The socio-economic challenges of managing pathogen evolution in agriculture.

Genetic resistance forms the foundation of infectious disease management in crops. However, rapid pathogen evolution is causing the breakdown of resistance and threatening disease control. Recent research efforts have identified strategies for resistance gene deployment that aim to disrupt pathogen adaptation and prevent breakdown. To date, there has been limited practical uptake of such strategies. In this paper, we focus on the socio-economic challenges associated with translating applied evolutionary research into scientifically informed management strategies to control pathogen adaptation. We develop a conceptual framework for the economic valuation of resistance and demonstrate that in addition to various direct benefits, resistance delivers considerable indirect and non-market value to farmers and society. Incentives for stakeholders to engage in stewardship strategies are complicated by the uncertain timeframes associated with evolutionary processes, difficulties in assigning ownership rights to genetic resources and lack of governance. These interacting biological, socio-economic and institutional complexities suggest that resistance breakdown should be viewed as a wicked problem, with often conflicting imperatives among stakeholders and no simple cause or solution. Promoting the uptake of scientific research outcomes that address complex issues in sustainable crop disease management will require a mix of education, incentives, legislation and social change. This article is part of the theme issue 'Infectious disease ecology and evolution in a changing world'.

A systematic review of meta-analyses in orthopaedic surgery between 2000 and 2016.

AIMS: The aims of this systematic review were to describe the quantity and methodological quality of meta-analyses in orthopaedic surgery published during the last 17 years. MATERIALS AND METHODS: MEDLINE, EMBASE, and PubMed, between 1 January 2000 and 31 December 2016, were searched for meta-analyses in orthopaedic surgery dealing with at least one surgical intervention. Meta-analyses were included if the interventions involved a human muscle, ligament, bone or joint. RESULTS: A total of 392 meta-analyses met eligibility criteria, for which the mean AMSTAR quality score was 7.1/11. There was a positive correlation between the year of publication and the quality of the meta-analysis (r = 0.238, p < 0.001). Between 2000 and 2011, the mean AMSTAR score corresponded to that of a medium quality review. However, between 2012 and 2016, the mean scores have been consistently equivalent to those of a high-quality review. The number of meta-analyses published increased 10-fold between 2005 and 2014. CONCLUSION: The quantity and quality of meta-analyses in orthopaedic surgery which have been published has increased, reaching a plateau in 2012. Methodological flaws remain to be addressed in future meta-analyses in order to continue increasing the quality of the orthopaedic literature. Cite this article: Bone Joint J 2018;100-B:1270-4.

Deficits in preference-based health-related quality of life after complications associated with tibial fracture.

Aims: The aims of this study were to quantify health state utility values (HSUVs) after a tibial fracture, investigate the effect of complications, to determine the trajectory in HSUVs that result in these differences and to quantify the quality-adjusted life years (QALYs) experienced by patients. Patients and Methods: This is an analysis of 2138 tibial fractures enrolled in the Fluid Lavage of Open Wounds (FLOW) and Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures (SPRINT) trials. Patients returned for follow-up at two and six weeks and three, six, nine and 12 months. Short-Form Six-Dimension (SF-6D) values were calculated and used to calculate QALYs. Results: Compared with those who did not have a complication, those with a complication treated either nonoperatively or operatively had lower HSUVs at all times after two weeks. The HSUVs improved in all patients with the passage of time. However, they did not return to the remembered baseline preinjury values nor to US age-adjusted normal values by 12 months after the injury. Conclusion: While the acute fracture and complications may have resolved clinically, the detrimental effect on a patient's quality of life persists up to 12 months after the injury. Cite this article: Bone Joint J 2018;100-B:1227-33.

Factors associated with health-related quality of life, hip function, and health utility after operative management of femoral neck fractures.

