The effect of tranexamic acid on artificial joint materials: a biomechanical study (the bioTRANX study)

Background

Tranexamic acid (TXA) has been successfully used to reduce bleeding in joint replacement. Recently local TXA has been advocated to reduce blood loss in total knee or hip replacement; however, this raised concerns about potential adverse effects of TXA upon the artificial joint replacement.

Materials and methods

In this biomechanical study we compared the effects of TXA and saline upon the following biomechanical properties of artificial joint materials—(1) tensile properties (ultimate strength, stiffness and Young’s modulus), (2) the wear rate using a multi-directional pin-on-plate machine, and (3) the surface topography of pins and plates before and after wear rate testing.

Results

There were no significant differences in tensile strength, wear rates or surface topography of either ultra-high-molecular-weight polyethylene pins or cobalt chromium molybdenum metal plates between specimens soaked in TXA and specimens soaked in saline.

Conclusion

Biomechanical testing shows that there are no biomechanical adverse affects on the properties of common artificial joint materials from using topical TXA.

Level of evidence

V     

Increase in minimum inhibitory concentration to quinolones and ceftriaxone in salmonellae causing enteric fever

Multidrug resistance among Salmonella typhi is well known. Reports of treatment failure in enteric fever with Ciprofloxacin made us undertake this study to determine the antibiotic susceptibility pattern of S. typhi and S. paratyphi A isolated from typhoid bacteremia cases, by disc diffusion and MIC by broth dilution method. A total of 50 strains were tested, 48 of Salmonella typhi and 2 of S. paratyphi A. The disc diffusion method was done using ampicillin, chloramphenicol, cotrimoxazole, tetracycline, ciprofloxacin, ofloxacin, cefuroxime and ceftriaxone as antibiotics. The MIC was performed using ciproloxacin, ofloxacin and ceftriaxone based on standard procedure. ACCOT resistance as determined by disc diffusion method was seen in 68% of isolates. All the strains remained susceptible to flouroquinolones cephalosporins and aminoglycosides. The MIC of ciprofloxacin, ofloxacin and ceftriaxone were in the recommended range of susceptibility as given by NCCLS, 14 (28%) strains had MIC of ciprofloxacin greater than 0.5 ug/ml with 4 strains having an MIC of 1.56 ug/ml; 25 (50%) strains had MIC of ofloxacin greater than 0.5 ug/ml and 20 (40%) strains had MIC of ceftriaxone greater than 0.5 ug/ml. The high levels of MIC of ciprofloxacin may account for treatment failure cases. The rising levels of MIC of ofloxacin and ceftriaxone in S. typhi and S. paratyphi is also of concern. We document here the emergence of high levels of MIC not only to ciprofloxacin, but also ofloxacin and ceftriaxone in S. typhi and S. paratyphi A. We recommend that MIC levels of ofloxacin and ceftriaxone should be monitored along with ciprofloxacin in treatment failure cases of enteric fever.     

Association of methylenetetrahydrofolate reductase (<Emphasis Type="Italic">MTHFR</Emphasis>) gene C677T polymorphism with autism: evidence of genetic susceptibility

Autism (MIM 209850) is a heterogeneous neurodevelopmental disease that manifests within the first 3 years of life. Numerous articles reported that dysfunctional folate-methionine pathway enzymes may play an important role in the pathophysiology of autism. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme of this pathway and MTHFR C677T polymorphism reported as risk factor for autism in several case control studies. However, controversial reports were also published. Hence the present meta-analysis was designed to investigate the relationship of the MTHFR C677T polymorphism with the risk of autism. Electronic databases were searched for case control studies with following search terms - ‘MTHFR’, ‘C677T’, in combination with ‘Autism’. Pooled OR with its corresponding 95 % CI was calculated and used as association measure to investigate the association between MTHFR C677T polymorphism and risk of autism. Total of thirteen studies were found suitable for the inclusion in the present meta-analysis, which comprises 1978 cases and 7257 controls. Meta-analysis using all four genetic models showed significant association between C677T polymorphism and autism (OR_Tvs.C = 1.48; 95 % CI: 1.18–1.86; P = 0.0007; OR_{TT + CT vs. CC} = 1.70, 95 % CI = 0.96–2.9, p = 0.05; OR_{TT vs. CC} = 1.84, 95 % CI = 1.12–3.02, p = 0.02; OR_{CT vs.CC} = 1.60, 95 % CI = 1.2–2.1, p = 0.003; OR_{TT vs.CT+CC} = 1.5, 95 % CI = 1.02–2.2, p = 0.03). In total 13 studies, 9 studies were from Caucasian population and 4 studies were from Asian population. The association between C677T polymorphism and autism was significant in Caucasian (OR_Tvs.C = 1.43; 95 % CI = 1.1–1.87; p = 0.009) and Asian population (OR_Tvs.C = 1.68; 95 % CI = 1.02–2.77; p = 0.04) using allele contrast model. In conclusion, present meta-analysis strongly suggested a significant association of the MTHFR C677T polymorphism with autism.     

