Discovery and Validation of a Urinary Exosome mRNA Signature for the Diagnosis of Human Kidney Transplant Rejection

BackgroundDeveloping a noninvasive clinical test to accurately diagnose kidney allograft rejection is critical to improve allograft outcomes. Urinary exosomes, tiny vesicles released into the urine that carry parent cells’ proteins and nucleic acids, reflect the biologic function of the parent cells within the kidney, including immune cells. Their stability in urine makes them a potentially powerful tool for liquid biopsy and a noninvasive diagnostic biomarker for kidney-transplant rejection.MethodsUsing 192 of 220 urine samples with matched biopsy samples from 175 patients who underwent a clinically indicated kidney-transplant biopsy, we isolated urinary exosomal mRNAs and developed rejection signatures on the basis of differential gene expression. We used crossvalidation to assess the performance of the signatures on multiple data subsets.ResultsAn exosomal mRNA signature discriminated between biopsy samples from patients with all-cause rejection and those with no rejection, yielding an area under the curve (AUC) of 0.93 (95% CI, 0.87 to 0.98), which is significantly better than the current standard of care (increase in eGFR AUC of 0.57; 95% CI, 0.49 to 0.65). The exosome-based signature’s negative predictive value was 93.3% and its positive predictive value was 86.2%. Using the same approach, we identified an additional gene signature that discriminated patients with T cell–mediated rejection from those with antibody-mediated rejection (with an AUC of 0.87; 95% CI, 0.76 to 0.97). This signature’s negative predictive value was 90.6% and its positive predictive value was 77.8%.ConclusionsOur findings show that mRNA signatures derived from urinary exosomes represent a powerful and noninvasive tool to screen for kidney allograft rejection. This finding has the potential to assist clinicians in therapeutic decision making.     

Augmentation of Shoulder Contour Using a Calf Implant

Sprengel deformity is a rare orthopedic condition that is associated with functional and cosmetic impairment. Results of orthopedic procedures are usually inconsistent and cosmetic results are far from satisfactory in these patients. A silicone-gel-filled calf prosthesis was used to correct the shoulder contour in a patient with Sprengel deformity. Cosmetically the deformity can be restored by using a calf implant for patients in whom orthopedic procedures are not likely to yield a satisfactory outcome.     

Influence of Indium (III) Chloride on Human Dermal Fibroblast Cell Adhesion on Tantalum/Silicon Oxide Nano-Composites

Cell adhesion is an essential biological function for division, migration, signaling and tissue development. While it has been demonstrated that this cell function can be modified by using nanometer-scale surface topographic structures, it remains unknown how contaminants such as indium (III) ion might influence this specific cell behavior. Herein, the influence of indium chloride on human dermal fibroblast (GM5565) adhesion characteristics was investigated, given the frequent contact of contaminants with skin. The morphology of the adherent cells and their mitochondrial reticulum was characterized on cell culture dishes and nanopatterned surfaces by using fluorescence confocal microscopy and scanning electron microscopy. Results showed a significant proportion of cells lost their ability to align preferentially along the line axes of the nanopattern upon exposure to 3.2 mM indium chloride, with cells aligned within 10° of the pattern line axes reduced by as much as ~70%. Concurrent with the cell adhesion behaviors, the mitochondria in cells exposed to indium chloride exhibit a punctate staining that contrasts with the normal network of elongated tubular geometry seen in control cells. Our results demonstrate that exposure to indium chloride has detrimental effects on the behavior of human fibroblasts and adversely impacts their mitochondrial morphology. This shows the importance of evaluating the biological impacts of indium compounds.     

颈动脉粥样硬化疾病的处理——美国血管外科学会临床实践指南

美国血管外科学会（SVS）任命了一个专家委员会制定颈动脉狭窄处理的循证临床指南。在制定临床实践推荐意见过程中，该委员会使用系统评价对当前最佳的证据进行了总结，采用GRADE标准对推荐意见的强度（强烈推荐为GRADEI级，一般推荐为GRADEⅡ级）和证据的质量（高、中、低和极低）进行了分级。对于轻度颈动脉狭窄患者（有症状患者狭窄程度〈50％和无症状患者狭窄程度〈60％），推荐进行最佳的内科治疗而非血管重建术（I级推荐，高质量证据）。对于有症状中到重度狭窄患者（狭窄程度〉150％），推荐行颈动脉内膜切除术（CEA）＋最佳的内科治疗（I级推荐，高质量证据）。对于围手术期风险高的有症状中到重度狭窄患者（狭窄程度≥50％），建议采用颈动脉支架置入术作为其替代治疗手段（Ⅱ级推荐，低质量证据）。对于中到重度狭窄的无症状患者（狭窄程度≥60％），只要围手术期风险较低，就推荐行CEA＋内科治疗（I级推荐，高质量证据）。对于中到重度狭窄的无症状患者（狭窄程度≥60％），不推荐行颈动脉支架置入术（I级推荐，低质量证据）。颈动脉狭窄≥80％但存在CEA高危解剖学风险的患者可能是一个例外。     