Aims: The primary aim of this prognostic study was to identify baseline factors associated with physical health-related quality of life (HRQL) in patients after a femoral neck fracture. The secondary aims were to identify baseline factors associated with mental HRQL, hip function, and health utility. Patients and Methods: Patients who were enrolled in the Fixation using Alternative Implants for the Treatment of Hip Fractures (FAITH) trial completed the 12-item Short Form Health Survey (SF-12), Western Ontario and McMaster Universities Arthritis Index, and EuroQol 5-Dimension at regular intervals for 24 months. We conducted multilevel mixed models to identify factors potentially associated with HRQL. Results: The following were associated with lower physical HRQL: older age (-1.42 for every ten-year increase, 95% confidence interval (CI) -2.17 to -0.67, p < 0.001); female gender (-1.52, 95% CI -3.00 to -0.05, p = 0.04); higher body mass index (-0.69 for every five-point increase, 95% CI -1.36 to -0.02, p = 0.04); American Society of Anesthesiologists class III ( versus class I) (-3.19, 95% CI -5.73 to -0.66, p = 0.01); and sustaining a displaced fracture (-2.18, 95% CI -3.88 to -0.49, p = 0.01). Additional factors were associated with mental HRQL, hip function, and health utility. Conclusion: We identified several baseline factors associated with lower HRQL, hip function, and utility after a femoral neck fracture. These findings may be used by clinicians to inform treatment and outcomes. Cite this article: Bone Joint J 2018;100-B:361-9.

Wound irrigation does not affect health-related quality of life after open fractures: results of a randomized controlled trial.

AIMS: The Fluid Lavage in Open Fracture Wounds (FLOW) trial was a multicentre, blinded, randomized controlled trial that used a 2 × 3 factorial design to evaluate the effect of irrigation solution (soap versus normal saline) and irrigation pressure (very low versus low versus high) on health-related quality of life (HRQL) in patients with open fractures. In this study, we used this dataset to ascertain whether these factors affect whether HRQL returns to pre-injury levels at 12-months post-injury. PATIENTS AND METHODS: Participants completed the Short Form-12 (SF-12) and the EuroQol-5 Dimensions (EQ-5D) at baseline (pre-injury recall), at two and six weeks, and at three, six, nine and 12-months post-fracture. We calculated the Physical Component Score (PCS) and the Mental Component Score (MCS) of the SF-12 and the EQ-5D utility score, conducted an analysis using a multi-level generalized linear model, and compared differences between the baseline and 12-month scores. RESULTS: We found no clinically important differences between irrigating solutions or pressures for the SF-12 PCS, SF-12 MCS and EQ-5D. Irrespective of treatment, participants had not returned to their pre-injury function at 12-months for any of the three outcomes (p < 0.001). CONCLUSION: Neither the composition of the irrigation solution nor irrigation pressure applied had an effect on HRQL. Irrespective of treatment, patients had not returned to their pre-injury HRQL at 12 months post-fracture. Cite this article: Bone Joint J 2018;100-B:88-94.

Predictors of physical functioning after total hip arthroplasty: a systematic review.

OBJECTIVE: The objective of this systematic review of the literature was to identify the predictors of functional outcome after total hip arthroplasty (THA). METHOD: A systematic literature search in Web of Science, CINAHL, EMBASE and PubMed was conducted on 23 June 2015. The articles were selected based on their quality, relevance and measurement of the predictive factor. The level of evidence of all studies was determined using the GRADE rating scheme. RESULTS: The initial search resulted in 1092 citations. After application of the inclusion and exclusion criteria, 33 articles met our eligibility criteria and were graded. Included studies were classified as level of evidence low (11), moderate (17) or high (5). Of the included studies, 18 evaluated body mass index (BMI), 17 evaluated preoperative physical functions, 15 evaluated age, 15 evaluated gender and 13 evaluated comorbidity. There was strong evidence suggesting an association between BMI, age, comorbidity, preoperative physical functions and mental health with functional outcome after THA. There was weak evidence suggesting an association between quadriceps strength and education with functional outcome after THA. The evidence was inconsistent for associations with gender and socioeconomic status and functional outcome following THA. We found limited evidence suggesting that alcohol consumption, vitamin D insufficiency and allergies were predictors of functional outcome following THA. CONCLUSIONS: We have identified multiple predictors of functional outcome after THA, which will enable general practitioners and orthopaedic surgeons to better predict the improvement in physical functioning for their patients with THA. They can use this information to provide patient-specific advice regarding the referral for THA and the expected outcomes after THA. Further research with consistent measurement tools, outcomes and duration of follow-up across studies is needed to confirm the influence of these factors.

