Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients

Hepatitis C virus (HCV) re-infection of the graft is universal and interferon based antiviral therapy remains at present the treatment of choice in HCV liver transplant recipients. Apart from the antiviral effects, interferon and ribavirin have both potent immunomodulatory properties resulting in a broad range of immune-related disorders including acute cellular rejection and chronic ductopenic rejection as well as de novo autoimmune hepatitis. Further complicating the picture, HCV infection per se is associated with a variety of autoimmune phenomena. We discuss here the immune-mediated complications and their relationship to chronic HCV and interferon based antiviral therapy.     

Development of a novel, physiologically relevant cytotoxicity model: Application to the study of chemotherapeutic damage to mesenchymal stromal cells

There is an increasing need for development of physiologically relevant in-vitro models for testing toxicity, however determining toxic effects of agents which undergo extensive hepatic metabolism can be particularly challenging. If a source of such metabolic enzymes is inadequate within a model system, toxicity from prodrugs may be grossly underestimated. Conversely, the vast majority of agents are detoxified by the liver, consequently toxicity from such agents may be overestimated.In this study we describe the development of a novel in-vitro model, which could be adapted for any toxicology setting. The model utilises HepG2 liver spheroids as a source of metabolic enzymes, which have been shown to more closely resemble human liver than traditional monolayer cultures. A co-culture model has been developed enabling the effect of any metabolised agent on another cell type to be assessed. This has been optimised to enable the study of damaging effects of chemotherapy on mesenchymal stem cells (MSC), the supportive stem cells of the bone marrow. Several optimisation steps were undertaken, including determining optimal culture conditions, confirmation of hepatic P450 enzyme activity and ensuring physiologically relevant doses of chemotherapeutic agents were appropriate for use within the model. The developed model was subsequently validated using several chemotherapeutic agents, both prodrugs and active drugs, with resulting MSC damage closely resembling effects seen in patients following chemotherapy.Minimal modifications would enable this novel co-culture model to be utilised as a general toxicity model, contributing to the drive to reduce animal safety testing and enabling physiologically relevant in-vitro study.     

Incremental value of real-time ultrasound elastography in differentiating breast masses

Aim of the work

To evaluate the value of real-time ultrasound elastography (RTE) in differentiating benign from malignant breast masses.

Materials and methods

This study included, whether palpable or non-palpable, 145 sonographically proven breast masses in 121 patients, imaged by conventional B-mode US, color-flow Doppler US and RTE with histopathological analysis considered as the golden standard reference.

Results

Lesions were differentiated into benign and malignant by conventional B-mode US (79; 45.5% and 66; 54.5%, respectively), RTE (80; 55.2% and 65; 44.8% respectively), and histopathology (82; 56.6% and 63; 43.4%, respectively). The mean difference in the mass size was significant between B-mode US and RTE in malignant masses (P = 0.002), while not significant among benign masses (P = 0.153). The B-mode US depicted sensitivity of 92.06%, specificity of 90.24%, PPV of 87.88%, NPV of 93.67% and accuracy of 91.03%, while the RTE showed sensitivity of 98.41%, specificity of 96.34%, PPV of 95.38%, NPV of 98.75% and accuracy of 97.24%.

Conclusion

Combined use of RTE can complement conventional B-mode US with improving its diagnostic performance in differentiating breast lesions with subsequent reduction in the rate of unnecessary biopsies in benign lesions.     

