bluuebunny/crossref_metadata_2025 huggingface dataset:
Gonadotropin Ratio Affects the In Vitro Growth of Rhesus Ovarian Preantral Follicles
Authors: Kim Yoon Young , Yun Jun-Won , Kim Jong Min , Park Chung Gyu , Rosenwaks Zev , Liu Hung Ching , Kang Byeong-Cheol , Ku Seung-Yup
Published: May 2016

In vitro follicle growth (IVFG) strategy is critical in the fertility preservation of cancer survivors; however, its optimal protocol needs to be developed using primate models since the availability of human samples is limited. Only a few previous studies have reported the successful IVFG of rhesus monkey ovaries using low-dose follicle-stimulating hormone (FSH) (0.3 or 3 ng/mL) and long-term culture (up to 5 weeks) and it is still uncertain in regard to the optimal culture duration and effective dose of treated gonadotropins applicable to the IVFG of rhesus preantral follicles. Recently, we have reported that the FSH to luteinizing hormone (LH) ratio affects the in vitro growth of murine ovarian follicles. We aimed to investigate whether gonadotropin ratios affect the efficiency of rhesus follicular growth in vitro. Ovaries were collected from six necropsied rhesus macaques (4–9 years) and preantral follicles were retrieved and cultured for 14 days using 200 mIU/mL FSH. The characteristics of follicular growth were compared between the FSH:LH=1:1 (n=24) and FSH:LH=2:1 (n=24) groups. High concentration gonadotropin treatment shortened the duration required for in vitro maturation of rhesus preantral follicles. The FSH:LH=2:1 group showed a faster follicular growth and enabled the acquisition of mature oocytes, although the expression of growth differentiation factor (GDF)-9 and anti-Müllerian hormone (AMH) did not differ significantly between the two groups. Taken together, high dose gonadotropin treatment can shorten the duration of IVFG and the gonadotropin ratio is important in the IVFG of rhesus monkey ovaries.
Lipoprotein(A) Level and Mif Gene Variant Predict Incident Metabolic Syndrome and Mortality
Authors: Onat Altan , Can Günay , Çoban Neslihan , Dönmez İbrahim , Çakır Hakan , Ademoğlu Evin , Erginel-Ünaltuna Nihan , Yüksel Hüsniye
Published: May 2016

Owing to the scarcity of available information, we aimed to assess the association of migration inhibitory factor (MIF)-173 G/C genotypes and serum lipoprotein(Lp)(a) with incident metabolic syndrome (MetS) and all-cause mortality, respectively. In population based, middle-aged adults (n=1297), stratified by gender and presence of MetS, we used Lp(a) quintiles to identify non-linear associations with outcomes using Cox regression models, adjusted for MIF genotype, age, smoking status, high density lipoprotein cholesterol, and systolic blood pressure. After 5.2 years of follow-up, 151 cases of incident MetS and 123 deaths were recorded. For incident MetS, adjusted HRs increased in each gender across four declining quintiles, starting from the highest quintile in men and from quintile 4 in women. The MIF CC-GC genotype appeared to contribute to the risk estimates in men. Similarly adjusted models in the whole sample disclosed that all-cause mortality tended to be inversely associated with Lp(a) quintiles and yielded an HR (2.42 (95% CI 1.03 to 5.81)) in men in quintile 2, whereas the MIF genotype additively predicted mortality (HR 1.79 (95% CI 1.01 to 3.18)) only in men. Excess risk of death was additively conferred on Turkish men by the MIF CC-GC genotype and by apparently reduced circulating Lp(a) assays, supporting the notion that ‘low’ serum Lp(a), mediating autoimmune activation, is a major determinant of metabolic disease risk and death. Damaged MIF protein and more complex autoimmune activation in women may be responsible from lack of relationship to MetS/mortality.
Investigational New Drug Applications: A 1-Year Pilot Study on Rates and Reasons for Clinical Hold
Authors: Lapteva Larissa , Pariser Anne R
Published: May 2016

Background

The Food and Drug Administration (FDA)'s Center for Drug Evaluation and Research (CDER) receives about 1500 initial Investigational New Drug applications (INDs) per year. In the first 30 days after initial IND submission, FDA conducts a review to determine whether the proposed investigation is safe to proceed, and if not, the IND may be placed on clinical hold.

Methods

A retrospective study of rates and reasons for clinical hold for all initial INDs submitted to CDER in fiscal year (FY) 2013 was performed. INDs were assessed for reasons that led to clinical hold, included chemistry, manufacturing and controls (CMC), animal toxicology or clinical issues. INDs were further categorized by commercial versus research sponsorship, and rare versus common disease indications. All INDs placed on hold were reassessed by whether they remained on hold within the first year following hold imposition.

Results

CDER received 1410 initial INDs in FY 2013, of which 125 (8.9%) were placed on hold during the first 30 days after initial submission. Of the INDs placed on hold, more than half became active within the first year after first imposition of hold. CMC reasons were most commonly cited, followed by clinical, then toxicology reasons. There were no substantive differences in rates and reasons for hold between INDs for rare or common disease indications, or between commercial or research INDs.