Utility of left subclavian artery revascularization in association with endoluminal repair of acute and chronic thoracic aortic pathology

BACKGROUND: A rapidly increasing number of thoracic aortic lesions are now treated by endoluminal exclusion by using stent grafts. Many of these lesions abut the great vessels and limit the length of the proximal landing zone. Various methods have been used to address this issue. We report our experience with subclavian artery revascularization in association with endoluminal repair of acute and chronic thoracic aortic pathology. METHODS: Thirty (43%) of 70 patients undergoing thoracic endovascular stent-graft placement from January 2001 to August 2005 had lesions adjacent to or involving the origin of the subclavian artery. The mean age was 62 years (range, 22-85 years; 63% were men, and 37% were women). This subgroup of 30 patients had indications for repair that included thoracic aortic aneurysm (n = 15), traumatic transection (n = 6), chronic dissection with pseudoaneurysm (n = 5), and acute dissection with intramural hematoma (n = 4). All 30 patients had the subclavian origin covered by the stent graft. In eight cases (27%), no effort was made to revascularize the subclavian artery before or during the endograft placement procedure. Twenty-three (77%) of 30 patients underwent subclavian to carotid artery transposition (n = 21) or bypass (n = 2) before (n = 12; average of 14 days before stent-graft placement), concomitant with (n = 10), or after (n = 1) the endovascular procedure. Physical examination and computed tomography scans were performed after surgery at 1, 6, and 12 months and annually thereafter. The mean follow-up was 18 months (range, 1-51 months). RESULTS: Five acute complications occurred in the eight patients (63%) who had the subclavian artery covered without pre-endograft revascularization and included four patients who experienced stroke (accounting for the only death) and one patient who developed symptomatic subclavian-vertebral steal that necessitated transposition 7 months later. Two (9%) of the 23 patients who had subclavian revascularization experienced left-sided vocal cord palsies, and 1 patient (4%) developed lower extremity paraparesis secondary to spinal cord ischemia. No late endoleaks related to retrograde sac perfusion from the most distal great vessel have been identified in any patient. CONCLUSIONS: Subclavian revascularization procedures can be performed with relatively low risk. Complications are rare, and patient recovery is rapid. Although this is not necessary in all cases, we advocate subclavian to carotid transposition when the aortic lesion is within 15 mm of the left subclavian orifice to prevent type II endoleak or perfusion of a dissected false lumen when the ipsilateral vertebral artery is patent and dominant or when coronary revascularization using an ipsilateral internal mammary artery is anticipated and in cases that necessitate extensive coverage of intercostals that contribute to spinal cord perfusion. Carotid to subclavian artery bypass should be reserved for patients with a patent internal mammary artery conduit perfusing a coronary vessel and should be combined with proximal subclavian ligation.     

Surface Curvature as a Classifier of Abdominal Aortic Aneurysms: A Comparative Analysis

An abdominal aortic aneurysm (AAA) carries one of the highest mortality rates among vascular diseases when it ruptures. To predict the role of surface curvature in rupture risk assessment, a discriminatory analysis of aneurysm geometry characterization was conducted. Data was obtained from 205 patient-specific computed tomography image sets corresponding to three AAA population subgroups: patients under surveillance, those that underwent elective repair of the aneurysm, and those with an emergent repair. Each AAA was reconstructed and their surface curvatures estimated using the biquintic Hermite finite element method. Local surface curvatures were processed into ten global curvature indices. Statistical analysis of the data revealed that the L2-norm of the Gaussian and Mean surface curvatures can be utilized as classifiers of the three AAA population subgroups. The application of statistical machine learning on the curvature features yielded 85.5% accuracy in classifying electively and emergent repaired AAAs, compared to a 68.9% accuracy obtained by using maximum aneurysm diameter alone. Such combination of non-invasive geometric quantification and statistical machine learning methods can be used in a clinical setting to assess the risk of rupture of aneurysms during regular patient follow-ups.