Hepatitis E virus infection in the liver transplant recipients:Clinical presentation and management

Hepatitis E virus(HEV) is an emerging pathogen and an increasingly recognized cause of graft hepatitis, especially in the post-orthotopic liver transplantation immunocompromised population. The exact incidence and prevalence of HEV infection in this population remains unclear but is certainly greater than historical estimates. Identifying acute HEV infection in this population is imperative for choosing the right course of management as it is very difficult to distinguish histologically from acute rejection on liver biopsy. Current suggested approach to manage acute HEV involves modifying immunosuppression, especially discontinuing calcineurin inhibitors which are the preferred immunosuppressive agents post-orthotopic liver transplantation. The addition of ribavirin monotherapy has shown promising success rates in clearing HEV infection and is used commonly in reported cases.     

Major comorbid disease processes associated with increased incidence of acute kidney injury

Acute kidney injury (AKI) is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS). This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including: Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co-morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI.     

CT screening for lung cancer: prevalence and incidence of mediastinal masses

PURPOSE: To determine the frequency and natural course of mediastinal masses in asymptomatic people at high risk for lung cancer who were undergoing computed tomographic (CT) screening. MATERIALS AND METHODS: Informed consent and institutional review board approval for this HIPAA-compliant study were obtained at each participating institution. All documented mediastinal masses among the 9263 baseline and 11 126 annual repeat screenings performed in the Early Lung Cancer Action Project (ELCAP) and its successor project, the New York ELCAP, were identified. Two radiologists confirmed all cases, identified the location and measured the diameter (average of length and width) of each mass, and reviewed all subsequent CT and clinical and surgical results. The prevalence and incidence of mediastinal masses were then determined. RESULTS: Of the 9263 individuals, 71 had a mediastinal mass seen at baseline screening (prevalence of 0.77%). Of the 71 masses, 41 were thymic, 16 were thyroidal, two were esophageal cancers, six were tracheal-esophageal diverticula, and six were other masses. Among the 11 126 annual repeat screenings, only one new mediastinal mass was identified (incidence of 0.01%). This suggests a long average duration for mediastinal masses in asymptomatic people. Among the 41 thymic masses, five were larger than 3.0 cm in diameter, and all five were resected; of these five, one was a thymic carcinoma and four were noninvasive thymomas. Of the remaining 36 thymic masses, 25 were evaluated at follow-up CT 1 year later: Five had increased in diameter, two had decreased, and 18 remained unchanged. All 16 thyroid masses were due to goiter; none of these were changed at follow-up CT 1 year later. CONCLUSION: Mediastinal masses found in the context of CT screening for lung cancer in asymptomatic people should be approached in a "conservative" manner; this includes thymic masses smaller than 3 cm in diameter, as most of these remain unchanged or even decrease in size.     

Diagnosing and phenotyping visual synaesthesia: a preliminary evaluation of the revised test of genuineness (TOG-R)

Synaesthesia, a neurological condition affecting approximately .05% of the population, is characterised by anomalous sensory perception: a stimulus in one sensory modality triggers an automatic, instantaneous, consistent response in another modality (e.g., sound evokes colour) or in a different aspect of the same modality (e.g., black text evokes colour). As evidence was limited to case studies based on self-report, the existence of synaesthesia was regarded with scepticism until the development of the Test of Genuineness (TOG) in 1987, which measures the consistency of stimulus-response linkage: synaesthetes typically score between 70-90% range, whereas controls typically score between 20-38%. However, the TOG had only limited ability to quantify the characteristics of visual synaesthesia. In this study, the revised Test of Genuineness (TOG-R), utilising the Pantone-based Cambridge Synaesthesia Charts, was given to 26 synaesthetes and 23 controls. Results confirmed that the TOG-R is equally accurate in the diagnosis of synaesthesia; synaesthetes scored significantly (t47 = 16.01, p < .001) higher (mean = 71.3%, SEM = 1.4%) than controls (mean = 33%, SEM = 2.0%). The TOG-R provides greater precision in quantifying the closeness of colour matches and enables a more detailed analysis of visual synaesthesia. Synaesthetes were phenotyped into broad- and narrowband based on their overall responsiveness to auditory stimuli, with bandwidth determined primarily by responsiveness to non-word stimuli. They were further sub-phenotyped based on responses to sub-groups of stimuli into word-colour (WC) and music-colour (MC). Development of this instrument has important implications for the diagnosis and phenotyping of visual synaesthesia.     