Conclusions

The vast majority of initial INDs moved forward within 30 days after submission, and for those applications placed on hold, most became active within 1 year. The findings also suggest that many holds for new drug product programs can be avoided by following the available guidelines for investigational product development.
Assessment of the Effect of Continuous Sedation with Mechanical Ventilation on Adrenal Insufficiency in Patients with Traumatic Brain Injury
Authors: Li Min , Zhang Ying , Wu Kang-Song , Hu Ying-Hong
Published: May 2016

The aim of this study was to assess the effect of continuous propofol sedation plus prolonged mechanical ventilation on adrenal insufficiency (AI) in patients with traumatic brain injury (TBI). Eighty-five adult patients diagnosed with moderate TBI (Glasgow Coma Scale (GCS) score 9–13) from October 2011 to October 2012 were included in this prospective study. The patients comprised three groups: no mechanical ventilation and sedation (n=27), mechanical ventilation alone (n=24) and mechanical ventilation plus sedation (n=34). The low-dose short Synacthen test was performed at 8:00 on the first, third, and fifth days after TBI. Logistic regression analysis was performed to identify factors affecting the use of mechanical ventilation and sedation, and the incidence of AI. On the fifth day after injury, the mean baseline cortisol and simulated cortisol levels were significantly lower in the mechanical ventilation plus sedation group compared with the other two groups. Multivariate regression analysis showed that the Acute Physiology and Chronic Health Evaluation (APACHE) score was independently associated with treatment with mechanical ventilation and sedation compared to mechanical ventilation alone. Furthermore, hypoxemia on admission and shock were associated with the development of AI. The findings showed that sedation is associated with an increased incidence of AI. Patients with TBI who are treated with continuous sedation should be monitored for AI carefully.
Oxidative Challenge in Alzheimer's Disease: State of Knowledge and Future Needs
Authors: Cervellati Carlo , Wood Paul L , Romani Arianna , Valacchi Giuseppe , Squerzanti Monica , Sanz Juana Maria , Ortolani Beatrice , Zuliani Giovanni
Published: May 2016

A large body of experimental and postmortem findings indicate that Alzheimer's disease (AD) is associated with increased oxidative stress (OxS) levels in the brain. Despite the current limitations of OxS assessment in living subjects, recent data suggest that oxidative challenge might increase early both in the central nervous system and peripheral fluids. The aim of this review was to provide an overview of the existing literature linking systemic OxS to brain OxS in AD. We firmly believe that continued research aimed at overcoming the methodological and design issues affecting the body of studies in this field is mandatory for successful development of an effective antioxidant-based treatment of AD.
Pharmacological Priming of Adipose-Derived Stem Cells Promotes Myocardial Repair
Authors: Burchfield Jana S , Paul Ashley L , Lanka Vishy , Tan Wei , Kong Yongli , McCallister Camille , Rothermel Beverly A , Schneider Jay W , Gillette Thomas G , Hill Joseph A
Published: May 2016

Adipose-derived stem cells (ADSCs) have myocardial regeneration potential, and transplantation of these cells following myocardial infarction (MI) in animal models leads to modest improvements in cardiac function. We hypothesized that pharmacological priming of pre-transplanted ADSCs would further improve left ventricular functional recovery after MI. We previously identified a compound from a family of 3,5-disubstituted isoxazoles, ISX1, capable of activating an Nkx2-5-driven promoter construct. Here, using ADSCs, we found that ISX1 (20 mM, 4 days) triggered a robust, dose-dependent, fourfold increase in Nkx2-5 expression, an early marker of cardiac myocyte differentiation and increased ADSC viability in vitro. Co-culturing neonatal cardiomyocytes with ISX1-treated ADSCs increased early and late cardiac gene expression. Whereas ISX1 promoted ADSC differentiation toward a cardiogenic lineage, it did not elicit their complete differentiation or their differentiation into mature adipocytes, osteoblasts, or chondrocytes, suggesting that re-programming is cardiomyocyte specific. Cardiac transplantation of ADSCs improved left ventricular functional recovery following MI, a response which was significantly augmented by transplantation of ISX1- pretreated cells. Moreover, ISX1-treated and transplanted ADSCs engrafted and were detectable in the myocardium 3 weeks following MI, albeit at relatively small numbers. ISX1 treatment increased histone acetyltransferase (HAT) activity in ADSCs, which was associated with histone 3 and histone 4 acetylation. Finally, hearts transplanted with ISX1-treated ADSCs manifested significant increases in neovascularization, which may account for the improved cardiac function. These findings suggest that a strategy of drug-facilitated initiation of myocyte differentiation enhances exogenously transplanted ADSC persistence in vivo, and consequent tissue neovascularization, to improve cardiac function.
Assessment of Right Ventricular Systolic and Diastolic Parameters in Pulmonary Sarcoidosis
Authors: Ipek Emrah , Demirelli Selami , Ermis Emrah , Yıldırım Erkan , Öztürk Mustafa , Yolcu Mustafa , Araz Ömer , Kalkan Kamuran
Published: May 2016

The clinical manifestations of cardiac involvement are seen in about 5% of patients with sarcoidosis; however, the incidence of cardiac involvement is higher in the autopsy series. About 14% of patients with pulmonary sarcoidosis (PS) without known cardiac involvement had diastolic dysfunction.

