Citations

AbstractBackground & AimsHepatocyte apoptosis, the hallmark of non‐alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis ofNASH, the final common step of apoptosis is executed by a family of cysteine‐proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan‐caspase inhibitor, ameliorates liver injury and fibrosis in a murine model ofNASH.MethodsC57/BL6J‐mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan.ResultsMice fed a HFD diet demonstrate a five‐fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5‐fold and 1.3‐fold increase in caspase‐3 and‐8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD‐Em). Likewise, liver injury and inflammation were reduced in mice fed HFD‐Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1‐β, TNF‐α, monocyte chemoattractant protein (MCP‐1) and C‐X‐C chemokine ligand‐2 (CXCL2) quantitative reverse‐transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR.ConclusionIn conclusion, these data demonstrate that in a murine model ofNASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy inNASH.

SUMMARYUnderstanding the flow alteration in side branches during flow diversion treatment of cerebral aneurysms is important to prevent ischemic complications and improve device designs. Flow diverters were placed in the aorta of four rabbits crossing the origin of side arteries. Subject‐specific computational models were constructed from 3D angiographies and Doppler ultrasounds (DUSs). Flow simulations were run before and after virtually deploying the flow diverters, assuming distal resistances remained unchanged after treatment. All jailed arteries remained patent angiographically 8 weeks after treatment. The computational models estimated decreases compared to pretreatment in the mean flow rates between 2% and 20% and in peak flow rates between 5% and 36%. The major changes were observed during systole. Flow patterns did not exhibit recirculation zones before treatment. Implantation of the flow diverters altered the flow structure only locally near the device wires. No major recirculation regions were created or destroyed. Flow diverters seem safe with respect to perforator or side branch occlusion. Relatively small changes in flow rates through jailed arteries are expected, even for moderate to large degrees of coverage of their origins. These results seem consistent with previous clinical experiences where no or very few complications related to perforator occlusion have been reported.Copyright © 2014 John Wiley & Sons, Ltd.

SUMMARY Quantification and characterization of the hemodynamic environment created after flow diversion treatment of cerebral aneurysms is important to understand the effects of flow diverters and their interactions with the biology of the aneurysm wall and the thrombosis process that takes place subsequently. This paper describes the construction of multi‐modality image‐based subject‐specific CFD models of experimentally created aneurysms in rabbits and subsequently treated with flow diverters. Briefly, anatomical models were constructed from 3D rotational angiography images, flow conditions were derived from Doppler ultrasound measurements, stent models were created and virtually deployed, and the results were compared with in vivo digital subtraction angiography and Doppler ultrasound images. The models were capable of reproducing in vivo observations, including velocity waveforms measured in the parent artery, peak velocity values measured in the aneurysm, and flow structures observed with digital subtraction angiography before and after deployment of flow diverters. The results indicate that regions of aneurysm occlusion after flow diversion coincide with slow and smooth flow patterns, whereas regions still permeable at the time of animal sacrifice were observed in parts of the aneurysm exposed to larger flow activity, that is, higher velocities, more swirling, and more complex flow structures. Copyright © 2014 John Wiley & Sons, Ltd.

AbstractObjectivesUrinary tract infection (UTI) is the most common infectious complication after kidney transplantation. We aim to determine its impact on allograft function as indicated by several measures such as iothalamate glomerular filtration rate (iGFR), estimated glomerular filtration rate (eGFR), and creatinine value.MethodsWe performed a single‐center retrospective cohort study to determine the impact ofUTIon kidney allograft outcome.ResultsThe study population consisted of 301 kidney transplant recipients; 84% were living donor transplants. One hundred and one patients (34%) developed at least one episode ofUTIand the incidence ofUTIduring the first year after transplantation was 25%. At the end of the follow‐up, theiGFRwas lower among patients who had developed at least oneUTI(p = 0.044). However,eGFRand creatinine values were not significantly different betweenUTIand non‐UTIgroups.ConclusionWhen kidney function was measured byeGFRand creatinine, there was no significant difference in allograft function between kidney recipients with or withoutUTI. However, when kidney function was measured by nuclear studies, there was a tendency toward impairment in allograft function among patients who developed atleast oneUTIafter transplantation.

Flow diversion treatment of cerebral aneurysms has increasingly been considered, especially for large complex aneurysms with wide necks that are difficult to treat with coils of by clipping. However, the relationship between the hemodynamic environment created immediately after implantation of flow diverters (FD) and the subsequent aneurysm occlusion is poorly understood [1].

Endovascular coiling is the most common treatment for cerebral aneurysms. The treatment consists of deploying coils of different shapes and sizes into the aneurysm with the intent of reducing blood flow therein. While the treatment has been shown to be more effective than conventional surgical methods, it is successful in only 50–80% of cases, depending on the type of aneurysm [1]. Treatment success has been correlated with favorable post-treatment hemodynamics [2]. Understanding of the effects of coils on post-treatment hemodynamics is limited, however, due to limited in-vivo and in-vitro flow measurement techniques. Previous computational studies have also suffered from drastic assumptions about coil geometry.

Since treatment of cerebral aneurysms with flow diverters (FD) has gained much attention in recent years, it is important to understand what is the effect of these devices on the flow through arteries jailed or crossed by these devices [1].

Prior to the 1970s, severe cases of antineutrophil cytoplasmic antibody associated vasculitis (AAV) were thought to be invariably fatal. However, the use of cyclophosphamide-based treatment regimens fundamentally altered disease outcomes, transforming AAV into a manageable, chronic illness. Despite the tremendous success of cyclophosphamide in the treatment of AAV, there remained a need for alternative therapies, due to high rates of treatment failures and significant toxicities. In recent years, with the introduction of targeted biologic response modifiers into clinical practice, many have hoped that the treatment options for AAV could be expanded. Rituximab, a chimeric monoclonal antibody directed against the B-lymphocyte protein CD20, has been the most successful biologic response modifier to be used in AAV. Following the first report of its use in AAV in 2001, experience with rituximab for treatment of AAV has rapidly expanded. Rituximab, in combination with glucocorticosteroids, is now well established as a safe and effective alternative to cyclophosphamide for remission induction for severe manifestations of granulomatosis with polyangiitis and microscopic polyangiitis. In addition, initial experiences with rituximab for remission maintenance in these diseases have been favorable, as have experiences for remission induction in eosinophilic granulomatosis with polyangiitis.

Abstract The American Joint Committee on Cancer/Union Internationale Contre le Cancer ( AJCC / UICC ) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression‐based stratification. These parameters rely on tumour‐cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named ‘Immunoscore’ has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC / UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC / UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM ‐I ( TNM ‐Immune). © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.