Collagen-like peptide sequences inhibit bacterial invasion of root dentine.

AIM: To investigate the effects of peptides derived from the sequence of collagen to inhibit penetration of human or bovine dentine by species of streptococci and enterococci. METHODOLOGY: Blocks of human or bovine root dentine were infected for 14 days with bacterial cultures, in the presence or absence of various collagen-like peptide sequences. Invasion of dentinal tubules was determined from microscopic images of histochemically stained dentine thin sections. Extent of invasion was expressed as tubule invasion index (TI), or tubule invasion factor (TIF) which, in addition to the density of invasion, took into account the depth of invasion. Data were analysed by two-way anova. RESULTS: Streptococcus gordonii, Streptococcus mutans and Enterococcus faecalis were associated with heavy invasion (TI >2.5, TIF >4) of human or bovine root dentinal tubules, with E. faecalis being the most penetrative. Incorporation of peptides Gly-Pro-Ala or Gly-Pro-Hyp into the in vitro model system significantly reduced (P < 0.05) dentine invasion by the three species of highly invasive organisms. Inhibition of bacterial invasion by the peptides was dose dependent, and the peptides did not inhibit bacterial growth in culture. CONCLUSION: Specific collagen-like peptide sequences inhibited the invasion of dentine in vitro by a range of oral bacteria. The peptides likely act as competitive inhibitors blocking bacterial collagen receptors and could potentially allow for target-specific control of dentine infections.

Management of young femoral neck fractures: is there a consensus?

BACKGROUND: Femoral neck fractures in young adults (ages <60) are high-energy injuries that are associated with major fracture healing complications such as avascular necrosis, nonunion, and significant shortening. Historically, evidence from small trials has suggested multiple cannulated screws were the optimal implant; however, newer studies and implant designs warrant reevaluation of screws as the gold standard among surgeons. In addition, controversies surrounding reduction technique and urgency of surgical fixation have been previously identified. We aimed to survey surgeon treatment preferences for these challenging fractures. METHODS: A 17-item survey was developed and tested for validity and reliability prior to administration. The questionnaire characterised surgeon demographics, treatment preferences for displaced and undisplaced fractures, and controversies for future clinical trials. The target population consisted of surgeons from the Canadian Orthopaedic Association, the Orthopaedic Trauma Association, and attendees at an international fracture course. RESULTS: 540 surgeons completed the survey, exceeding our sample size requirement. There was a similar proportion of respondents from academic and community hospitals. Most surgeons (61%) treat 1-5 young adult femoral neck fractures per year. For undisplaced fractures, 78% of respondents prefer to use multiple cannulated screws. For displaced fractures, equal preference for multiple screws (46%) and the sliding hip screw (SHS, 49%) was reported. The majority of surgeons perform an open reduction in less than 25% of cases, and the time to fixation was typically between 8 and 24h. CONCLUSIONS: Multiple cannulated screws remain the preferred treatment for most surgeons treating undisplaced fractures; however, there is an equal divide in preference between multiple screws and the SHS for displaced fractures. This increased preference for the SHS contradicts previous survey and small trial data recommending multiple screws for all fracture patterns. The lack of surgeon consensus and the high rates of fracture complications associated with fixation of young femoral neck fractures supports the need for definitive clinical trials to optimise patient important outcomes.

Complications following young femoral neck fractures.