Detection and monitoring of methotrexate-associated lung injury using serum markers KL-6 and SP-D in rheumatoid arthritis

The applicability of monitoring concentrations of serum KL-6 and serum surfactant protein-D (SP-D) in the detection of methotrexate-associated lung injury (MTX pneumonitis) in patients with rheumatoid arthritis (RA) was investigated. The concentrations of these markers, sequentially measured in two patients with RA complicated with MTX pneumonitis, were increased in accordance with the severity of MTX pneumonitis. Conversely, the concentrations of these markers were decreased with the improvement of MTX pneumonitis, suggesting that the monitoring of these markers could be applicable not only for detecting the onset of MTX pneumonitis, but also for detecting the therapeutic response of MTX pneumonitis.     

Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration

Parkin and the glial cell line–derived neurotrophic factor (GDNF) receptor RET have both been independently linked to the dopaminergic neuron degeneration that underlies Parkinson’s disease (PD). In the present study, we demonstrate that there is genetic crosstalk between parkin and the receptor tyrosine kinase RET in two different mouse models of PD. Mice lacking both parkin and RET exhibited accelerated dopaminergic cell and axonal loss compared with parkin-deficient animals, which showed none, and RET-deficient mice, in which we found moderate degeneration. Transgenic expression of parkin protected the dopaminergic systems of aged RET-deficient mice. Downregulation of either parkin or RET in neuronal cells impaired mitochondrial function and morphology. Parkin expression restored mitochondrial function in GDNF/RET-deficient cells, while GDNF stimulation rescued mitochondrial defects in parkin-deficient cells. In both cases, improved mitochondrial function was the result of activation of the prosurvival NF-κB pathway, which was mediated by RET through the phosphoinositide-3-kinase (PI3K) pathway. Taken together, these observations indicate that parkin and the RET signaling cascade converge to control mitochondrial integrity and thereby properly maintain substantia nigra pars compacta dopaminergic neurons and their innervation in the striatum. The demonstration of crosstalk between parkin and RET highlights the interplay in the protein network that is altered in PD and suggests potential therapeutic targets and strategies to treat PD.     

Giant Cell Lesions Associated with Primary Hyperparathyroidism

Aims and Objective

To evaluate the prevalence, clinical features, diagnostic laboratory values and treatment outcome of giant cell lesions (brown tumors) associated with primary hyperparathyroidism (PHPT) in oral and maxillofacial region.

Study Design

A 5 year retrospective data was analyzed wherein all histopathologically proven cases of giant cell lesions involving oral and maxillofacial region were evaluated. Out of these cases, those associated with PHPT were tabulated. Correlation was established with other concomitant clinical features and also with the laboratory values of altered serum calcium, phosphate, alkaline phosphate and parathormone. Follow up of these cases after the correction of PHPT was also noted.

Result

Out of 85 cases of histopathologically proven giant cell lesions, five cases were associated with PHPT. There was involvement of maxilla and mandible in one case each. Only frontal bone was involved in two cases. Fifth case had multiple lytic lesions in maxilla and frontal bone. All patients consistently showed very high values of alkaline phosphate and parathormone. Hypercalcemia and hypophosphatemia was noted in four cases. All cases showed regression of the lytic lesion after parathyroidectomy obviating the need for surgical excision of the jaw lesions.

