Bone infection: a clinical priority for clinicians, scientists and educators.

Bone infection has received increasing attention in recent years as one of the main outstanding clinical problems in orthopaedic-trauma surgery that has not been successfully addressed. In fact, infection may develop across a spectrum of patient types regardless of the level of perioperative management, including antibiotic prophylaxis. Some of the main unknown factors that may be involved, and the main targets for future intervention, include more accurate and less invasive diagnostic options, more thorough and accurate debridement protocols, and more potent and targeted antimicrobials. The underlying biology dominates the clinical management of bone infections, with features such as biofilm formation, osteolysis and vascularisation being particularly influential. Based on the persistence of this problem, an improved understanding of the basic biology is deemed necessary to enable innovation in the field. Furthermore, from the clinical side, better evidence, documentation and outreach will be required to translate these innovations to the patient. This review presents the findings and progress of the AO Trauma Clinical Priority Program on the topic of bone infection.

Oral steroid decreases the progression of joint destruction of large joints in the lower extremities in rheumatoid arthritis.

To identify the risk factors for destruction of large joints in the lower extremities in patients with rheumatoid arthritis (RA) during a 4-year follow-up period in a prospective study.We enrolled consecutive patients who participated in both 2012 and 2016. Clinical data, disease activity, and types of medication were collected in 2012. Standard anteroposterior radiographs of weight-bearing joints (hips, knees, and ankles) were taken in 2012 and 2016. Radiographic progression was defined as progression in the Larsen grade or the need for joint arthroplasty or arthrodesis. The association between baseline characteristics and the incidence of radiographic progression was statistically assessed.A total of 213 patient were enrolled, and, after exclusion, 186 patients were analyzed. Sixty 9 patients (37.1%) showed radiographic progression in 1 of the large joints in the lower extremities. Multivariate regression analysis showed that radiographic progression was associated with older age, higher disease activity, and the presence of radiographic destruction at the baseline. The lower dosage of oral prednisolone was a significant risk factor compared with higher dosage when used.Patients with the risk factors should be followed closely to limit the progression of large joint destruction in the lower extremities.

Distinct biomarkers for different bones in osteoporosis with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. METHODS: We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. RESULTS: The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32-85), 21.3 (12.3-30.0), and 3.2 (0.1-5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. CONCLUSIONS: Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

Effect of tibial component alignment on knee kinematics and ligament tension in medial unicompartmental knee arthroplasty.

OBJECTIVES: Unicompartmental knee arthroplasty (UKA) is one surgical option for treating symptomatic medial osteoarthritis. Clinical studies have shown the functional benefits of UKA; however, the optimal alignment of the tibial component is still debated. The purpose of this study was to evaluate the effects of tibial coronal and sagittal plane alignment in UKA on knee kinematics and cruciate ligament tension, using a musculoskeletal computer simulation. METHODS: The tibial component was first aligned perpendicular to the mechanical axis of the tibia, with a 7° posterior slope (basic model). Subsequently, coronal and sagittal plane alignments were changed in a simulation programme. Kinematics and cruciate ligament tensions were simulated during weight-bearing deep knee bend and gait motions. Translation was defined as the distance between the most medial and the most lateral femoral positions throughout the cycle. RESULTS: The femur was positioned more medially relative to the tibia, with increasing varus alignment of the tibial component. Medial/lateral (ML) translation was smallest in the 2° varus model. A greater posterior slope posteriorized the medial condyle and increased anterior cruciate ligament (ACL) tension. ML translation was increased in the > 7° posterior slope model and the 0° model. CONCLUSION: The current study suggests that the preferred tibial component alignment is between neutral and 2° varus in the coronal plane, and between 3° and 7° posterior slope in the sagittal plane. Varus > 4° or valgus alignment and excessive posterior slope caused excessive ML translation, which could be related to feelings of instability and could potentially have negative effects on clinical outcomes and implant durability.Cite this article: K. Sekiguchi, S. Nakamura, S. Kuriyama, K. Nishitani, H. Ito, Y. Tanaka, M. Watanabe, S. Matsuda. Bone Joint Res 2019;8:126-135. DOI: 10.1302/2046-3758.83.BJR-2018-0208.R2.

Scintillator-based transverse proton beam profiler for laser-plasma ion sources.

