An Integrative Genetics Approach to Identify Candidate Genes Regulating BMD: Combining Linkage,Gene Expression,and Association

Numerous quantitative trait loci (QTLs) affecting bone traits have been identified in the mouse; however, few of the underlying genes have been discovered. To improve the process of transitioning from QTL to gene, we describe an integrative genetics approach, which combines linkage analysis, expression QTL (eQTL) mapping, causality modeling, and genetic association in outbred mice. In C57BL/6J × C3H/HeJ (BXH) F₂ mice, nine QTLs regulating femoral BMD were identified. To select candidate genes from within each QTL region, microarray gene expression profiles from individual F₂ mice were used to identify 148 genes whose expression was correlated with BMD and regulated by local eQTLs. Many of the genes that were the most highly correlated with BMD have been previously shown to modulate bone mass or skeletal development. Candidates were further prioritized by determining whether their expression was predicted to underlie variation in BMD. Using network edge orienting (NEO), a causality modeling algorithm, 18 of the 148 candidates were predicted to be causally related to differences in BMD. To fine‐map QTLs, markers in outbred MF1 mice were tested for association with BMD. Three chromosome 11 SNPs were identified that were associated with BMD within the Bmd11 QTL. Finally, our approach provides strong support for Wnt9a, Rasd1, or both underlying Bmd11. Integration of multiple genetic and genomic data sets can substantially improve the efficiency of QTL fine‐mapping and candidate gene identification.     

Giant platelets in a case of deletion 11q24‐qter confirmed by fluorescence in situ hybridization

Here we report the association of giant platelets and an increase in platelet volume in a 19‐month‐old black female with de novo del 11q24‐qter. The deletion, which was visible on karyotype, was further confirmed and more precisely localized by fluorescence in situ hybridization studies (FISH) that showed the deletion to lie distal to the MLL gene region (11q23). Clinically, the case presented less severe symptoms than Jacobsen syndrome‐the well known partial deletion of the distal end of chromosome 11. Platelet glycoproteins CD 41, CD 42a, C 42b, CD 61, and PAC‐1 were also assayed and found to be normally expressed. To our knowledge, giant platelets are described for the first time in the relevant deleted region. © 2002 Wiley‐Liss, Inc.     

Anemia management in chronic heart failure: lessons learnt from chronic kidney disease

The importance of anemia in chronic kidney disease (CKD) has become increasingly well recognized over recent years, as have the benefits of treating anemic CKD patients with recombinant human erythropoietin (rHuEPO, epoetin). As well as reducing the need for blood transfusions and the complications associated with renal failure in CKD patients, rHuEPO treatment decreases patient morbidity and mortality, particularly as a result of cardiovascular disease. The strong correlation between anemia, renal failure and cardiac failure is one that has received much attention recently, with each factor recognized to cause the other to worsen in a 'vicious cycle'. Recent studies have concentrated on the possible benefits of anemia treatment in patients with CHF. Currently available data suggest improvements in CHF symptoms, left ventricular ejection fraction (LVEF) and a reduction of hospitalizations associated with anemia correction through epoetin treatment. Available data from CKD patients suggest that anemia management should begin as early as possible, although the optimal target level for individual patients is as yet unclear. In addition to the currently available evidence, additional large, randomized, controlled studies are required to further define the morbidity/mortality benefits of epoetin treatment in CHF patients with anemia.     

Clinical epidemiology of arteriovenous fistula in 2007

The native arteriovenous fistula (AVF) is considered the best access for hemodialysis due to its longer survival and lower complication rates as compared with other forms of vascular access. However, broad practice variation exists in the use of AVF among different countries and even within the same country among different regions and centers. Several barriers to AVF placement have been identified in the last decade that might explain its suboptimal use among both prevalent and incident patients. The present review summarizes and discusses recent findings from epidemiological studies on practice patterns and risk factors for AVF failure. Special emphasis is devoted to drawbacks and payoffs consequent upon the choice of the AVF as access for dialysis. In fact the AVF requires major investments in the short run but far less assistance and rework thereafter. Primary AVF failure, due to early failure or lack of maturation, is currently considered a key area of investigation to improve vascular access outcomes. The main challenge for the nephrologist today is to minimize the risk of primary failure while attempting to provide most patients with a native AVF. Improving vascular access outcomes is clearly a complex and difficult task. Recent experience from the United States suggests that multidisciplinary management is the most appropriate approach to deal with all the multifaceted aspects of end-stage renal disease care and to increase the likelihood of success.     

