Comparison of the extent to which total hip and total knee arthroplasty restore patient-reported physical function.

OBJECTIVE: To evaluate the extent to which elective total hip arthroplasty (THA) and total knee arthroplasty (TKA) for osteoarthritis (OA) restore normal patient-reported physical function in men and women. METHODS: Pain and physical function (WOMAC-PF) were prospectively measured pre- and post-operatively. The relationship between surgical procedure and achieving physical function equivalent to age and sex-matched adults with no hip or knee joint problems was modeled using sex-specific logistic regression. Percent change in function was also compared between groups using sex-specific generalized linear models adjusted for age, BMI, pain, comorbid conditions, time from surgery, and subsequent surgery. RESULTS: Individuals with pre- and post-operative WOMAC data were classified exclusively into either THA (287M:306F) or TKA (239M:424F) groups. The median follow-up was 476 (THA) and 474 (TKA) days for men, and 495 (THA) and 526 (TKA) days for women. MAIN OUTCOME: women with THA compared with TKA were more likely to achieve a normal level of postoperative PF while there were no significant differences between procedures in men. Additional analyses: we found slightly lower preoperative PF in THA compared with TKA. This difference resolved postoperatively in men, but women who underwent THA reported greater improvement and better PF than those who had TKA. CONCLUSION: In women, THA results in greater improvement in WOMAC-PF at approximately 1-year follow-up and better approximates physical function of community-dwelling older adults without OA than TKA does. In contrast, in men, a lack of between-group post-operative WOMAC-PF differences suggests that procedures result in a similar degree of improvement.

Coronary artery bypass grafting in the awake patient combining high thoracic epidural and femoral nerve block: first series of 15 patients.

BACKGROUND: We present a 15-patient series of awake 'off-pump' [without cardiopulmonary bypass (CPB)] coronary artery bypass graft surgery, facilitated by thoracic epidural analgesia (TEA) and femoral nerve block. METHODS: Surgery was performed with a conventional median sternotomy. Analgesia was provided with TEA at T1-2 or 2-3 interspace, using bupivacaine 0.5% and sufentanil 1.66 microg ml(-1), initially at 20 ml litre(-1) until T1-10 dermatomal block was achieved, then maintained at 2-14 ml litre(-1) throughout surgery. Femoral nerve block was performed before operation with neuro-stimulation at the saphenous vein harvest site with 10 ml each of bupivacaine 0.25% and lidocaine 2%. Successful awake surgery, avoiding general anaesthesia (GA) with adequate surgical conditions, without CPB was the primary end point. RESULTS: Fifteen men, mean (sd) age of 63 (9) yr (range 49-81 yr), weight 78 (10) kg, underwent surgery. Three patients (20%) needed conversion to GA: one patient due to insufficient thoracic analgesia, another required initiation of CPB, and the third needed stabilization of the heart for graft suturing due to profound respiratory movements. All three were successfully extubated immediately after surgery. Awake surgery was successful and uneventful in 80% of cases. CONCLUSIONS: Combined TEA and femoral block is a novel anaesthetic technique, and is feasible, for cardiac surgery. However, certain technical limitations need to be overcome to evaluate the full potential of 'awake' cardiac surgery.

Incidental findings in CT imaging of coronary artery bypass grafts: results from a Canadian multicenter prospective cohort.

OBJECTIVE: To assess the prevalence and clinical significance of incidental findings identified during computed tomography imaging of coronary artery bypass grafts. RESULTS: This prospective study includes 144 patients undergoing coronary graft patency assessment using computed tomography. Incidental findings were classified as significant if they were considered to need an immediate action or treatment, short-term work-up or follow-up, or minor. A total of 211 incidental findings were present in 109 (75.7%) patients. Seventy-one incidental findings (33.6%) were cardiac and 140 (66.4%) were extracardiac. Most common cardiac incidental findings were atrial dilatation [39 patients, 48 incidental findings (67.6%)] and aortic valve calcifications (7 patients, 9.9%). Among the 140 extracardiac incidental findings, the most common were lung nodules (51 patients, 54 nodules, 38.6%), and emphysema (21 patients, 15%). Thirty-six (25.7%) extracardiac incidental findings were significant and notably, 23 (63.9%) were lung nodules. Follow-up was recommended in 37 cases, among which all patients with significant lung nodules (23 patients, 62.2%). In conclusion, most common computed tomography incidental findings in patients with coronary grafts were lung nodules and emphysema.

Bolus endovascular PDGFR-beta antisense treatment suppressed intimal hyperplasia in a rat carotid injury model.

