Coagulation cascade activation triggers early failure of pig hearts expressing human complement regulatory genes

Abstract: Background: Hyperacute rejection (HAR) and early graft failure (EGF) have been described in a minority of pig‐to‐baboon heart transplants using organs transgenic for human complement regulatory proteins (hCRP). Here we investigate the role of coagulation cascade activation in the pathogenesis of HAR and EGF in a consecutive series where a high incidence of these outcomes was observed. Methods: Twenty‐eight naïve wild‐caught Papio anubis baboons received heterotopic heart transplants from pigs transgenic for hDAF (n = 23) or hMCP (n = 5). Immunosuppression consisted of cyclosporine A, cyclophosphamide and MMF (n = 18) or anti‐CD154 mAb (IDEC‐131) and ATG (n = 10). Eleven received anti‐Gal carbohydrates (GAS914, n = 8, or NEX1285, n = 3), of which four also underwent extracorporeal immunoadsorption (EIA), and 12 also received pharmacologic complement inhibitors (C1 INH, n = 9, or APT070, n = 3). Results: Excluding one technical failure, 14 of 27 transplants (11 hDAF, 3 hMCP) exhibited either HAR (n = 10) or EGF (n = 4). Surprisingly, neither complement inhibition (with C1 INH or APT070) nor anti‐Gal antibody depletion with GAS914, NEX1285, or additional EIA consistently prevented HAR or EGF despite low or undetectable complement deposition. Strikingly, most grafts with HAR/EGF exhibited prominent fibrinogen and platelet deposition associated with systemic coagulation cascade activation, consistent with non‐physiologic intravascular coagulation, in many instances despite little evidence for antibody‐mediated complement activation. Conclusion: We conclude that dysregulated coagulation correlates closely with and probably causes primary failure of pig hearts transgenic for hCRP. These data support efforts to define effective strategies to prevent dysregulated coagulation in pig organ xenografts.     

椎间盘源性腰痛的诊断与治疗

目的探讨腰椎间盘源性疼痛的诊断方法及采用前路经腹膜外入路椎间盘切除人工椎间盘置换或椎间cage植骨融合的临床疗效。方法35例经保守治疗无效的椎间盘源性腰痛患者接受手术治疗。椎间盘源性腰痛的诊断标准为：（1）腰部及下肢疼痛的部位与神经根定位不符；（2）症状反复发作，病程在半年以上；（3）MRI病变椎间盘T2加权像低信号；（4）椎间盘造影阳性，相邻节段为阴性对照；（5）关节突关节封闭除外关节突关节退变引起的疼痛。患者年龄25-67岁，平均43．6岁。L4-5 14例，L5S1 16例，L4-5和L5S1双间隙5例。前路经腹膜外入路椎间盘切除后行人工椎间盘置换13例16个椎间盘，椎间cage融合22例24个椎间盘。术后3-7天下地活动。腰围固定3个月。结果所有患者随访6～26个月，平均18个月。术后腰痛及下肢痛症状明显缓解，均恢复正常生活或工作。VAS评分由术前平均72分，降至术后18分，随访6个月时6．5分。ODI评分由术前平均21．5分。降至随访6个月时3分。椎间隙高度从术前平均9．5mm增加至术后13．5mm。手术时间70-120min，出血量100-400ml。随访时未发现肠梗阻、逆行射精和假体位置移动。结论椎间盘源性腰痛由于临床和影像学表现不典型，常被误诊或漏诊，可结合腰椎MRI及椎间盘造影进行诊断。腰椎前路椎间盘切除人工椎间盘置换或椎间cage融合是治疗椎间盘源性腰痛的有效选择。     

Pelvic Ring Fractures: Utility of Clinical Examination in Patients with Impaired Consciousness or Tracheal Intubation