We aimed to determine the role of parameters of right ventricular (RV) systolic and diastolic function in patients with PS without evidence of cardiac symptoms. Our study population consisted of 28 patients with grades 1–4 PS and 24 healthy subjects. This study was a clinical prospective cohort study. RV end-diastolic area was found to be significantly higher in the PS group (p=0.032). RV fractional area change (RVFAC) and tricuspid annular plane systolic excursion (TAPSE) were shown to be statistically lower in the PS group as compared to the control group (p<0.001). However, pulmonary arterial systolic pressure was significantly higher in the PS group (p=0.003). The tricuspid E velocity and E/A ratio were found to be significantly lower in the PS group (p=0.025 and 0.009, respectively), while the tricuspid A velocity and myocardial performance index (MPI) were found to be significantly lower in the control group (p=0.034 and 0.007, respectively). Early detection of cardiac involvement in PS is crucial because of the increased morbidity and risk of sudden cardiac death. RV diastolic Doppler parameters, tissue Doppler MPI, RVFAC and TAPSE are practical and cheap techniques in the diagnosis of cardiac involvement in patients with PS. A thorough transthorasic echocardiographic examination including RV systolic and diastolic functions and tissue Doppler MPI should constitute the mainstay of initial management and follow-up in PS.
Evaluation of Responses to Vitamin D3 (Cholecalciferol) in Patients on Dialysis: A Systematic Review and Meta-Analysis
Authors: Xu Chen , Li Yan-chun , Zhao Su-mei , Li Zhong-xin
Published: May 2016

Vitamin D plays a key role in mineral metabolism and its deficiency is often noted in patients on dialysis for end-stage renal disease (ESRD). We evaluated the efficacy and responses to vitamin D3 (cholecalciferol) in patients undergoing dialysis for ESRD. Randomized controlled trials or prospective studies comparing vitamin D3 supplementation to placebo in patients with ESRD on dialysis were searched from medical databases using the terms, ‘Calcitriol/Cholecalciferol, vitamin D, chronic kidney disease, hemodialysis, serum calcium, parathyroid hormones (PTH), phosphorus, 25(OH)D, and 1,25(OH)2D’. The outcomes analyzed were serum calcium, PTH, phosphorus, 25(OH)D, and 1,25(OH) 2D levels. Of the 259 records identified, 9 studies with a total of 368 patients were chosen for the current meta-analysis. The number of patients, age, and gender distribution among the groups were comparable. Results reveal a greater increase in both 25(OH)D (Pooled difference in means=0.434, 95% CI 0.174 to 0.694, p=0.001) and 1,25(OH) 2D (Pooled difference in means=0.978, 95% CI 0.615 to 1.34, p<0.001) in the treatment arm, as compared to the placebo. There was no difference in the serum calcium or PTH among the two groups. However, patients in the treatment arm had a significant increase in phosphorus levels (Pooled difference in means=0.434, 95% CI 0.174 to 0.694, p=0.001). Vitamin D supplementation facilitated the maintenance of increased levels of 25(OH) D and 1,25(OH) 2D in patients undergoing dialysis for ESRD. This increase in vitamin D was not associated with hypercalcemia or significant changes in PTH levels.
Development and Validation of a Composite Score for Excessive Alcohol Use Screening
Authors: Tu Wanzhu , Chu Chenghao , Li Shanshan , Liangpunsakul Suthat
Published: May 2016

This study was undertaken to develop a composite measure that combines the discriminant values of individual laboratory markers routinely used for excessive alcohol use (EAU) for an improved screening performance. The training sample consisted of 272 individuals with known history of EAU and 210 non-alcoholic individuals. The validation sample included 100 EAU and 75 controls. We used the estimated regression coefficients and the observed marker values to calculate the individual's composite screening score; this score was converted to a probability measure for excessive drinking in the given individual. A threshold value for the screening score based on an examination of the estimated sensitivity and specificity associated with different threshold values was proposed. Using regression coefficients estimated from the training sample, a composite score based on the levels of aspartate aminotransferase, alanine aminotransferase, per cent carbohydrate-deficient transferrin and mean corpuscular volume was calculated. The areas under the receiver operating characteristic curve (AUC) value of the selected model was 0.87, indicating a strong discriminating power and the AUC was better than that of each individual test. The score >0.23 corresponded to a sensitivity of 90% and a specificity of nearly 60%. The AUC value remained at a respectable level of 0.83 with the sensitivity and specificity at 91% and 49%, respectively, in the validation sample. We developed a novel composite score by using a combination of commonly used biomakers. However, the development of the mechanism-based biomarkers of EAU is needed to improve the screening and diagnosis of EAU in clinical practice.
Practical Prediction Model for the Risk of 2-Year Mortality of Individuals in the General Population
Authors: Goldfarb-Rumyantzev Alexander , Gautam Shiva , Brown Robert S
Published: May 2016