A high repetition rate scintillator-based transverse beam profile diagnostic for laser-plasma accelerated proton beams has been designed and commissioned. The proton beam profiler uses differential filtering to provide coarse energy resolution and a flexible design to allow optimisation for expected beam energy range and trade-off between spatial and energy resolution depending on the application. A plastic scintillator detector, imaged with a standard 12-bit scientific camera, allows data to be taken at a high repetition rate. An algorithm encompassing the scintillator non-linearity is described to estimate the proton spectrum at different spatial locations.

Coexisting lateral tibiofemoral osteoarthritis is associated with worse knee pain in patients with mild medial osteoarthritis.

OBJECTIVE: To examine the clinical impact of coexisting lateral osteoarthritis (OA) in knees with mild medial OA. DESIGN: In patients with Kellgren/Lawrence (K/L) grade 2 OA in the medial compartment (n = 100; age: 56-89 years; 80.0% female), anteroposterior knee radiography was used to assess the presence of lateral OA, using grading systems from the Osteoarthritis Research Society International (OARSI) atlas and the K/L classification. The Japanese Knee Osteoarthritis Measure (JKOM), knee range of motion (ROM), and performance-based functional measures (10 m walk, timed up and go and five repetition chair stand maneuvers) were evaluated. The outcomes were compared between patients with and without lateral OA using an analysis of covariance (ANCOVA) or nonparametric rank ANCOVA. Furthermore, ordinal logistic regression analysis was performed, with responses on individual JKOM pain questionnaires as the outcomes and lateral OA as the predictor. RESULTS: Knees with coexisting lateral OA had a significantly worse score of JKOM pain question compared with those without, after adjusting for covariates. The presence of lateral OA was significantly associated with knee pain while ascending/descending stairs and standing. These results were consistent between different definitions of the K/L and OARSI grading systems. The knee ROM and performance-based functional measures were not significantly different between patients with and without lateral OA. CONCLUSION: Knees with concomitant lateral and mild medial OA may be more symptomatic compared to those without lateral OA. These findings might help to define a clinically distinct subgroup based on a simple radiographic finding in mild knee OA.

Physiological exercise loading suppresses post-traumatic osteoarthritis progression via an increase in bone morphogenetic proteins expression in an experimental rat knee model.

OBJECTIVE: To evaluate the dose-response relationship of exercise loading in the cartilage-subchondral bone (SB) unit in surgically-induced post-traumatic osteoarthritis (PTOA) of the knee. DESIGN: Destabilized medial meniscus (DMM) surgery was performed on the right knee of 12-week-old male Wistar rats, and sham surgery was performed on the contralateral knee. Four weeks after the surgery, the animals were subjected to moderate (12 m/min) or intense (21 m/min) treadmill exercises for 30 min/day, 5 days/week for 4 weeks. PTOA development in articular cartilage and SB was examined using histological and immunohistochemical analyses, micro-computed tomography (micro-CT) analysis, and biomechanical testing at 8 weeks after surgery. Gremlin-1 was injected to determine the role of bone morphogenetic protein (BMP) signaling on PTOA development following moderate exercise. RESULTS: Moderate exercise increased BMP-2, BMP-4, BMP-6, BMP receptor 2, pSmad-5, and inhibitor of DNA binding protein-1 expression in the superficial zone chondrocytes and suppressed cartilage degeneration, osteophyte growth, SB damage, and osteoclast-mediated SB resorption. However, intense exercise had little effect on BMP expression and even caused progression of these osteoarthritis (OA) changes. Gremlin-1 injection following moderate exercise caused progression of the PTOA development down to the level of the non-exercise DMM-operated knee. CONCLUSIONS: Exercise regulated cartilage-SB PTOA development in DMM-operated knees in a dose-dependent manner. Our findings shed light on the important role of BMP expression in superficial zone chondrocytes in attenuation of PTOA development following physiological exercise loading. Further studies to support a mechanism by which BMPs would be beneficial in preventing PTOA progression are warranted.

Indels within promoter and intron 1 of bovine prion protein gene modulate the gene expression levels in the medulla oblongata of two Japanese cattle breeds.