BACKGROUND: Femoral neck fractures in patients 60 years of age or younger are challenging injuries to treat because of the high-energy trauma mechanisms and the displaced fracture patterns typically found in this patient population. Understanding the burden of disease is an important first step in addressing treatment controversies in this population. The purpose of the current study is to quantitatively pool the incidence of patient important complications following internal fixation of young femoral neck fractures. METHODS: A comprehensive search of the Medline, Embase, CINAHL, Cochrane Database of Systematic Reviews, and Central databases was completed under the direction of a biomedical librarian. Multiple outcomes of interest (complications) were collected and included: reoperation, femoral head avascular necrosis, fracture non-union, infection, implant failure, and malunion. RESULTS: 1558 fractures from 41 studies were included in the meta-analysis. An18.0% pooled reoperation incidence was observed for isolated femoral neck fractures. The total pooled incidence of avascular necrosis (AVN) was 14.3%, and the total incidence of nonunion was 9.3%. When stratified for fracture displacement displaced fractures were more likely to undergo reoperation and to result in AVN or non-union. The total incidence of malunion was 7.1%, implant failure was 9.7%, and surgical site infection was 5.1%. Complications associated with a femoral neck fracture treated in conjunction with an ipsilateral femoral shaft fracture were lower overall than the pooled estimates for isolated neck fractures. CONCLUSIONS: The results of our analysis demonstrate that the incidence of complications experienced by young femoral neck fracture patients is relatively high. Reoperation following internal fixation of isolated femoral neck fractures occurred in nearly 20% of cases, and AVN and nonunion were the most common complications that likely contributed to repeat surgeries. These results highlight the importance of further efforts to improve the clinical outcomes in this population.

Effects of bariatric surgery for knee complaints in (morbidly) obese adult patients: a systematic review.

Obesity is a major risk factor for the development of knee osteoarthritis, and over the past 30 years the prevalence of obesity has more than doubled. In an advanced-stage knee osteoarthritis is treated with total knee arthroplasty, and the demand for primary total knee arthroplasties is expected to grow exponentially. However, total knee arthroplasty in obese patients is associated with more complications, longer hospital stay and higher costs. We aimed to determine the effects of bariatric surgery on knee complaints in (morbidly) obese (body mass index >30 kg m(-2) ) adult patients. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, TRIP, BIOSIS-Previews and reference lists of retrieved publications were systematically searched from earliest available up to 20 April 2014 for any English, German, French and Dutch studies. There was no restriction on study design. We included studies on the effect of surgically induced weight reduction on knee complaints in (morbidly) obese adult patients, with a minimal follow-up of 3 months. Studies on the effects of lipectomy or liposuction and studies in which patients had already received a total knee arthroplasty were excluded. Thirteen studies were included in this systematic review with a total of 3,837 patients. Although different assessment tools were used, an overall significant improvement in knee pain was seen in 73% out of the used assessments. All studies measuring intensity of knee pain, knee physical function and knee stiffness showed a significant improvement after bariatric surgery. The quality of evidence was very low or too low for most of the included studies and moderate for one study. Bariatric surgery with subsequent marked weight loss is likely to improve knee pain, physical function and stiffness in (morbidly) obese adult patients. However, with the current available evidence, there is need for high-quality studies.

Results of the PeRception of femOroaCetabular impingEment by Surgeons Survey (PROCESS).

PURPOSE: Currently, there is a lack of high-level evidence addressing the variety of treatment options available for patients diagnosed with femoroacetabular impingement (FAI). The objective was to determine the current state of practice for FAI in Canada. METHODS: A questionnaire was developed and pretested to address the current state of knowledge among orthopaedic surgeons regarding FAI treatment using a focus group of experts, reviewing prior surveys, and reviewing online guidelines addressing surgical interventions for FAI. The membership of the Canadian Orthopaedic Association (COA) was surveyed through email and mail in both French and English. RESULTS: Two hundred and two surveys were obtained (20 % response rate), of which 74.3 % of respondents manage patients under age 40 with hip pain. Most surgeons (62 %) considered failure of non-operative management as the most important indication for the surgical management of FAI, usually by treating both bony and soft tissue damage (54.4 %). The majority of surgeons were unsure of the existence of evidence supporting the best clinical test for FAI, the use of a diagnostic intra-articular injection for diagnosis of FAI, and for non-operative management of FAI. One in four respondents supported a sham surgery (24.8 %) control arm for a trial evaluating the impact of surgical intervention on FAI. CONCLUSIONS: This survey elucidates areas of research for future studies relevant to FAI and highlights controversial areas of treatment. The results suggest that the current management of FAI by members of the COA is limited by a lack of awareness of high-level evidence.