Biochemical,histopathological, and transmission electron microscopic ultrastructural changes in mice after exposure to silver nanoparticles

Four‐week‐old mice, weighing about 25–35 g were divided into five groups (8 mice in each group): vehicle control, low‐ (0.5 g/kg), middle‐ (1 g/kg), high‐ (3 g/kg), and exceptionally high‐dose (5 g/kg). After first and second weeks of intraperitoneal exposure to AgNPs, biochemical, histopathological, and electron microscopic ultrastructural changes were investigated. No significant changes were observed in SGOT and ALP levels after first week of exposure, while the level of SGPT significantly increased (p < 0.05) in 2nd week treated mice, indicating that inflammatory of liver might be induced by high‐dose (3 and 5 g/kg) of AgNPs. No obvious changes were observed for UA and BUN in all groups of treated mice. However, significant (p < 0.05) decrease in CR level was noticed in all groups of treated mice only at high‐dose (3 and 5 g/kg). No remarkable changes in lipid profile were observed. Light microscopic histopathological investigation shows that first week treatment had not perceptible effect on the cytoarchitecture on liver, kidney, and spleen; while, second week treatment had only sporadic mild effects on these organs. However, no ultrastructural electron microscopic changes were observed in liver, kidney, and spleen of mice treated with 0.5, 1, and 3 g/kg of AgNPs when sacrificed on first and second week; while, exceptionally high‐dose (5 g/kg) of AgNPs resulted in slight nuclear chromatin condensation and irregularities in nuclear membrane. The results suggested that AgNPs could be well tolerated in mice when given intraperitoneally and no death has been found during the experiment in any groups of treated mice. Interestingly, significant (<0.05) decrease in glucose levels in all experiment group is suggestive of curious hypoglycemic role of AgNPs warranting further study to explore its possible therapeutic potential in hyperglycemic conditions as well as its mechanism of action at molecular level. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 945–956, 2016.     

Is miR‐34a a Well‐equipped Swordsman to Conquer Temple of Molecular Oncology?

Overwhelmingly increasing advancements in miRNA biology have opened new avenues for pharmaceutical companies to initiate studies on designing effective, safe, and therapeutically active candidates using miRNA mimetics and miRNA inhibitors. In accordance with this approach, development of miravirsen and SPC3649, an LNA‐based (locked nucleic acid) antisense molecule against miR‐122, to treat hepatitis C has sparked interest in identifying most efficient microRNAs for journey from bench‐top toward pharmaceutical industry and breakthroughs in delivery technology will pave the way to ‘final frontier’. MRX34, a liposome‐formulated mimic of miR‐34 for treatment of metastatic cancer with liver involvement and unresectable primary liver cancer, has also entered in clinical trial. There is a successive increase in the research work related to miR‐34 biology and miRNA regulation of modulators of intracellular signaling cascades. We partition this review into how miR‐34a is regulated by different proteins and how Wnt‐ and TGF‐induced intracellular signaling cascades are modulated by miR‐34a. In this review, we bring to limelight how miR‐34a regulates its target genes to induce apoptosis and inhibit cell proliferation as evidenced by in vitro and in vivo analysis. We also discuss miR‐34 regulation of PDGFR and c‐MET and recent advancements in nanotechnologically delivered miR‐34a. Spotlight is also set on modulation of chemotherapeutic sensitivity by miR‐34a in cancer cells using reconstruction studies. Clinical trial of miR‐34 is indicative of its tremendous potential, and continuous cutting research will prove to be effective in efficiently translating laboratory findings into clinically effective therapeutics.     

Patients’ perception toward various dental treatments provided in the internship program

Objectives:

To evaluate patients’ perception regarding treatment and environment in the interns’ clinic at a university dentistry clinic.