Genetic differences which exist in the prion protein gene (PRNP) have been reported to influence susceptibility of humans, sheep and goats to prion diseases. In cattle, however, none of the known coding polymorphisms has a direct effect on bovine spongiform encephalopathy (BSE). It has been reported that 23-bp insertion/deletion (indel) polymorphisms within the promoter region have a tentative association to BSE susceptibility in German cattle, and a lower number of 24-bp repeat units in the open reading frame (ORF) was reported to reduce BSE susceptibility in transgenic mice. In this study, because of the hypothesis that bovine PRNP promoter polymorphisms cause changes in PRNP expression, we genotyped PRNP polymorphisms in the promoter and intron 1 using 218 genomic DNA samples from two Japanese cattle breeds. We also analysed the expression levels of prion in 40 animals by quantification of real-time PCR using mRNAs extracted from the medulla oblongata to study the relationship between PRNP genotypes and PRNP expression. We found a significant correlation between promoter indel polymorphisms and PRNP-mRNA expression (P(0.0413)) and therefore hypothesize that differences in polymorphisms could be one of the causes of differences in PRNP expression levels. We also report a novel difference in PRNP expression (P < 0.0001) between Japanese Black and Japanese Brown cattle breeds. There was no significant difference based on age and sex of the animals.

Celecoxib inhibits production of MMP and NO via down-regulation of NF-kappaB and JNK in a PGE2 independent manner in human articular chondrocytes.

The purpose of this study was to examine the effects of celecoxib on matrix metalloproteinases (MMP-1 and MMP-3), nitric oxide (NO), and the phosphorylation of nuclear factor-kappaB (NF-kappaB) and three mitogen-activated protein kinases (MAPKs), (p38, JNK and ERK) in human articular chondrocytes from normal, osteoarthritis, and rheumatoid arthritis cartilages. Celecoxib at 100 nM reduced the IL-1beta-induced productions of MMP-1, MMP-3, iNOS, and NO, whereas indomethacin at 100 nM showed no effect. The additional stimulation of prostaglandin E2 (PGE2) failed to restore those productions, while the production of PGE2 were reduced by 1 and 10 microM but not 100 nM of celecoxib. The inhibitors of NF-kappaB, JNK and p38, but not ERK, decreased IL-1beta-enhanced MMP-1, MMP-3 and NO production, respectively, and 100 nM celecoxib down-regulated the phosphorylation of NF-kappaB and JNK but has no effect on either p38 or ERK. Celecoxib has inhibitory effects on MMP-1, MMP-3 and NO productions, suggesting the protective roles directly on articular chondrocytes. Despite the COX-2 selectivity, celecoxib affects those productions via not PGE2 but NF-kappaB and JNK MAPK.

A comprehensive expression analysis of all members of a gene family encoding cell-wall enzymes allowed us to predict cis-regulatory regions involved in cell-wall construction in specific organs of Arabidopsis.

The Arabidopsis thaliana genome sequencing project has revealed that multigene families, such as those generated by genome duplications, are more abundant among plant genomes than among animal genomes. To gain insight into the evolutionary implications of the multigene families in higher plants, we examined the XTH gene family, a group of genes encoding xyloglucan endotransglucosylase/hydrolase, which are responsible for cell-wall construction in plants. Expression analysis of all members (33 genes) of this family, using quantitative real-time RT-PCR, revealed that most members exhibit distinct expression profiles in terms of tissue specificity and responses to hormonal signals, with some members exhibiting similar expression patterns. By comparing the flanking sequences of individual genes, we identified four sets of large-segment duplications and two sets of solitary gene duplications. In each set of gene duplicates, long nucleotide sequences, ranging from one to two hundred base pairs, are conserved. Furthermore, gene duplicates exhibit similar organ-specific expression profiles. These facts allowed us to predict putative cis-regulatory regions, particularly those responsible for cell-wall construction, and hence for morphogenesis, that are specific for certain organs or tissues in plants.

Endoxyloglucan transferase is localized both in the cell plate and in the secretory pathway destined for the apoplast in tobacco cells.

Intracellular trafficking of enzymes responsible for constructing and modifying the cell wall architecture in plants is mostly unknown. To examine their translocation pathways, we employed an endoxyloglucan transferase (EXGT), a key enzyme responsible for forming and rearranging the cellulose/xyloglucan network of the cell wall. We traced its intracellular localization in suspension-cultured cells of tobacco bright yellow-2 by means of green fluorescent protein-fusion gene procedures as well as by indirect immunofluorescence. During interphase the protein was extensively secreted into the apoplast via the endoplasmic reticulum-Golgi apparatus network, whereas during cytokinesis, the protein was exclusively located in the phragmoplast and eventually transported to the cell plate. These results clearly indicate commitment of EXGT protein to the construction of both the cell plate and the cell wall. This study also visualized the process of phragmoplast development at a level of vesicle translocation in the living cell.

Growth regulation mechanisms in higher plants under microgravity conditions - changes in cell wall metabolism.