The effects of different orthodontic appliances upon microbial communities.

OBJECTIVES: Orthodontic appliances can promote accumulation of dental plaque, with associated enamel decalcification or gingival inflammation. The aim of this study was to examine longer-term microbiological changes during orthodontic treatment with fixed appliances. MATERIALS AND METHODS: Twenty-four orthodontic patients aged 11-14 years undergoing fixed appliance therapy were recruited into the study. Each was randomized for cross-mouth assignment of molar bands and bonded molar tubes to contralateral quadrants of the mouth. All patients received self-ligating brackets, but again using randomization, one upper lateral incisor bracket (left or right) also received an elastomeric ligature. Plaque samples from the molars and upper lateral incisors were obtained at intervals during treatment and up to 1 year after appliance removal. Denaturing gradient gel electrophoresis and 16S rDNA microarray were used to compare plaque microbial fingerprints. RESULTS: Plaque populations changed within 3 months of commencing treatment at all sites. The greatest differences in plaque composition were seen with self-ligating brackets with an elastomeric ligature. Post-treatment plaque associated with both types of molar attachment contained increased levels of periodontal pathogens Porphyromonas gingivalis, Tannerella forsythia, and Eubacterium nodatum, while Campylobacter rectus, Parvimonas micra, and Actinomyces odontolyticus were also elevated with bonds. CONCLUSIONS: The results suggest that orthodontic treatment may cause sustained changes in plaque microbiotas and that molar bond-associated plaque may have raised disease potential.

Elevated incidence of fractures in solid-organ transplant recipients on glucocorticoid-sparing immunosuppressive regimens.

This study was conducted to assess the occurrence of fractures in solid-organ transplant recipients. Methods. Medical record review and surveys were performed. Patients received less than 6 months of glucocorticoids. Results. Of 351 transplant patients, 175 patients provided fracture information, with 48 (27.4%) having fractured since transplant (2-6 years). Transplants included 19 kidney/liver (50% male), 47 kidney/pancreas (53% male), 92 liver (65% male), and 17 pancreas transplants (41% male). Age at transplant was 50.8 ± 10.3 years. Fractures were equally seen across both genders and transplant types. Calcium supplementation (n = 94) and bisphosphonate therapy (n = 52) were observed, and an association with a lower risk of fractures was noted for bisphosphonate users (OR = 0.45 95% C.I. 0.24, 0.85). Fracture location included 8 (16.7%) foot, 12 (25.0%) vertebral, 3 (6.3%) hand, 2 (4.2%) humerus, 5 (10.4%) wrist, 10 (20.8%) fractures at other sites, and 7 (14.6%) multiple fractures. The estimated relative risk of fracture was nearly seventeen-times higher in male liver transplant recipients ages 45-64 years compared with the general male population, and comparable to fracture rates on conventional immunosuppressant regimens. Conclusion. We identify a high frequency of fractures in transplant recipients despite limited glucocorticoid use.

Cross-linked versus conventional polyethylene for total hip replacement: a meta-analysis of randomised controlled trials.

We conducted a systematic review and meta-analysis of randomised controlled trials comparing cross-linked with conventional polyethylene liners for total hip replacement in order to determine whether these liners reduce rates of wear, radiological evidence of osteolysis and the need for revision. The MEDLINE, EMBASE and COCHRANE databases were searched from their inception to May 2010 for all trials involving the use of cross-linked polyethylene in total hip replacement. Eligibility for inclusion in the review included the random allocation of treatments, the use of cross-linked and conventional polyethylene, and radiological wear as an outcome measure. The pooled mean differences were calculated for bedding-in, linear wear rate, three-dimensional linear wear rate, volumetric wear rate and total linear wear. Pooled risk ratios were calculated for radiological osteolysis and revision hip replacement. A search of the literature identified 194 potential studies, of which 12 met the inclusion criteria. All reported a significant reduction in radiological wear for cross-linked polyethylene. The pooled mean differences for linear rate of wear, three-dimensional linear rate of wear, volumetric wear rate and total linear wear were all significantly reduced for cross-linked polyethylene. The risk ratio for radiological osteolysis was 0.40 (95% confidence interval 0.27 to 0.58; I(2) = 0%), favouring cross-linked polyethylene. The follow-up was not long enough to show a difference in the need for revision surgery.

