycan (PG) biosynthesis and cross-linking has traditionally enjoyed immense success as an antibiotic target in multiple bacterial pathogens, except in Mycobacterium tuberculosis, where it has so far been underexploited. d-Cycloserine, a clinically approved antituberculosis therapeutic, inhibits enzymes within the d-alanine subbranch of the PG-biosynthetic pathway and has been a focus in our laboratory for understanding peptidoglycan biosynthesis inhibition and for drug development in studies of M. tuberculosis During our studies on alternative inhibitors of the d-alanine pathway, we discovered that the canonical alanine racemase (Alr) inhibitor ß-chloro-d-alanine (BCDA) is a very poor inhibitor of recombinant M. tuberculosis Alr, despite having potent antituberculosis activity. Through a combination of enzymology, microbiology, metabolomics, and proteomics, we show here that BCDA does not inhibit the d-alanine pathway in intact cells, consistent with its poor in vitro activity, and that it is instead a mechanism-based inactivator of glutamate racemase (MurI), an upstream enzyme in the same early stage of PG biosynthesis. This is the first report to our knowledge of inhibition of MurI in M. tuberculosis and thus provides a valuable tool for studying this essential and enigmatic enzyme and a starting point for future MurI-targeted antibacterial development.

Imaging of femoroacetabular impingement-current concepts.

Following the recognition of femoroacetabular impingement (FAI) as a clinical entity, diagnostic tools have continuously evolved. While the diagnosis of FAI is primarily made based on the patients' history and clinical examination, imaging of FAI is indispensable. Routine diagnostic work-up consists of a set of plain radiographs, magnetic resonance imaging (MRI) and MR-arthrography. Recent advances in MRI technology include biochemically sensitive sequences bearing the potential to detect degenerative changes of the hip joint at an early stage prior to their appearance on conventional imaging modalities. Computed tomography may serve as an adjunct. Advantages of CT include superior bone to soft tissue contrast, making CT applicable for image-guiding software tools that allow evaluation of the underlying dynamic mechanisms causing FAI. This article provides a summary of current concepts of imaging in FAI and a review of the literature on recent advances, and their application to clinical practice.