During Space Shuttle STS-95 mission, we cultivated seedlings of rice (Oryza sativa L. cv. Koshihikari and cv. Tan-ginbozu) and Arabidopsis (Arabidopsis thaliana L. cv. Columbia and cv. etr1-1) for 68.5, 91.5, and 136 hr on board, and then analyzed changes in the nature of their cell walls, growth, and morphogenesis under microgravity conditions. In space, elongation growth of both rice coleoptiles and Arabidopsis hypocotyls was stimulated. Also, the increase in the cell wall extensibility, especially that in the irreversible extensibility, was observed for such materials. The analyses of the amounts, the structure, and the physicochemical properties of the cell wall constituents indicated that the decreases in levels and molecular masses of cell wall polysaccharides were induced under microgravity conditions, which appeared to contribute to the increase in the wall extensibility. The activity of certain wall enzymes responsible for the metabolic turnover of the wall polysaccharides was increased in space. By the space flight, we also confirmed the occurrence of automorphogenesis of both seedlings under microgravity conditions; rice coleoptiles showed an adaxial bending, whereas Arabidopsis hypocotyls elongated in random directions. Furthermore, it was shown that spontaneous curvatures of rice coleoptiles in space were brought about uneven modifications of cell wall properties between the convex and the concave sides.

Expression of endoxyloglucan transferase genes in acaulis mutants of Arabidopsis.

A mutant of Arabidopsis with reduced internodal cell length, acaulis5 (acl5), has recently been shown to have reduced transcript levels of a gene for endoxyloglucan transferase, EXGT-A1 (Y. Hanzawa, T. Takahashi, Y. Komeda [1997] Plant J 12: 863-874). In the present study, we cloned genomic fragments of five members of the EXGT gene family, EXGT-A1, EXGT-A3, EXGT-A4, XTR2, and XTR3, and examined their expression in the wild type and in a series of acl mutants. In wild-type plants, the EXGT-A3 gene showed higher expression in lower internodes (internodes between nodes bearing axillary shoots) than in upper and young internodes, in which EXGT-A1 was highly expressed. EXGT-A4 was preferentially expressed in roots and XTR3 in siliques. The XTR2 gene was constitutively expressed. In acl1, acl3, and acl4 mutants, which have a severe defect in leaf expansion as well as in internode elongation, the EXGT-A1 gene showed reduced levels of expression before bolting of plants. In contrast, XTR3 was increased in these mutant seedlings. Reduction of EXGT-A1 expression was also detected after bolting of all acl mutants except acl2, whose growth defect is restricted to lower internodes. These results suggest the involvement of each EXGT in different aspects of organ development.

Coronary artery stenosis evaluated by combined carotid and coronary angiography in patients undergoing carotid endarterectomy.

The relationship between coronary artery stenosis and the postoperative outcome was investigated in patients who underwent carotid endarterectomy (CEA). The benefit of combined carotid and coronary angiography was also evaluated. Combined carotid and coronary angiography was performed in 72 patients treated with CEA (mean age 64.0 years). Fourteen patients with a history of ischemic heart disease (IHD) had a higher Gensini score for coronary artery stenosis than patients with no history of IHD (37.9 +/- 36.8 vs. 7.9 +/- 12.5, p < 0.0001). However, 39.7% of patients with no history of IHD had a Gensini score exceeding 6. Patients with diabetes mellitus had a significantly higher Gensini score than nondiabetic patients. Eleven patients (15.3%) underwent percutaneous transluminal coronary angioplasty and three (4.2%) underwent coronary artery bypass grafting during the CEA perioperative period. None of the patients who underwent combined angiography showed signs of IHD during or after CEA (mean follow-up period 30 months). Combined angiography was not performed in 189 previous patients. Of these, two died of acute myocardial infarction in the postoperative period, 11 manifested nonfatal IHD, and 18 succumbed to IHD (mean follow-up period 8 years). Although patients with a history of IHD manifested more severe coronary artery stenosis than patients without such a history, the possibility of coronary artery stenosis must be considered in patients with no history of IHD, especially those with diabetes mellitus. Combined carotid and coronary angiography and careful management of coronary artery stenosis can be expected to decrease the mortality and morbidity in patients treated with CEA.

Endoxyloglucan transferase cDNA isolated from pea roots and its fluctuating expression in hydrotropically responding roots.