Abstract Objective: To define the diagnostic accuracy of clinical examination in patients with impaired consciousness or endotracheal intubation to detect pelvic ring fractures and to identify those with severe bleeding. Methods: Included in this prospective data collection with retrolective data analysis were a consecutive series of blunt trauma victims with either a Glasgow Coma Scale ≤ 13 or tracheal intubation. Clinical examination comprised testing for stability of the iliac wings. Results: From 784 subjects (injury severity score 23.3 ± 17.4) 93 patients (11.9%) were found to have a pelvic ring fracture. Clinical instability of the pelvic ring was found in 42 patients. There was only one false positive. Fifty-two fractures could not be identified by clinical examination, including nine fractures (17%) that required surgical fracture stabilization (sensitivity of clinical examination 44.1%). Seventeen fractures (18.3%) were associated with a blood loss larger than 20% of circulating blood volume. Sixteen of those were identified by clinical instability of the pelvic ring (sensitivity 94.1%, specificity 97.0%, positive predictive value 38.1%, negative predictive value 99.9%). Conclusions: Clinical examination for stability of the pelvis in this selected group of patients missed a significant number of pelvic ring fractures including fractures that require surgical stabilization. The finding of a clinically unstable identifies most of the patients with the pelvic ring fracture being a major source of bleeding. A stable pelvis makes pelvic ring fracture as being the source of bleeding quite unlikely.     

Quantification of Basal and Stimulated ROS Levels as Predictors of Islet Potency and Function

We have developed a luminol-based assay using intact islets, which allows for quantification of reactive oxygen species (ROS). In addition, an index capable of characterizing metabolic and mitochondrial integrity prior to transplantation was created based on the capacity of islets to respond to high glucose and rotenone (mitochondrial respiratory chain complex I inhibitor) by production of ROS. To validate this assay, lipid peroxidation and antioxidative defense capacity were evaluated by detection of malondialdehyde (MDA) levels and glutathione peroxidase activity (GPx), respectively. Also, flow cytometric analyses of ROS (dihydroethidine), apoptosis (Annexin V, active caspases), necrosis (Topro3), and mitochondrial membrane potential (JC-1) were done in parallel to correlate with changes in luminol-measured ROS. ATP/ADP ratios were quantified by HPLC and the predictive value of ROS measurement on islet functional potency was correlated with capacity to reverse diabetes in a streptozotocin-induced diabetic NOD.scid mouse model as well as in human transplant recipients. Our data demonstrate that levels of ROS in islets correlate with the percentage of apoptotic cells and their functional potency in vivo. The ROS indices following glucose and rotenone exposure are indicative of metabolic potency and mitochondrial integrity and can be used as surrogate markers to evaluate the quality of islets prior to transplantation.     

Integrity of the lateral femoral wall in intertrochanteric hip fractures: an important predictor of a reoperation

BACKGROUND: Reoperations after intertrochanteric fractures are often necessitated by fracture displacement following mobilization of the patient. The biomechanical complexity of the fracture, the position of the implant, and the patient's characteristics are known to influence postoperative outcome. We investigated the importance of an intact lateral femoral wall as a factor in postoperative fracture displacement after fixation with a sliding compression hip screw. METHODS: Two hundred and fourteen consecutive patients with an intertrochanteric fracture were treated with a 135 degrees sliding compression hip screw with a four-hole side-plate between 2002 and 2004. The fractures were classified on preoperative radiographs according to the AO/OTA classification system. The status of the greater and lesser trochanters, the integrity of the lateral femoral wall, and the position of the implant were assessed postoperatively. Reoperations due to technical failure were recorded for six months postoperatively. RESULTS: Only 3% (five) of 168 patients with an intact lateral femoral wall postoperatively underwent a reoperation within six months, whereas 22% (ten) of forty-six patients with a fractured lateral femoral wall were operated on again (p < 0.001). Multivariate logistic regression analyses combining demographic and biomechanical parameters showed a compromised lateral femoral wall to be a significant predictor of a reoperation (p = 0.010). Seventy-four percent (thirty-four) of the forty-six fractures of the lateral femoral wall occurred during the operative procedure itself. A fracture of the lateral femoral wall occurred in only 3% (three) of the 103 patients with an AO/OTA type-31-A1.1, A1.2, A1.3, or A2.1 intertrochanteric fracture compared with 31% (thirty-one) of the ninety-nine with an AO/OTA type 31-A2.2 or A2.3 fracture (p < 0.001). CONCLUSIONS: A postoperative fracture of the lateral femoral wall was found to be the main predictor for a reoperation after an intertrochanteric fracture. Consequently, we concluded that patients with preoperative or intraoperative fracture of the lateral femoral wall are not treated adequately with a sliding compression hip-screw device, and intertrochanteric fractures should therefore be classified according to the integrity of the lateral femoral wall, especially in randomized trials comparing fracture implants.     