Evaluation of cinacalcet HCl treatment after kidney transplantation.

BACKGROUND: Hyperparathyroidism often remains or develops after kidney transplantation. Vitamin D sterol used as treatment for an elevated parathyroid hormone (PTH) level and associated bone disease may be contraindicated due to hypercalcemia. The calcimimetic cinacalcet HCl (cinacalcet), which lowers PTH and calcium (Ca) in chronic kidney disease patients, may represent an alternate therapeutic modality. METHODS: This multicenter, retrospective, observational study examined 41 kidney transplant patients receiving cinacalcet for ≥3 months starting ≥3 months posttransplantation. Levels of intact PTH, Ca, and phosphorus (P) were examined during the assessment phase (3-6 months after initiation). RESULTS: Median PTH decreased 21.8% during the assessment phase (P < .001), with 32.5% of patients exhibiting a ≥30% decrease in PTH from baseline. Median Ca decreased 6.8% (P < .0001). Median serum P rose 10.0% (P = .0124), but remained within normal limits. The estimated glomerular filtration rate was stable throughout the study. CONCLUSIONS: Cinacalcet may be useful for the treatment of hyperparathyroidism after kidney transplantation. Randomized, prospectively designed clinical trials are required to confirm these results.

Lanthanum carbonate vs. sevelamer hydrochloride for the reduction of serum phosphorus in hemodialysis patients: a crossover study.

AIMS: The aim of this crossover study was to compare the reduction of serum phosphorus (SP) with fixed doses of the non-calcium-containing phosphate binders lanthanum carbonate (LC) and sevelamer hydrochloride (SH) in hemodialysis patients. METHODS: Following washout (2 - 3 weeks), 182 patients with SP >or= 6.0 mg/dl and calcium >or= 8.4 mg/dl were randomized (1:1) to receive LC (2,250 to 3,000 mg/day) or SH (4,800 to 6,400 mg/day) for 4 weeks. Patients underwent a second washout (2 weeks) and switched to the alternative binder for 4 weeks. RESULTS: At the end of treatment, LC had reduced SP by 1.7 +/- 0.1 mg/dl, compared with 1.4 +/- 0.1 mg/dl for SH; the difference was not statistically significant in the primary analysis (LOCF, p = 0.133). However, the reduction with LC was significantly greater than with SH in a prespecified key secondary analysis of patients who completed 4 weeks of treatment with each binder (0.5 mg/dl difference, p = 0.007). The reduction of SP was also greater with LC than SH after 1 week of treatment (p = 0.024). CONCLUSIONS: Although the primary analysis found no difference between LC and SH in the reduction of SP, a significant difference in favor of LC was observed in patients who completed treatment. The results of this study show interesting trends with respect to onset and duration of action that warrant further investigation in longer-term studies.

Beta2-microglobulin stimulates osteoclast formation.