This study proposed to validate a prediction model and risk-stratification tool of 2-year mortality rates of individuals in the general population suitable for office practice use. A risk indicator (R) derived from data in the literature was based on only 6 variables: to calculate R for an individual, starting with 0, for each year of age above 60, add 0.14; for a male, add 0.9; for diabetes mellitus, add 0.7; for albuminuria >30 mg/g of creatinine, add 0.7; for stage ≥3 chronic kidney disease (CKD), add 0.9; for cardiovascular disease (CVD), add 1.4; or for both CKD and CVD, add 1.7. We developed a univariate logistic regression model predicting 2-year individual mortality rates. The National Health and Nutrition Examination Survey (NHANES) data set (1999–2004 with deaths through 2006) was used as the target for validation. These 12,515 subjects had a mean age of 48.9±18.1 years, 48% males, 9.5% diabetes, 11.7% albuminuria, 6.8% CVD, 5.4% CKD, and 2.8% both CKD and CVD. Using the risk indicator R alone to predict mortality demonstrated good performance with area under the receiver operating characteristic (ROC) curve of 0.84. Dividing subjects into low-risk (R=0–1.0), low intermediate risk (R>1.0–3.0), high intermediate risk (R>3.0–5.0) or high-risk (R>5.0) categories predicted 2-year mortality rates of 0.52%, 1.44%, 5.19% and 15.24%, respectively, by the prediction model compared with actual mortality rates of 0.29%, 2.48%, 5.13% and 13.40%, respectively. We have validated a model of risk stratification using easily identified clinical characteristics to predict 2-year mortality rates of individuals in the general population. The model demonstrated performance adequate for its potential use for clinical practice and research decisions.
Novel Myokine: Irisin May be An Independent Predictor for Subclinic Atherosclerosis in BehçEt'S Disease
Authors: Icli Abdullah , Cure Erkan , Cumhur Cure Medine , Uslu Ali Ugur , Balta Sevket , Arslan Sevket , Sakiz Davut , Kucuk Adem
Published: May 2016

Behçet's disease (BD) is a vasculitic and inflammatory disease causing endothelial dysfunction. Irisin is a metabolic hormone related to insulin resistance and endothelial functions. In this study, we investigated the relationship between irisin and carotid intima-media thickness (cIMT), which is a marker of atherosclerosis in patients with BD. 48 patients with BD and 50 healthy individuals were enrolled in the study. Disease severity was evaluated by BD current activity form. Irisin, glucose, insulin, C reactive protein, erythrocyte sedimentation rate and lipid panel were examined in all patients. Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was used to calculate insulin resistance. A simple and inexpensive cIMT test was used as indicator of atherosclerosis. cIMT was 0.62 (0.45–1.05) mm in the patients, while it was 0.38 (0.25–0.65) mm in the control group (p<0.001). Irisin value was found to be 197.3 (24.8–834.2) ng/mL in the control group, while it was 85.4 (4.7–471.1) ng/mL in the patient group (p=0.007). There was a negative correlation between irisin level and cIMT (r=−0.511, p<0.001) and HOMA-IR (r=−0.371, p=0.009). Decreased irisin levels (OR 0.996, 95% CI 0.992 to 1.000, p=0.041), male gender (OR 7.634, 95% CI 1.415 to 41.191, p=0.018), and HOMA-IR (OR 2.596, 95% CI 1.451 to 4.643, p=0.001) are independent risk factors for cIMT in patients with BD. We detected a very strong relationship between cIMT, which is an indicator of subclinical atherosclerosis, and decreased irisin levels in patients with BD. BD is characterized by chronic inflammation, and low serum irisin levels in BD may be related to atherosclerosis.
Detection of Chromosomal Changes in Chronic Lymphocytic Leukemia Using Classical Cytogenetic Methods and Fish: Application of Rich Mitogen Mixtures for Lymphocyte Cultures
Authors: Koczkodaj Dorota , Popek Sylwia , Zmorzyński Szymon , Wąsik-Szczepanek Ewa , Filip Agata A
Published: May 2016

One of the research methods of prognostic value in chronic lymphocytic leukemia (CLL) is cytogenetic analysis. This method requires the presence of appropriate B-cell mitogens in cultures in order to obtain a high mitotic index. The aim of our research was to determine the most effective methods of in vitro B-cell stimulation to maximize the number of metaphases from peripheral blood cells of patients with CLL for classical cytogenetic examination, and then to correlate the results with those obtained using fluorescence in situ hybridization (FISH). The study group involved 50 consecutive patients with CLL. Cell cultures were maintained with the basic composition of culture medium and addition of respective stimulators. We used the following stimulators: Pokeweed Mitogen (PWM), 12- O-tetradecanoylphorbol 13-acetate (TPA), ionophore, lipopolysaccharide (LPS), and CpG-oligonucleotide DSP30. We received the highest mitotic index when using the mixture of PWM+TPA+I+DSP30. With classical cytogenetic tests using banding techniques, numerical and structural aberrations of chromosomes were detected in 46 patients, and no change was found in only four patients. Test results clearly confirmed the legitimacy of using cell cultures enriched with the mixture of cell stimulators and combining classical cytogenetic techniques with the FISH technique in later patient diagnosing.
Hydroxychloroquine in Patients with Systemic Lupus Erythematosus with End-Stage Renal Disease
Authors: Bethel Monique , Yang Frances M , Li Shuang , Nahman N Stanley , Oliver Alyce M , Machua Wambui , Carbone Laura D
Published: May 2016

Objectives

To determine dosing patterns and examine predictors of filled hydroxychloroquine (HCQ) prescriptions in patients with systemic lupus erythematosus (SLE) with end-stage renal disease (ESRD).