The dopaminergic stabilizer ASP2314/ACR16 selectively interacts with D2High receptors

Dopaminergic stabilizers are recognized as compounds that can either enhance or antagonize dopamine (DA)‐dependent behaviors depending on the prevailing dopaminergic tone. The dopaminergic stabilizer ASP2314 is being tested clinically and has been reported to have antipsychotic effects in a clinical trial as an add on medication. To elucidate the mechanisms of action of this dopaminergic stabilizer, its potency on the functional dopamine D2^High receptors was examined. In competition with D2 receptors selectively labeled by [³H]domperidone, ASP2314 had a dissociation constant, Ki^High, of 1.62 μM for D2^High in human cloned D2Long receptors and 0.83 μM for rat homogenized striata. Using the D2 agonist ligand [³H](+)‐4‐propyl‐3,4,4a,5,6,10b‐hexahydro‐2H‐naphtho[1,2‐b][1,4]oxazin‐9‐ol ((+)PHNO), ASP2314 had a high‐affinity K_i of 32 nM for D2^High for rat homogenized striata. ASP2314 stimulated the incorporation of [³⁵S]GTP‐γ‐S into rat striata by 50% at 43 nM, and into the cloned D2Long membranes by 50% at 3.2 μM (compared to 100% stimulation by 10 μM dopamine). With similar concentrations of ASP2314 inhibiting the binding of ligands at D2^High and stimulating [³⁵S]GTP‐γ‐S incorporation, the data indicate that the dopaminergic stabilizing action of ASP2314 may be related to the selectivity for the D2^high state of the D2 receptor. Synapse 63:930–934, 2009. © 2009 Wiley‐Liss, Inc.     

Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review

OBJECTIVES: To conduct a systematic review of incidence and prevalence studies of rheumatoid arthritis (RA), based on the 1987 revised American College of Rheumatology (ACR) criteria, to compare their methodologies and summarize their results, and to investigate the possible geographic variations and changes over time in the frequency of the disease. METHODS: We conducted a Medline search between January 1988 and December 2005. Studies reporting the incidence and prevalence of RA in adult populations (16 to 20 years and over), based on 1987 ACR criteria, were eligible for inclusion. From each study included, we extracted the country, year of publication, type of study (retrospective, prospective, or cross-sectional), and incidence or prevalence rates. The study areas were grouped into (a) North American countries; (b) north European countries; (c) south European countries; and (d) developing countries. We examined the geographical differences of prevalence and incidence rates using the Mann-Whitney and the Kruskall-Wallis tests. RESULTS: A total of 28 studies were identified meeting the inclusion criteria. Nine were incidence studies, 17 were prevalence studies, and 2 estimated both prevalence and incidence rates. Incidence studies were not available from developing countries. There is a significant difference of prevalence estimates between northern European and American countries and developing countries. South European countries have lower median incidence rates than North American and north European countries. As concerning the time trends of RA occurrence, only 3 incidence studies provided secular data from the same study area, based on ACR criteria, using the same methods of case ascertainment. Two of these studies indicate a decreasing incidence of RA in Finland and United States of America. CONCLUSIONS: The occurrence of RA varies among countries and areas of the world. A decreasing trend has been observed in countries characterized by high rates of RA incidence and prevalence. However, the relatively small number of studies for most areas of the world and the lack of incidence studies for the developing countries limits the understanding of worldwide RA epidemiology.     

Imaging in Heart Transplant Patients

Heart transplantation is an accepted treatment for select patients with end-stage heart failure. Improvements to immunosuppressive therapies and patient management have increased the half-life of heart transplant patients to over 10 years. Despite this success, rejection remains the “Achilles heel” of heart transplantation. The early detection of acute rejection and cardiac allograft vasculopathy are paramount to avoiding graft loss. Unlike in kidney and liver transplantation, there are no clinically validated biomarkers for detecting heart transplant rejection. Existing methods for monitoring the cardiac allograft are invasive. The endomyocardial biopsy is the standard-of-care for monitoring for acute rejection but carries risks of complications, and histologic assessment is often subjective. Equally, intracoronary angiography remains the standard-of-care for detecting cardiac allograft vasculopathy, but it is invasive and less than ideally sensitive. Newer echocardiographic techniques, computed tomography, magnetic resonance, and positron emission tomography are less invasive than conventional biopsy and show promise in excluding rejection thereby potentially decreasing the frequency of biopsies in low-risk patients. Intravascular ultrasonography and optical coherence tomography, although still invasive, improve on the assessment of the coronary tree through increased resolution, evaluation of the microvasculature, and visualization of the vessel wall. This review outlines the invasive and noninvasive imaging modalities that are employed in the routine care of heart transplant patients and examines newer techniques that are under evaluation.     

Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells

Pancreatic cancer is a serious healthcare problem worldwide because of its high mortality. Gemcitabine, a DNA synthesis inhibitor, is the standard first-line treatment for advanced pancreatic cancer and is also expected as a key drug for the combination therapy of this malignancy. Retinoids, which are derivatives of vitamin A, exert anti-tumor effects in various types of human malignancies, including pancreatic cancer. This study examined whether combination therapy with gemcitabine and acyclic retinoid (ACR), a new synthetic retinoid, had enhanced anti-tumor efficacy in pancreatic cancer. ACR, 9-cis-retinoic acid and gemcitabine preferentially inhibited the growth of human pancreatic cancer cells (Panc-1 and KP-2) in comparison to PE normal human pancreatic epithelial cells. The combination of ACR plus gemcitabine synergistically inhibited the growth of Panc-1 cells. The combined treatment with these two agents also acted synergistically to induce apoptosis and to inhibit Ras activation in these cancer cells. In vivo, the combination therapy augmented tumor growth inhibition through the induction of apoptosis and inhibition of cell proliferation in tumor tissue. These results suggest that the combination of ACR plus gemcitabine may therefore be an effective regimen for the chemotherapy of pancreatic cancer.     

Low Back Pain in the Emergency Department—Are the ACR Appropriateness Criteria Being Followed?

PurposeTo assess the prevalence of appropriate imaging among emergency department (ED) patients with low back pain.MethodsOur level-1 ED records were retrospectively searched for patients with a chief compliant of “low back pain” from January to April 2013. Of 624 patients, 100 were randomly selected and analyzed for their demographics, presentation, imaging, treatment, and outcomes. The study indication for imaging was compared with the ACR Appropriateness Criteria, and the indication was deemed appropriate if it received a rating of ≥5.ResultsThe mean age of the study population was 48 years (50% women, 50% men). The majority presented with acute or acute on chronic low back pain (94 patients), and half had a precipitating event (50 patients). A total of 28 (28%) patients underwent imaging in the ED; 24 (24%) had outpatient imaging; 54 (54%) had neither ED nor outpatient imaging. In all, 96% (27 of 28) of patients imaged in the ED, and 96% (23 of 24) imaged as outpatients, were appropriately imaged. Of patients who did not undergo imaging, 96% (52 of 54) were appropriately not imaged. A total of 76 patients (76%) had follow-up after discharge: of these, 42 (55%) had resolution or return of pain to baseline with conservative management; 18 (24%) had improvement with intervention (epidural steroid injection or kyphoplasty); 8 (10%) improved with surgery; and 8 had persistent pain (11%).ConclusionsThe majority of patients presenting to the ED with low back pain did not undergo imaging. The vast majority of those who underwent imaging were appropriately imaged, based on the ACR Appropriateness Criteria.     

阿克拉霉素A治疗恶性淋巴瘤23例临床研究

阿克拉霉素A(ACR)是一种新的蒽环类抗肿瘤抗生素,动物模型研究表明其心脏毒性较低。我们对23例经病理确诊的恶性淋巴瘤患者进行了前瞻性研究,其中20例可评价疗效,23例均町评价毒性反应。我们采用了两种剂量方案:ACR12.5mg/m~2/日×5天;25mg/m~2/日×3天。结果表明:本组总有效率为55％(11/20),其中3例(15％)获CR,8例(40％)为PR。胃肠道毒性常见但不严重。血液学毒性为剂量限制性毒性,表现为轻到中度的骨髓抑制。腹泻、口腔炎及静脉炎少见,无脱发及充血性心衰。全组有4例出现不伴临床症状的ECG改变,发生率为17.4％。对于ACR治疗淋巴瘤的合适剂量方案及远期作用尚需进一步研究。