BACKGROUND: Intimal thickening in accelerated arteriopathies relies on the migration of medial vascular smooth muscle cells (VSMCs) and their proliferation within the neointima. Activation of platelet-derived growth factor receptor-beta (PDGFR-beta) expressed in injured VSMCs is responsible for the migration of medial VSMCs to the intima. In the present study, we wanted to assess whether a single local endovascular delivery of antisense PDGFR-beta in injured rat carotid arteries would be sufficient to prevent intimal hyperplasia and how it might contribute to the vascular healing process. METHODS AND RESULTS: A bolus of antisense PDGFR-beta delivered into injured rat carotid arteries reduced PDGFR-beta protein overexpression by >90% from day 3 to 28 after injury. At day 28 after injury, compared with injured untreated carotids, treatment with antisense PDGFR-beta reduced intimal hyperplasia by 58% and medial VSMC migration by 49% and improved vascular reendothelialization by 100% and vascular reactivity (EC(50)) to acetylcholine by 5-fold. CONCLUSIONS: A single-bolus luminal delivery of antisense PDGFR-beta to injured rat carotids reduced intimal hyperplasia, improved the reendothelialization process, and led to the recovery of endothelium-dependent regulation of vascular tone.

Expression of Hox A11 in the limb and the regeneration blastema of adult newt.

Homeoproteins are functionally involved in pattern formation of developing systems and are potentially good candidates to regulate positional information during limb regeneration in the newt. Here we report the molecular structure of Hox A11 and its pattern of expression during the regeneration of adult newt appendages. The transcriptional unit of the gene is composed of two exons separated by an intron. Northern blots revealed two major transcripts; a size difference would result from using two different polyadenylation signals. Therefore, the gene would encode a single protein that is very homologous to other vertebrate counterparts. The pattern of expression of Hox A11 in the adult newt shows interesting findings in relation to limb regeneration. First, expression is found in both intact limb and tail, showing maintenance of expression of an important regulator of development in the appendages of the adult newt. Second, Hox A11 is expressed mainly in the muscle and the bone of intact limbs, two tissue fractions known to participate in blastemal fate determination. Third, the level of Hox A11 expression increases drastically in both limb and tail regeneration blastemas, suggesting that the population of expressing cells is preferentially recruited during blastemal formation. Finally, proximal blastemas (mid-humerus) significantly express higher levels of transcript compared with distal ones (mid-radius and ulna). These features of expression suggest that Hox A11 may participate in limb pattern formation by specifying positional information to the progenitor cells of the regenerate.

Homeobox-containing genes in the newt are organized in clusters similar to other vertebrates.

In vertebrates, the majority of homeobox (HBox) genes are found in four clusters and this structural organization is believed to be of functional importance. Many HBox genes sustain their expression in the appendages of the adult newt. To further understand their regulation, the genomic loci of four newt HBox genes (two from the human HBox (HOX)-2 complex and two from the HOX-3 complex) were analysed and compared with homologous loci in other vertebrates. Notophthalmus viridescens HBox (NvHBox) genes were selected from a lambda EMBL3 library and analysed by restriction mapping and nucleotide (nt) sequencing. The nt sequences of the NvHBox genes have a very high degree of homology (more than 90%) with the human and mouse HBox genes, HOX-3.3, HOX-3.4, HOX-2.7 and HOX-2.8. The sequences flanking the HBox are also very homologous to their human and mouse counterparts. Moreover, the size of the DNA spacer separating NvHBox-3.3 from NvHBox-3.4, and NvHBox-2.7 from NvHBox-2.8 in the newt is similar in the homologous regions of the mouse and human, despite there being a C value ten times greater in the newt genome. Finally, three of these NvHBox genes are expressed in the limbs of the adult newt.

Celastrol protects ischaemic myocardium through a heat shock response with up-regulation of haeme oxygenase-1.

BACKGROUND AND PURPOSE: Celastrol, a triterpene from plants, has been used in traditional oriental medicine to treat various diseases. Here, we investigated the cardioprotective effects of celastrol against ischaemia. EXPERIMENTAL APPROACH: Protective pathways induced by celastrol were investigated in hypoxic cultures of H9c2 rat cardiomyoblasts and in a rat model of myocardial infarction, assessed with echocardiographic and histological analysis. KEY RESULTS: In H9c2 cells, celastrol triggered reactive oxygen species (ROS) formation within minutes, induced nuclear translocation of the transcription factor heat shock factor 1 (HSF1) resulting in a heat shock response (HSR) leading to increased expression of heat shock proteins (HSPs). ROS scavenger N-acetylcysteine reduced expression of HSP70 and HSP32 (haeme oxygenase-1, HO-1). Celastrol improved H9c2 survival under hypoxic stress, and functional analysis revealed HSF1 and HO-1 as key effectors of the HSR, induced by celastrol, in promoting cytoprotection. In the rat ischaemic myocardium, celastrol treatment improved cardiac function and reduced adverse left ventricular remodelling at 14 days. Celastrol triggered expression of cardioprotective HO-1 and inhibited fibrosis and infarct size. In the peri-infarct area, celastrol reduced myofibroblast and macrophage infiltration, while attenuating up-regulation of TGF-ß and collagen genes. CONCLUSIONS AND IMPLICATIONS: Celastrol treatment induced an HSR through activation of HSF1 with up-regulation of HO-1 as the key effector, promoting cardiomyocyte survival, reduction of injury and adverse remodelling with preservation of cardiac function. Celastrol may represent a novel potent pharmacological cardioprotective agent mimicking ischaemic conditioning that could have a valuable impact in the treatment of myocardial infarction.