Methods

This was a retrospective cohort study of patients with SLE in the US Renal Data System (USRDS) database in fiscal year 2011. All patients were Medicare Part D beneficiaries. Patients with a diagnosis of SLE were identified by the International Classification of Diseases, 9th revision code 710. The prevalence, dosing, and predictors of filled HCQ prescriptions (demographic factors, dialysis type, and provider subspecialty) were determined.

Results

There were 10,276 patients with SLE identified; 2048 (19.9%) had a prescription for HCQ filled. The mean daily dose of HCQ was 321 mg (range 58–2000 mg). The most common daily doses were 200 (n=768, 37.5%) and 400 mg (n=1161, 56.7%). In multivariable logistic regression analysis, significant predictors of filled HCQ prescriptions included black/African-American race (OR 1.34, 95% CI (1.17 to 1.46)), hemodialysis (1.50, 95% CI (1.29 to 1.74)), and care from a rheumatologist (5.06, 95% CI (4.56 to 5.62)). Negative predictors of filled HCQ prescriptions included male gender (OR 0.72, 95% CI (0.63 to 0.83)) and those aged 45 years or older (compared to 20 years old and younger, aged 45–64 years, OR 0.66, 95% CI (0.54 to 0.79); aged 65–74 years, OR 0.58, 95% CI (0.44 to 0.76); aged 75 years and older, OR 0.56, 95% CI (0.39 to 0.82)).

Conclusions

In patients with SLE with ESRD, the dosing strategies for HCQ with regard to potential toxicity and disparities in prescribing patterns need further study.
Line-1 Hypomethylation and Mutational Status in Cutaneous Melanomas
Authors: Pramio Dimitrius T , Pennacchi Paula C , Maria-Engler Silvya S , Campos Antônio H J F M , Duprat João P , Carraro Dirce M , Krepischi Ana C V
Published: May 2016

Epigenetic dysregulation is an important emerging hallmark of cutaneous melanoma development. The global loss of DNA methylation in gene-poor regions and transposable DNA elements of cancer cells contributes to increased genomic instability. Long interspersed element-1 (LINE-1) sequences are the most abundant repetitive sequence of the genome and can be evaluated as a surrogate marker of the global level of DNA methylation. In this work, LINE-1 methylation levels were evaluated in cutaneous melanomas and normal melanocyte primary cell cultures to investigate their possible association with both distinct clinicopathological characteristics and tumor mutational profile. A set of driver mutations frequently identified in cutaneous melanoma was assessed by sequencing (actionable mutations in BRAF, NRAS, and KIT genes, and mutations affecting the TERT promoter) or multiplex ligation-dependent probe amplification (MLPA) ( CDKN2A deletions). Pyrosequencing was performed to investigate the methylation level of LINE-1 and CDKN2A promoter sequences. The qualitative analysis showed a trend toward an association between LINE-1 hypomethylation and CDKN2A inactivation (p=0.05). In a quantitative approach, primary tumors, mainly the thicker ones (>4 mm), exhibited a trend toward LINE-1 hypomethylation when compared with control melanocytes. To date, this is the first study reporting in cutaneous melanomas a possible link between the dysregulation of LINE-1 methylation and the presence of driver mutations.
Protein Signaling and Regulation of Gene Transcription in Leukemia: Role of the Casein Kinase Ii-Ikaros Axis
Authors: Gowda Chandrika S , Song Chunhua , Ding Yali , Kapadia Malika , Dovat Sinisa
Published: May 2016

Protein signaling and regulation of gene expression are the two major mechanisms that regulate cellular proliferation in leukemia. Discerning the function of these processes is essential for understanding the pathogenesis of leukemia and for developing the targeted therapies. Here, we provide an overview of one of the mechanisms that regulates gene transcription in leukemia. This mechanism involves the direct interaction between Casein Kinase II (CK2) and the Ikaros transcription factor. Ikaros ( IKZF1) functions as a master regulator of hematopoiesis and a tumor suppressor in acute lymphoblastic leukemia (ALL). Impaired Ikaros function results in the development of high-risk leukemia. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. In vivo, Ikaros is a target for CK2, a pro-oncogenic kinase. CK2 directly phosphorylates Ikaros at multiple amino acids. Functional experiments showed that CK2-mediated phosphorylation of Ikaros, regulates Ikaros’ DNA binding affinity, subcellular localization and protein stability. Recent studies revealed that phosphorylation of Ikaros by CK2 regulates Ikaros binding and repression of the terminal deoxytransferase (TdT) gene in normal thymocytes and in T-cell ALL. Available data suggest that the oncogenic activity of CK2 in leukemia involves functional inactivation of Ikaros and provide a rationale for CK2 inhibitors as a potential treatment for ALL.
The Role of 99M Tc-Rbc Scintigraphy in Lower Gastrointestinal Hemorrhage
Authors: Duraiswamy Sangeethapriya , Schmulewitz Nathan , Rockey Don C
Published: May 2016