We isolated an endoxyloglucan transferase cDNA (Ps-EXGT1) from the roots of an agravitropic pea mutant, ageotropum. The putative product of the cDNA was 34.1 kDa and consisted of 293 amino acid residues. The predicted amino acid sequence was 75.1-88.6% identical to those of EXGT genes in other plants. The Ps-EXGT1 cDNA was strongly expressed in elongating roots and stems but not in either mature stems or young leaves. In roots, the transcription level of Ps-EXGT1 was most abundant in the rapidly growing region. When root elongation was inhibited by a water stress, Ps-EXGT1 transcription was repressed. The roots curved hydrotropically due to differential growth of the cortical cells in the elongation zone when the root cap was exposed to a gradient of water potential; the length of the cells on the side of lower water potential was much longer than those on the side of higher water potential. The expression pattern of Ps-EXGT1 in the hydrotropically responding roots fluctuated between the side of the higher water potential and that of the lower water potential in the elongation zone. In other words, the accumulation of Ps-EXGT1 mRNA was much greater on the side of lower water potential than on that of higher potential just prior to the commencement of positive hydrotropism. When the roots started to curve slightly away from the side of higher water potential causing a rhythmic oscillatory movement [Takano et al. (1995) Planta 197: 410], there was more transcription of Ps-EXGT1 on the side of higher water potential. These results suggest that the transcription of Ps-EXGT1 is involved in cell growth and that this regulation of transcription plays a role in the differential growth of hydrotropically responding roots.

Agravitropic mutant for the study of hydrotropism in seedling roots.

Roots have been shown to respond to a moisture gradient by positive hydrotropism. Agravitropic mutant plants are useful for the study of the hydrotropism in roots because on Earth hydrotropism is obviously altered by the gravity response in the roots of normally gravitropic plants. The roots are able to sense water potential gradient as small as 0.5 MPa mm(-1). The root cap includes the sensing apparatus that causes a differential growth at the elongation region of roots. A gradient in apoplastic calcium and calcium influx through plasmamembrane in the root cap is somehow involved in the signal transduction mechanism in hydrotropism, which may cause a differential change in cell wall extensibility at the elongation region. We have isolated an endoxy loglucan transferase (EXGT) gene that is strongly expressed in pea roots and appears to be involved in the differential growth in hydrotropically responding roots. Thus, it is now possible to study hydrotropism in roots by comparing with or separate from gravitropism. These results also imply that microgravity conditions in space are useful for the study of hydrotropism and its interaction with gravitropism.

Hyperperfusion syndrome following carotid endarterectomy: evaluation using diffusion-weighted magnetic resonance imaging--case report.

A 65-year-old female developed hyperperfusion syndrome following carotid endarterectomy for severe stenosis of the left internal carotid artery. Transcranial Doppler monitoring showed a sharp increase in flow velocity in the middle cerebral artery (MCA). Diffusion-weighted magnetic resonance (MR) imaging demonstrated diffuse hyperintensity in the region of the left MCA, which diminished markedly 9 days later. The abnormal hyperintensity decreased as the patient's symptoms improved, suggesting that diffusion-weighted MR imaging can be used for evaluating the course of hyperperfusion syndrome.

[Effect of epidural pressure gradient on buprenorphine flux through the dural hole after combined spinal-epidural anesthesia--comparison between bolus injection and continuous infusion].

Combined spinal-epidural anesthesia is a useful technique. However, there has been no attempt to investigate the risk of epidural opioid, especially buprenorphine, flux through the dural hole. The purpose of this study was to compare the effect of epidural buprenorphine administered across the dura into subarachnoid space, between two different methods of administration; bolus injection (Group I) and continuous infusion (Group II). Sixty patients for transvaginal hysterectomy were divided into two groups. Group I received buprenorphine 0.1-0.2 mg with 0.25% bupivacaine, and Group II 0.4 mg with 0.25% bupivacaine 40 ml continuously (infusion rate was 1.7 ml.h-1). Pain relief was similar in both groups, but the total buprenorphine requirement was lower in Group I than in Group II. The incidence of nausea and vomiting was significantly higher in Group I than that in Group II, 73% and 16%, respectively. It indicates that the increase of nausea and vomiting is predominantly determined by a high rate of flux into subarachnoid space and only partly determined by blood concentrations. In contrast to continuous infusion, the drug movement through the dural hole may increase by bolus injection due to its higher pressure. We recommend careful injection of epidural buprenorphine such as by continuous infusion with low pressure after combined spinal-epidural anesthesia.