Moxonidine improves cardiac structure and performance in SHR through inhibition of cytokines, p38 MAPK and Akt.

BACKGROUND AND PURPOSE: Regression of left ventricular hypertrophy by moxonidine, a centrally acting sympatholytic imidazoline compound, results from a sustained reduction of DNA synthesis and transient stimulation of DNA fragmentation. Because apoptosis of cardiomyocytes may lead to contractile dysfunction, we investigated in spontaneously hypertensive rats (SHR), time- and dose-dependent effects of in vivo moxonidine treatment on cardiac structure and function as well as on the inflammatory process and signalling proteins involved in cardiac cell survival/death. EXPERIMENTAL APPROACH: 12 week old SHR received moxonidine at 0, 100 and 400 µg·kg(-1)·h(-1) , s.c., for 1 and 4 weeks. Cardiac function was evaluated by echocardiography; plasma cytokines were measured by elisa and hearts were collected for histological assessment of fibrosis and measurement of cardiac proteins by Western blotting. Direct effects of moxonidine on cardiac cell death and underlying mechanisms were investigated in vitro by flow cytometry and Western blotting. KEY RESULTS: After 4 weeks, the sub-hypotensive dose of moxonidine (100 µg) reduced heart rate and improved global cardiac performance, reduced collagen deposition, regressed left ventricular hypertrophy, inhibited Akt and p38 MAPK phosphorylation, and attenuated circulating and cardiac cytokines. The 400 µg dose resulted in similar effects but of a greater magnitude, associated with blood pressure reduction. In vitro, moxonidine inhibited norepinephrine-induced neonatal cardiomyocyte mortality but increased fibroblast mortality, through I(1)-receptor activation and differential effects on downstream Akt and p38 MAPK. CONCLUSIONS AND IMPLICATIONS: While the antihypertensive action of centrally acting imidazoline compounds is appreciated, new cardiac-selective I(1)-receptor agonists may confer additional benefit.

Stem cell therapy for the broken heart: mini-organ transplantation.

BACKGROUND: Myocardial infarction (MI) is characterized by irreversible loss of cardiomyocytes, resulting in impaired ventricular function. Stem cell therapy using autologous progenitor cells has emerged as a promising approach. Experimental studies have demonstrated that highly selected hematopoeitic stem cells, which are characterized by the presence of the surface markers CD34 and CD133, may contribute to repair of the acutely infarcted myocardium by inducing neovascularization, inhibiting apoptosis, and promoting cardiomyogenesis. We sought, to evaluate the intracoronary injection of CD133+ stem cells for cardiac repair in patients with dysfunctional myocardium after an acute MI. PATIENTS AND METHODS: In this Canadian randomized, double-blind, placebo-controlled, Phase I-II study ("COMPARE-AMI"), we are evaluating the feasibility, safety, and efficacy of intracoronary injection of selected CD133+ stem cells for cardiac repair in patients with impaired cardiac function after successfully stented acute MI. Since November 2007, we have enrolled 14 patients in the study. Their mean age was 50.5 +/- 9.1 years, including 93% men. The culprit lesion was always on the left anterior descending artery (LAD). Their maximum troponin and CKMB levels were 8.4 +/- 6.1 microg/L and 322 +/- 225 U/L, respectively. RESULTS: Compared with the baseline, we observed a significant 8.7% improvement in left ventricular ejection fraction at 4 months follow-up, namely, from 41.3 +/- 5.5% to 50.0 +/- 8.2% (n = 7; P = .008). There were no protocol-related complications. Our trial is designed to recruit 40 patients who are randomized 1:1 to receive CD133+ cells or placebo. PERSPECTIVE: There is a need to seek out new therapeutics for the treatment of ischemic heart disease addressing the early loss of viable myocytes. Stem cell transplantation has shown early promise; this appraisal needs well-designed, controlled studies.

Pulmonary recruitment protocol for organ donors: a new strategy to improve the rate of lung utilization.

Because lung transplantation is the only effective therapy for terminal respiratory failure, the demand for donor lungs has increased steadily. However, the number of donors has remained fairly constant over the years, which results in an increasing duration of waiting for lung transplantation. To overcome the lack of organs, various strategies have been developed by transplant centers including use of marginal donors. To increase the lung utilization rate in multiorgan donors, we implemented a simple lung recruitment protocol involving a brief period of controlled sustained inflation. In 2005, the lung utilization rate in the transplant program at our institution was only 20% in multiorgan donors. With the lung recruitment protocol, the rate of lung utilization for transplantation increased to 33%, in 2006, 24% in 2007, and 24% in 2008. Following the lung recruitment protocol, the arterial oxygen tension/fraction of inspired oxygen ratio increased to greater than 15% in more than 40% of donors. We were able to improve gas exchange sufficiently that as many as two-thirds of the lungs were suitable for transplantation. During the protocol, no complications were reported, and no patient became hemodynamically unstable, precluding organ procurement. We believe that optimization of multiorgan donor management with simple interventions may improve oxygenation, reducing the number of inadequate donor lungs and increasing the overall donor pool and organ availability.