Given the controversy surrounding the use of 99m Tc-RBC scintigraphy (TRBCS) in lower gastrointestinal hemorrhage (LGIH), we examined how often it was performed and whether it led to specific therapy. We performed a retrospective cohort study of 565 admissions with a primary diagnosis of LGIH. We obtained detailed clinical data on all subjects, focusing in particular on outcomes after TRBCS. 199 TRBCS studies were performed during 166 patient admissions (a patient admission was defined as an incident LGIH episode in a single patient). Of the 166 patient admissions in which TRBCS was performed, the scan was positive in approximately half (84/166; 51%); if TRBCS themselves were considered, they were positive 42% (84/199) of the time. Of the 84 admissions with a positive TRBCS, angiography was performed 54 times. Among this group, angiography revealed bleeding in only 20 patients (11 patients underwent embolization and 9 had hemostatic therapy). Out of 64 patients with a positive TRBCS who underwent colonoscopy, only 3 patients underwent endoscopic hemostatic therapy. Surgery was performed in 20 patients after a positive TRBCS (including in 17/54 patients after angiogram) and hemostasis was achieved in 16. Angiography, surgery and therapeutic colonoscopy were more commonly performed after positive than after a negative TRBCS. Patients who underwent angiography within 4 h of a positive TRBCS were neither more likely to have active bleeding found nor to undergo successful embolization. Not all patients with a positive TRBCS underwent angiography, and an abnormal TRBCS did not appear to predict successful angiographic therapy; further, a positive TRBCS was not predictive of subsequent definitive therapy. Because TRBCS appears to be followed up inconsistently, the data bring into question its routine use in clinical practice, and specifically raise the possibility that it is overused in patients with LGIH.
A Departmental Initiative for Clinical and Translational Research
Authors: Colombo Christopher J , Baer Stephanie , Blake Lindsay , Bollag Wendy B , Colombo Rhonda , Diamond Matthew , George Varghese , Huber Lu , Merchen Lee , Miles Kathy , Yang Frances , Nahman N Stanley
Published: May 2016

To encourage departmental research activities, the Department of Medicine of the Medical College of Georgia (MCG) introduced an internally funded Translational Research Program (TRP) in 2014. Patterned after the Vanderbilt Institute for Clinical and Translational Research, the program offers research studios for project guidance, research mentoring and the availability of limited financial support through research vouchers. Additional academic services include abstract reviewing, conducting research conferences, organizing departmental research programs for students, and offering courses in biostatistics. During the first 15 months of its existence, the TRP working group addressed 132 distinct activities. Research mentoring, publications, and the conduct of research studios or voucher approvals encompassed 49% of working group activities. Other academic services constituted the remaining 51%. Twenty-four per cent of TRP committee activities involved research mentoring of 32 investigators (25% faculty and 75% trainees). Mentored projects generated 17 abstracts, 2 manuscripts and $87,000 in funds. The TRP conducted 13 research studios; trainees presented 54%. The TRP reviewed 36 abstracts for local and state organizations. Monthly research conferences and statistical courses were conducted and well attended. Our experience thus far indicates that a departmental TRP may serve to facilitate the growth of patient-oriented research with minimal financial support. It requires active engagement of volunteer faculty and departmental leadership willing to balance research with the other demands of the academic mission.
Patent Foramen Ovale (Pfo), Stroke and Pregnancy
Authors: Chen Lei , Deng Wenjun , Palacios Igor , Inglessis-Azuaje Ignacio , McMullin David , Zhou Dong , Lo Eng H , Buonanno Ferdinando , Ning MingMing
Published: May 2016

Patent foramen ovale (PFO)-related stroke is increasingly recognized as an important etiology of ischemic embolic stroke—accounting for up to 50% of strokes previously considered ‘cryptogenic’ or with an unknown mechanism. As a ‘back door to the brain,’ PFO can allow venous clots to enter arterial circulation via interatrial right-to-left shunting, potentially resulting in ischemic stroke. We observe that clinically, PFO-related stroke affects women of childbearing age, and that pregnancy—owing to major changes in hemocoagulative, hormonal, and cardiovascular parameters—can enhance stroke risks. However, no systematic study has been performed and little is known regarding complications, pregnancy outcomes and treatment for PFO-related stroke during pregnancy. To identify and characterize the complications and clinical outcomes related to PFOs during pregnancy, we performed a literature review and analysis from all reported cases of pregnancy with PFO-related complications in the medical literature from 1970 to 2015. We find that during pregnancy and post-partum, PFO is associated with complications affecting multiple organs, including the brain, heart and lung. The three principal complications reported are stroke, pulmonary emboli and myocardial infarction. In contrast to other pregnancy-related stroke etiologies, which peak during later pregnancy and postpartum, PFO-related stroke peaks during early pregnancy (first and second trimester—60%), and most patients had good neurological outcome (77%). In patients with PFO with recurrent stroke during pregnancy, additional key factors include high-risk PFO morphology (atrial septal aneurysm), larger right-to-left shunt, multiple gestation and concurrent hypercoagulability. Compared to strokes of other etiologies during pregnancy, most PFO stroke patients experienced uneventful delivery (93%) of healthy babies with a good clinical outcome. We conclude with recommended clinical treatment strategies for pregnant patients with PFO suggested by the data from these cases, and the clinical experience of our Cardio-Neurology Clinic.
Statin Therapy for Cardiac Hypertrophy and Heart Failure
Authors: Liao James K.
Published: May 2016