Antimicrobial locks: putting the lock on catheter infections

Infectious complications resulting from catheter use in the hemodialysis population remain as the significant cause of morbidity and mortality in this patient population. Because conservation of vascular access sites remains a therapeutic mainstay for chronic hemodialysis patients, clinical investigators have evaluated the safety and efficacy of catheter preservation with antimicrobial lock solutions instilled into the lumens of catheters to treat and prevent infectious complications. The recommended treatment of catheter-related bacteremia includes administration of systemic antibiotics with catheter removal. To date, 4 studies in the hemodialysis population have evaluated the use of systemic antibiotics with an antimicrobial lock solution for treatment of catheter-related bacteremias to amplify the success of catheter salvage. The use of antimicrobial lock solutions for the treatment of catheter-related bacteremia has resulted in successful catheter salvage in approximately 69% of patients, with the remainder requiring catheter removal following a lack of clinical improvement after 48 hours. The antimicrobial lock has also been studied as a prophylactic measure to prevent catheter-related bacteremia. Six studies in the hemodialysis population have evaluated the use of an antimicrobial lock for the prevention of catheter-related bacteremia with an overall 64%-100% reduction in the frequency of catheter-related bacteremia. Although the use of antimicrobial lock for prophylaxis has demonstrated efficacy in clinical trials, its long-term consequences, including potential impact on antimicrobial resistance, are unknown. The objectives of this review are to evaluate the current body of evidence espousing the utilization of an antimicrobial lock solution in tunneled cuffed and uncuffed catheters that are utilized during chronic intermittent hemodialysis.     

The loading patterns of a short femoral stem in total hip arthroplasty: gait analysis at increasing walking speeds and inclines

Background

The purpose of this study was to examine the gait pattern of total hip arthroplasty (THA) patients with a new short femoral stem at different speeds and inclinations.

Materials and methods

A total of 40 unilateral THA patients were tested on an instrumented treadmill. They comprised two groups (shorter stemmed THA n?=?20, longer stemmed THA n?=?20), both which had the same surgical posterior approach. The shorter femoral stemmed patients were taken from an ongoing hip trial with minimum 12 months postop. The comparative longer THR group with similar disease and severity were taken from a gait database along with a demographically similar group of healthy controls (n?=?35). All subjects were tested through their entire range of gait speeds and inclines with ground reaction forces collected. Body weight scaling was applied and a symmetry index to compare the implanted hip to the contralateral normal hip. An analysis of variance with significance set at α?=?0.05 was used.

Results

The experimental groups were matched demographically and implant groups for patient reported outcome measures and radiological disease. Both THA groups walked slower than controls, but symmetry at all intervals for all groups were not significantly different. Push-off loading was less favourable for both the shorter and longer stemmed THR groups (p?<?0.05) depending on speed.

Conclusions

Irrespective of femoral stem length, symmetry for ground reaction forces for both THA groups were returned to a normal range when compared to controls. However individual implant performance showed inferior (p?<?0.05) push-off forces and normalised step length in both THR groups when compared to controls.

Level of evidence

III.

     

False-negative plain cervical spine x-rays in blunt trauma

Although considered very accurate, false-negative plain cervical radiographs of blunt trauma patients will occur with potentially devastating complications. We sought to define the population of patients who fall into this category and the overall accuracy of adequate three-view cervical spine radiography in the blunt trauma population. A retrospective search was carried out of blunt trauma patients entered into our trauma registry. All patients with the ICD-9 codes indicating cervical spine injury with a negative three-view cervical spine radiograph reading had their charts and radiographs reviewed. Institutional statistics for blunt cervical trauma evaluation and injury were obtained from the trauma registry. Fifty-eight of 936 blunt trauma patients (6.2%) were diagnosed with cervical spine injury over the 9-month study period. Of 649 patients with adequate three-view plain radiographs, three patients were identified with negative plain radiographs and significant cervical spine injury, a false-negative rate of 0.5 per cent. Sensitivity was 90.3 per cent, specificity was 96.3 per cent, positive predictive value was 54.9 per cent, and negative predictive value was 99.5 per cent. Three-view plain radiograph series of the cervical spine remains a highly sensitive and specific test for cervical spine injury following blunt trauma. However, the fact that we identified three patients with significant fractures after negative plain radiographs suggests that serious consideration of computed tomography must be applied in treating symptomatic, high-risk blunt trauma patients when plain radiographs do not reveal an injury.