Methods:

This cross-sectional study was conducted between July 2012 to May 2013 at the College of Dentistry, University of Dammam, Dammam, Kingdom of Saudi Arabia. A self-directed questionnaire was distributed to 220 randomly selected patients, and the response rate was approximately 68%. Patients’ were asked regarding dentists’ behavior, treatment, and clinical environment along with their demographics, and socioeconomic status.

Results:

Out of the 220 randomly selected patients, 150 participated in the study. The average age of a respondent was 32.5 years (±14.5), 89 of the 150 participants were Saudi nationals. Collectively, 86% were satisfied with the doctors’ behavior, and approximately 94% responded that the dentist listens to their concerns. Most (83%) were satisfied with the treatment plan provided by the interns.

Conclusion:

The findings in this study showed that more than 80% of the participants were satisfied with the quality of treatment and clinical environment. The dissatisfaction rate was minimal (13%) and for this reason, it is difficult to establish the factors for patients dissatisfaction.Evaluation of patients’ satisfaction and meeting their expectations helps to quantify quality of services provided to them. Identifying patient expectations by obtaining their feedback helps to improve the quality of services provided in the clinics. In an academic institution, it is crucial to evaluate quality of care provided to patients. An increase in the number of satisfied patients increases patient cooperation, and motivation.1 Patients’ attitude toward health care experience develops over time, and can be influenced by numerous factors.2 Overall satisfaction is also influenced by the age of a patient, and when satisfaction was related to communication, young male participants produced a higher satisfaction score than other respondents.3,4 Furthermore, a direct relation was found between education level and patients’ satisfaction, and low income group consistently produced low satisfaction scores.5,6 However, features such as neatness, comfort of seating, magazine selection, and background music of the clinic facilities have been reported to influence patient perceptions.7 The College of Dentistry in the University of Dammam facilitates its students by providing them a one year internship program. After finishing course work, students must serve one year in the clinics under the supervision of a faculty member to enhance their skills. The aim of this study was to evaluate patients who visited the interns’ clinics regarding treatment they received, and their satisfaction with the treatment, and clinical environment.     

ROBO1, a tumor suppressor and critical molecular barrier for localized tumor cells to acquire invasive phenotype: Study in African‐American and Caucasian prostate cancer models

High‐risk populations exhibit early transformation of localized prostate cancer (CaP) disease to metastasis which results in the mortality of such patients. The paucity of knowledge about the molecular mechanism involved in acquiring of metastatic behavior by primary tumor cells and non‐availability of reliable phenotype‐discriminating biomarkers are stumbling blocks in the management of CaP disease. Here, we determine the role and translational relevance of ROBO1 (an organogenesis‐associated gene) in human CaP. Employing CaP‐progression models and prostatic tissues of Caucasian and African‐American patients, we show that ROBO1 expression is localized to cell‐membrane and significantly lost in primary and metastatic tumors. While Caucasians exhibited similar ROBO1 levels in primary and metastatic phenotype, a significant difference was observed between tumor phenotypes in African‐Americans. Epigenetic assays identified promoter methylation of ROBO1 specific to African‐American metastatic CaP cells. Using African‐American CaP models for further studies, we show that ROBO1 negatively regulates motility and invasiveness of primary CaP cells, and its loss causes these cells to acquire invasive trait. To understand the underlying mechanism, we employed ROBO1‐expressing/ROBO1‐C2C3‐mutant constructs, immunoprecipitation, confocal‐microscopy and luciferase‐reporter techniques. We show that ROBO1 through its interaction with DOCK1 (at SH3‐SH2‐domain) controls the Rac‐activation. However, loss of ROBO1 results in Rac1‐activation which in turn causes E‐Cadherin/β‐catenin cytoskeleton destabilization and induction of cell migration. We suggest that ROBO1 is a predictive biomarker that has potential to discriminate among CaP types, and could be exploited as a molecular target to inhibit the progression of disease as well as treat metastasis in high‐risk populations such as African‐Americans.     

Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts

Purpose

To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.

Methods

H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.

Results

In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.

Conclusions

High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.