Cardiac hypertrophy leading to heart failure is a major cause of morbidity and mortality worldwide. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, have been shown to inhibit cardiac hypertrophy and improve symptoms of heart failure by cholesterol-independent mechanisms. Statins block the isoprenylation and function of members of the Rho guanosine triphosphatase family, such as Rac1 and RhoA. Because Rac1 is a requisite component of reduced nicotinamide adenine dinucleotide phosphate oxidase, which is a major source of reactive oxygen species in cardiovascular cells, the ability of statins to inhibit Rac1-mediated oxidative stress contributes importantly to their inhibitory effects on cardiac hypertrophy. Furthermore, inhibition of RhoA by statins leads to the activation of protein kinase B/Akt and up-regulation of endothelial nitric oxide synthase in the endothelium and the heart. This results in increased angiogenesis and myocardial perfusion, decreased myocardial apoptosis, and improvement in endothelial and cardiac function. Because these effects of statins occur independently of cholesterol lowering, statins may have therapeutic benefits in nonhyperlipidemic patients with cardiac hypertrophy and heart failure.
Consequences of Cold Ischemic Injury of Kidneys in Clinical Transplantation
Authors: Salahudeen Abdulla K.
Published: May 2016

Cold storage allows the effective utilization of organs retrieved for transplantation. However, prolonged cold ischemia contributes to organ damage and increases patients' morbidity and mortality and health care cost. Using recent data from the United Network for Organ Sharing, this paper examines the outcomes of live donor and deceased donor kidney transplants in relation to cold ischemia time.
Simvastatin Induces Death of Multiple Myeloma Cell Lines
Authors: Gronich Naomi , Drucker Liat , Shapiro Hava , Radnay Judith , Yarkoni Shai , Lishner Michael
Published: May 2016

Background

Accumulating reports indicate that statins widely prescribed for hypercholesteromia have antineoplastic activity. We hypothesized that because statins inhibit farnesylation of Ras that is often mutated in multiple myeloma (MM), as well as the production of interleukin (IL)-6, a key cytokine in MM, they may have antiproliferative and/or proapoptotic effects in this malignancy.

Methods

U266, RPMI 8226, and ARH77 were treated with simvastatin (0-30 μM) for 5 days. The following aspects were evaluated: viability (IC50), cell cycle, cell death, cytoplasmic calcium ion levels, supernatant IL-6 levels, and tyrosine kinase activity.

Results

Exposure of all cell lines to simvastatin resulted in reduced viability with IC50s of 4.5 μM for ARH77, 8 μM for RPMI 8226, and 13 μM for U266. The decreased viability is attributed to cell-cycle arrest (U266, G1; RPMI 8226, G2M) and cell death. ARH77 underwent apoptosis, whereas U266 and RPMI 8226 displayed a more necrotic form of death. Cytoplasmic calcium levels decreased significantly in all treated cell lines. IL-6 secretion from U266 cells was abrogated on treatment with simvastatin, whereas total tyrosine phosphorylation was unaffected.

Conclusions

Simvastatin displays significant antimyeloma activity in vitro. Further research is warranted for elucidation of the modulated molecular pathways and clinical relevance.
Molecular Mechanisms of Increased Glucose Production: Identifying Potential Therapeutic Targets
Authors: Proietto Joseph , Andrikopoulos Sofianos
Published: May 2016

Many patients with type 2 diabetes go on to require insulin therapy to achieve adequate control. A need remains to develop new classes of oral hypoglycemic agents to complement those already in use. A useful target is the inappropriately elevated endogenous glucose production present in patients with type 2 diabetes. This review discusses mechanisms of increased glucose production and possible strategies and targets for its suppression. Several approaches are being investigated, including inhibitors of glycogenolysis and gluconeogenesis, inhibitors of stimulatory hormones or their receptors, metabolic modulators, and agents that alter gene expression. There is a high probability that one of these approaches will soon result in a safe and effective inhibitor of glucose production.
Forming Your Phase III Trial's Data and Safety Monitoring Board: A Perspective on Safety
Authors: Wittes Janet
Published: May 2016