Dialysis-related amyloidosis is a complication of long-term chronic kidney disease (CKD) resulting in deposition of beta(2)-microglobulin (beta(2)M) amyloid in osteoarticular tissue. Clinical manifestations include destructive arthropathy, bone cysts, and fractures. Since osteolytic lesions are prominent findings around the beta(2)M deposits, we sought evidence whether beta(2)M causes bone destruction by directly stimulating osteoclast activity and if this was mediated by local cytokine production. A dose-dependent increase in the number of tartrate-resistant alkaline phosphatase-positive multinucleated cells was found in cultured mouse marrow cells treated with beta(2)M. Osteoprotegerin was unable to block this osteoclastogenic effect of beta(2)M. Osteoblasts or stromal cells were not necessary to induce this osteoclastogenesis, as formation was induced by incubating beta(2)M with colony-forming unit granulocyte macrophages (the earliest identified precursor of osteoclasts) or the murine RAW 264.7 monocytic cell line. beta(2)M Upregulated tumor necrosis factor-alpha (TNF-alpha) and IL-1 expression in a dose-dependent manner; however, a TNF-alpha-neutralizing antibody blocked beta(2)M-induced osteoclast formation. These results show that beta(2)M stimulates osteoclastogenesis, supporting its direct role in causing bone destruction in patients with CKD.

Pre-ischemic exercise reduces matrix metalloproteinase-9 expression and ameliorates blood-brain barrier dysfunction in stroke.

Exercise reduces ischemia and reperfusion (I/R) injury in the rat stroke model. We investigated whether pre-ischemic exercise ameliorates blood-brain barrier (BBB) dysfunction in stroke by reducing matrix metalloproteinase (MMP)-9 expression and strengthening basal lamina. Adult male Sprague-Dawley rats were subjected to a 30 min exercise program on a treadmill 5 days a week for 3 weeks. Stroke was induced by a 2-h middle cerebral artery (MCA) occlusion using an intraluminal filament in the exercised and non-exercised groups. Brain infarction was measured and neurological deficits were scored. BBB dysfunction was determined by examining brain edema and Evans Blue extravasation. Expression of collagen IV, the major component of basal lamina essential for maintenance of the endothelial permeability barrier, was quantitatively detected by Western blot and immunocytochemistry. Ex vivo techniques were used to compare collagen IV-labeled vessels in response to ischemic insult. Temporal relationship of expression of MMP-9 and its endogenous inhibitor, the tissue inhibitors of metalloproteinase-1 (TIMP-1), was determined by real-time PCR for mRNA and Western blot for protein during reperfusion. Brain edema and Evans Blue leakage were both significantly (P<0.01) reduced after stroke in the exercised group, in association with reduced brain infarct volume and neurological deficits. Western blot analysis indicated that exercise enhanced collagen IV expression and reduced the collagen loss after stroke. Immunocytochemistry demonstrated that collagen IV-labeled vessels were significantly (P<0.01) increased in exercised rats. In the ex vivo study, after exercised brains were incubated with ischemic brain tissue, a significantly (P<0.01) higher level of collagen IV-labeled vessels was observed as compared with non-exercised brains following the same treatment. The ex vivo study also revealed a key role of MMP-9 in exercise-strengthened collagen IV expression against I/R injury. TIMP-1 protein levels were significantly (P<0.01) increased by exercise. Our results indicate that pre-ischemic exercise reduces brain injury by improving BBB function and enhancing basal lamina integrity in stroke. This study suggests that the neuroprotective effect of physical exercise is associated with an imbalance of MMP-9 and TIMP-1 expression.

Clinical and economic burden of fractures in patients with renal osteodystrophy.

UNLABELLED: Renal osteodystrophy is a key cause of fractures in patients with chronic kidney disease (CKD). AIMS: This article reviews the clinical and economic burden of fractures and explores the types of studies that need to be conducted in order to fully understand the impact of fractures in renal osteodystrophy. We also discuss the role that active vitamin D compounds and calcimimetics play in treating secondary hyperparathyroidism. MATERIALS AND METHODS: Medline was searched for relevant articles on renal osteodystrophy and fractures. RESULTS: CKD-related fractures are the source of significant morbidity and costs. Extensive osteoporosis research has been utilized to guide fracture prevention and improve disease management, but further costs and outcomes analyses are needed for renal osteodystrophy. Recent research regarding newer, present-day treatment paradigms has suggested that distinct cost savings and improved patient outcomes are possible. CONCLUSIONS: In order to realize such economic and human benefits, the medical community must first have sufficient pathologic, pharmacoeconomic and epidemiologic data to properly understand, manage and prevent renal osteodystrophy and fractures.