Tissue expansion of free and pedicled flaps after transfer: possibilities and indications

Tissue expansion in combination with flap transfer has been widely reported as preexpansion of flaps, but only once as expansion of a free flap after transfer. Three free flaps and one pedicled flap were expanded after transfer. Indication, timing of expander implantation and explantation, technical aspects, and complications are reviewed. Indications for expander implantation after flap coverage were adjacent scar contracture, a secondary ulcer, or correction of contour deformity. The expander was placed as early as 4.5 months after free flap transfer. Low grade infection and seroma were complications necessitating early expander removal in two cases. The outcome was satisfactory in all four patients. Tissue expansion after flap transfer has been shown to be a reliable reconstructive option in selected cases. Indications are rare and include hypertrophic scar formation, scar contracture, secondary ulceration, or reconstructive procedures. In early free flap expansion, it is critical to avoid mechanical pressure of the pedicle. In musculocutaneous flaps, this can be accomplished by placing the expander subcutaneously. If more than 6 months have passed since transfer of the flap, the randomized blood supply is sufficient to place the expander anywhere under the flap.     

Effects of exercise and weight loss on blood pressure during daily life

PURPOSE: The objective of this study was to investigate the effects of exercise training and weight loss on blood pressure (BP) associated with physical activity and emotional stress during daily life. METHODS: One hundred twelve participants with unmedicated high normal or stage 1 to stage 2 hypertension were randomized to one of three conditions: a combined exercise and behavioral weight management group (WM), an exercise-only group (EX), or a wait list control group (CON). BP was assessed in the clinic and during 15 h of daytime ambulatory BP monitoring at baseline and after 6 months of treatment. RESULTS: Increased levels of physical activity and emotional distress measured during daily life were associated with increases in systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), and rate pressure product (RPP). After treatment, the WM group had significantly lower DBP, HR, and RPP responses during both high and low levels of physical activity and emotional distress compared with the CON group. The EX group had similar BP levels as the WM group, although the EX group had significantly lower BP than the CON group during low but not high levels of physical activity and emotional distress. CONCLUSION: These findings indicate that exercise, especially when combined with weight loss, reduces BP levels at rest and in situations that typically elevate BP such as intense physical activity and emotional distress.     

Five-year results from chemonucleolysis with chymopapain or collagenase: a prospective randomized study

STUDY DESIGN: A 5-year clinical follow-up assessment of a prospective randomized study of chemonucleolysis using chymopapain (4000 IU) or collagenase (400 ABC units) was performed. SUMMARY OF BACKGROUND DATA: Intradiscal therapy can be performed for patients with contained discs by chemonucleolysis, percutaneous discectomy, or laser ablation. The oldest intradiscal therapy is chemonucleolysis with chymopapain. OBJECTIVE: The purpose of this study was to compare prospectively the efficacy of chymopapain and collagenase for intradiscal injection. METHODS: In this study, 100 patients with indication for intradiscal therapy were prospectively randomized to treatment with either chymopapain or collagenase. All the injections were performed by the double-needle technique with the patient under general anesthesia. The mean age of the patients was 35.5 years in the chymopapain group and 38 years in the collagenase group. An equal number of injections was performed at L4-L5 and L5-S1. RESULTS: After 5 years, good and excellent results were observed in 72% of the chymopapain group and 52% of the collagenase group when the surgically treated and lost patients were graded as poor. Using a scale of 0 (no pain) to 10 (intractable pain), the pain level dropped from 8.5 to 0.7 in the chymopapain group and from 8.6 to 0.9 in the collagenase group. Microdiscectomy at the injected level was required for 23 patients (14 in the collagenase group and 9 in the chymopapain group). CONCLUSIONS: After 5 years, no deterioration had occurred, as compared with the 1-year follow-up assessment. Chymopapain has proved to be safe, with one minor anaphylactic reaction, and effective even over the long term. Collagenase may need further study and cannot be recommended at this time.