Attenuation of transplant arteriosclerosis by oral feeding of major histocompatibility complex encoding chitosan-DNA nanoparticles

One promising approach for the induction of transplant tolerance is the pre-treatment of transplant recipients with donor MHC-alloantigen. Our study focuses on the oral delivery of MHC-antigen encoding genes via chitosan-DNA nanoparticles to modulate the alloimmune response in order to reduce the development of transplant arteriosclerosis, the hallmark feature of chronic rejection after heart transplantation. Therefore, we performed fully allogeneic mouse abdominal aortic transplants using C57BL/6 (H2^b) mice as donors and CBA.J (H2^k) mice as recipients. Aortic grafts were analyzed by histology and morphometry on day 30 after transplantation, levels of circulating alloantibodies were detected by FACS analysis. Pre-treatment of recipient mice with chitosan-DNA nanoparticles encoding for K^b, one of the MHC-I molecules of the donor, resulted in a significant reduction of intimal proliferation compared to untreated controls. When Ovalbumin was fed instead of K^b encoding nanoparticles (K^b-NP) or Balb/c (H2^d) grafts were used instead of C57BL/6 (H2^b) grafts as antigen controls, both groups showed no reduction of intimal thickness indicating an antigen-specific mechanism. In addition, analysis of peripheral blood of the transplanted mice showed significant suppression of alloantibody formation in the K^b-NP fed group compared to all other allogeneic transplanted groups suggesting modulation of the humoral immune response. These results demonstrate the potential of chitosan-DNA nanoparticles to induce K^b-specific tolerance and to reduce the development of transplant arteriosclerosis.     

Prediction of postoperative pain after percutaneous nephrolithotomy: can preoperative experimental pain assessment identify patients at risk?

Postoperative pain remains a significant problem and the individual variance in postoperative pain is not fully understood. In recent years, there has been focus on identifying risk factors predicting patients with high postoperative pain intensity or consumption of analgesics, which may facilitate an improvement in rehabilitation. This study evaluates the relationship between preoperative experimental pain assessment and postoperative pain and opioid consumption. Forty-four patients with uni- or bilateral kidney stone disease scheduled for percutaneous nephrolithotomy were included. The preoperative pain thresholds were measured using electrical (single and 5 repeated) and pressure pain stimulation over the flank bilaterally (stone-side = operation side and control-side = non-operation side). Postoperative pain scores were recorded on a numerical rating scale and analgesic consumption was registered. The responses to repeated electrical stimuli (temporal summation) were preoperatively increased on the stone-side compared to the control-side (P = 0.016). Preoperative electrical pain thresholds from the control-side correlated inversely with postoperative opioid consumption (single stimuli: ρ = ?0.43, P < 0.01; repeated stimuli: ρ = ?0.45, P < 0.005). This correlation was more pronounced for the 22 patients with unilateral renal calculi (single stimuli: ρ = ?0.54, P < 0.02; repeated stimuli: ρ = ?0.58, P < 0.01). There were no other correlations between the preoperative sensory tests and postoperative pain or opioid consumption. This study showed a correlation between the preoperative electrical pain thresholds on the control-side and postoperative opioid consumption after percutaneous nephrolithotomy. Preoperative measurement of the electrical pain thresholds may, therefore, be useful as a screening tool to identify patients at high risk of postoperative pain.     

Relevance of Bilateral Cervical Thymectomy in Patients with Renal Hyperparathyroidism: Analysis of 161 Patients Undergoing Reoperative Parathyroidectomy

Background

The most frequent location of ectopic or supernumerary inferior parathyroid is the thymus. Bilateral cervical thymectomy has therefore been recommended as an essential part of the initial surgery for renal hyperparathyroidism (rHPT) to avoid persistent or recurrent cervical disease. The aim of this study was to evaluate how often reoperation might have been avoidable if an appropriate cervical thymectomy had been performed during initial surgery.

Methods

A prospective database of patients with rHPT was screened for patients on permanent dialysis who underwent reoperative parathyroidectomy (PTX) between 1976 and 2010. Data were retrospectively analyzed for the performance of bilateral cervical thymectomy during previous surgeries and the presence of ectopic and/or supernumerary intrathymic parathyroid glands during reoperative PTX.

Results

Of 161 patients who underwent reoperative PTX, 95 had neck reexploration. Among them were 29 patients with total PTX and autotransplantation, seven with subtotal PTX (3.5 glands resected), and 59 with incomplete PTX during the initial surgery. Bilateral cervical thymectomy during the initial PTX was performed in only 12 of 95 patients (12.6 %). It was revealed to be incomplete in six of them, inheriting an intrathymic parathyroid gland during reoperative interventions. Reoperative PTX revealed intrathymic parathyroid glands in 27 of 95 patients (28.4 %). The intrathymic parathyroid glands were ectopic in 17 (63.0 %) patients and supernumerary in 8 (29.6 %). Both ectopic and supernumerary intrathymic parathyroid glands were found in two patients (7.4 %).

Conclusions

The risk for persistent and recurrent disease based on intrathymic parathyroid glands is a relevant problem during initial surgery for rHPT. Thus, routine bilateral cervical thymectomy that is as complete as possible is essential during the initial PTX for rHPT.     

Management of fingolimod in clinical practice

The efficacy of the innovative oral drug fingolimod has been proven in the largest study program in multiple sclerosis (MS) demonstrating reduced relapse and reduced disability progression in relapsing-remitting MS patients. Based on the extensive safety data of all clinical trials and the natural distribution pattern of fingolimod interacting receptors in organism, careful clinical monitoring is recommend and reviewed in this paper. Safety and tolerability data from clinical studies as well as current post-marketing experience present with high tolerability and easy-to-perform management of fingolimod. Here we present the recommended management of fingolimod in clinical practice starting with preparatory steps, first-dose application and long-term treatment period with fingolimod. This management of fingolimod in clinical practice ensure a safe treatment algorithm using fingolimod. We recommend documentation of fingolimod patients in clinical registries to generate postmarketing data on efficacy and safety of fingoilimod.     

Early loss of pericytes and perivascular stromal cell-induced scar formation after stroke

Despite its limited regenerative capacity, the central nervous system (CNS) shares more repair mechanisms with peripheral tissues than previously recognized. Scar formation is a ubiquitous healing mechanism aimed at patching tissue defects via the generation of fibrous extracellular matrix (ECM). This process, orchestrated by stromal cells, can unfavorably affect the capacity of tissues to restore function. Vascular mural cells have been found to contribute to scarring after spinal cord injury. In the case of stroke, little is known about the responses of pericytes (PCs) and stromal cells. Here, we show that capillary PCs are rapidly lost after cerebral ischemia in both experimental and human stroke. Coincident with this loss is a massive proliferation of resident platelet-derived growth factor receptor beta (PDGFRβ)⁺ and CD105⁺ stromal cells, which originate from the neurovascular unit and deposit ECM in the ischemic mouse brain. The presence of PDGFRβ⁺ stromal cells demarcates a fibrotic, contracted, and macrophage-laden lesion core from the rim of hypertrophic astroglia in both experimental and human stroke. We suggest that a previously unrecognized population of CNS-resident stromal cells drives a dynamic process of scarring after cerebral ischemia, which appears distinct from the glial scar and represents a novel target for regenerative stroke therapies.