Conclusion

Giant cell lesions (brown tumors) associated with PHPT in oral and maxillofacial region are rare clinical entities. The prevalence of PHPT associated giant cell lesions is 5.9 %. They are clinically, radiologically and histopathologically similar to any other peripheral or central giant cell tumor. Relevant history may alert the clinician and altered biochemical values may help in correlating the oral and maxillofacial findings with the underlying systemic disease. At times, the brown tumor maybe the only presenting sign leading to the diagnosis of PHPT.     

Renal transplantation in HLA sensitized patients: Traversing the immunological barrier

Successful renal transplantation across HLA barrier in sensitized individuals has been on the rise during the past decade, primarily due to improved desensitization regimes. The aim of this study was to share outcome of desensitization in renal transplant recipients with donor‐specific anti‐HLA antibodies (DSA). This was a retrospective analysis of all HLA immunized individuals who were prospective renal transplant recipients. All such patients underwent preconditioning as per the institutional desensitization protocol. Complement‐dependent cytoxicity‐based crossmatch (CDC‐XM), luminex‐based crossmatch (LM‐XM) and flowcytometry‐based crossmatch (FC‐XM) were done in all cases. If any of these tests turned out positive, single antigen bead assay (SAB) was performed. Desensitization for DSA was performed in 55 patients and all patients were followed‐up for 1 year to assess graft function and patient outcome. CDC‐XM being a less sensitive assay, could not detect incompatibility in 29 (52.73%) cases. After desensitization, even though SAB and LM‐XM results revealed an MFI within acceptable range, FC‐XM being an extremely sensitive assay, continued to give a positive result in eight (14.55%) cases. The mean ± SD number of pretransplant TPE were 3.44 ± 0.98 (2‐11). Out of 55, there were 10 patients who were lost to follow up. Patient and graft survival of 45 patients at 1 year was found to be 100%. Preconditioning for renal transplants in the form of immunosuppression with TPE is an extremely useful auxiliary for transplantation in HLA sensitized renal transplant recipients.     

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.Emphysema is a major subset of chronic obstructive pulmonary disease (COPD) and is defined anatomically as the destruction of the distal lung parenchyma and enlargement of the air spaces. Pulmonary emphysema is one of the main causes of morbidity and death worldwide. The most studied factor in developing COPD has long been recognized to be cigarette smoking. However, only 10% to 20% of heavy smokers develop clinically significant COPD.^1,2 Importantly, recent studies indicate that complementary pathogenic mechanisms, such as proteolytic/antiproteolytic imbalance, oxidative stress, apoptosis, or altered innate immunity, are involved in the development and progression of alveolar destruction.^3–6Cathepsins have been implicated in mediating alveolar destruction via their proteolytic activity. Cathepsins are intracellular hydrolases and include serine proteases (cathepsins A and G), aspartic proteases (cathepsins D and E), and cysteine cathepsins (cathepsins B, C, F, H, K, L, O, S, V, X, and W). Cathepsin E (Cat E), a nonlysosomal intracellular aspartic protease, is homologous to aspartic protease cathepsin D, a major proteolytic activity in the lysosomal component.⁷ Recent studies have reported that Cat E plays an important role in antigen processing via the major histocompatibility complex class II pathway, host defense against cancer cells and invading microorganisms, gastric differentiation, and development of signet-ring cell carcinoma.^8–12 However, Cat E has not been linked to lung disease.Human lung sections from persons with COPD indicated increased expression of Cat E protein in the lung epithelial cells. To investigate if increased expression of lung epithelial Cat E could lead to emphysema, we generated lung-targeted constitutive and inducible Cat E transgenic (Tg) mice. Our data indicated that inducible Cat E Tg mice developed emphysema-like lung changes as early as 1 week. We noted robust caspase 3 activation, and, when mice were administered a caspase inhibitor, emphysema was prevented. To our surprise, we did not find changes in caspases usually associated with caspase 3 activation, such as caspases 8 and 9, in Cat E Tg mice. Instead, we found significant induction of a mitochondrial fission protein, dynamin-related protein 1 (Drp1). When we inhibited Drp1 in Cat E Tg mice with Mdivi-1, a small molecule Drp1 inhibitor, we completely abolished the development of emphysema. Collectively, our data indicate that increased Cat E is a clinically relevant finding in human COPD and invoke a novel role for Cat E in mitochondrial fission-induced emphysema.