A data safety monitoring board (DSMB) established in a phase III trial to monitor the safety of participants in a clinical trial views itself as protecting participants and ensuring the integrity of the study. The DSMB should operate under a clear charter, with expectations understood by all members of the Board, the sponsor, and the investigators. Sponsors must trust their DSMBs. The sponsor must give the DSMB the tools and the data that it needs to operate effectively in protecting the safety of the participants.
Clinical Experience with Drotrecogin Alfa in Treating Gram-Positive and -Negative Pathogens in Patients with Severe Sepsis
Authors: Cone Lawrence A. , Stone Richard A. , Jesser Kenneth , Nelson Richard
Published: May 2016

Background

Newer concepts in the management of severe sepsis and, in particular, in the understanding of the relationship between proinflammatory and procoagulant activities during severe infection have led to the introduction of activated protein C (drotrecogin) into the therapeutic program. The combination of effective antimicrobial therapy, aggressive supportive care, and efforts to antagonize procoagulants and inhibitors of fibrinolysis was used in this study.

Methods

We treated 12 patients with severe sepsis using this combination of antimicrobial agents and drotrecogin. All patients presented with hypotension and organ failure and some with multiple organ failure. Infected patients were separated into those with gram-positive and those with gram-negative infections.

Results

In contrast to an expected mortality rate of nearly 40% in this group of patients, only 2 (9%) expired. Both deaths were due to infection by gram-negative organisms in patients with complicated abdominal infections and concurrent cancer. All patients with gram-positive organisms survived.

Conclusion

Those patients with infections caused by gram-positive organisms seemed to have a better prognosis than those with gram-negative infections, perhaps because their illnesses are less complicated by local disease. Although our study is small, it suggests that activated protein C will have a significant beneficial effect on the future treatment of severe sepsis and can reduce the mortality rate significantly. Further improvement in survival rates will require more effective treatment of local disease and associated noninfectious ailments.
Risk Stratification Using Gated Stress Myocardial Perfusion Imaging: Comparison between Patients with and without Sexual Dysfunction
Authors: Tan Yusuf Ziya , Ozdemir Semra , Bekler Adem , Akbas Alpaslan , Gencer Meryem , Celik Fatmanur
Published: May 2016

Sexuality is an indispensable part of life. When a problem is encountered related to this topic, the quality of life is negatively affected. Therefore, every problem related to sexuality is extremely private and important to an individual. This study aims to investigate the use of myocardial perfusion scintigraphy (MPS) for advanced assessment of patients with known or suspected coronary artery disease, cardiovascular disease, and in the intermediate risk group for SD. The study included 250 patients (150 male, 100 female, mean age 54±12.10) sent by the Cardiology Clinic to the Nuclear Medicine Clinic for MPS due to suspected cardiovascular disease (CVD). The questionnaire study was applied by two methods as face-to-face interviews or online. Data on sociodemographic characteristics and cardiovascular diseases together with risk factors for sexual activity were collected using a general information form. Patients were divided into three categories of risk depending on major risk factors for cardiovascular diseases: low, intermediate, and high risk. On comparing the risk scores between the groups, it was seen that there was a statistically clear reduction in the intermediate risk group of patients with SD according to MPS scoring. MPS is a cost-effective, reliable, and accurate non-invasive diagnostic method necessary for routine use to assess cardiovascular disease and in the intermediate risk group for SD.
Hepatorenal Syndrome in Hospitalized Patients with Chronic Liver Disease: Results from the Nationwide Inpatient Sample 2002–2012
Authors: Pant C , Jani B S , Desai M , Deshpande A , Pandya Prashant , Taylor Ryan , Gilroy R , Olyaee M
Published: May 2016

Hepatorenal syndrome (HRS) is one of the leading causes of hospitalizations in patients with chronic liver disease (CLD). We conducted a retrospective national database study to determine the epidemiology of HRS in hospitalized patients with CLD. Data from a Nationwide Inpatient Sample were extracted from 2002 to 2012 using ICD-9-CM codes related to CLD and HRS. The following outcomes were examined: in-hospital mortality, total charges, length of stay (LOS), patient demographics, procedures, complications, and comorbidities. Statistical analysis including regression was performed to examine factors associated with HRS. During 2002–2012, hospital discharges related to CLD increased from 407,246 to 836,475 with an increase of 37.9% for HRS as a complication in this population. Patients with CLD and HRS had worse outcomes compared with patients with CLD without HRS. This was manifested as a higher mortality rate (32.0% vs 10.3%), increased LOS (median 7 vs 5 days), and increased hospital costs (median $16,000 vs $11,000). Logistic regression demonstrated that HIV/AIDS (adjusted OR 2.9, 95% CI 2.2 to 3.9), pneumonia (aOR 2.8, 95% CI 2.3 to 3.2), and esophageal variceal bleeding (aOR 1.9, 95% CI 1.7 to 2.0) were associated with higher mortality in patients with HRS. Conversely, liver transplantation (aOR 0.1, 95% CI 0.1 to 0.1), transjugular intrahepatic portosystemic shunt (aOR 0.5, 95% CI 0.4 to 0.6), and hospitalization in the Midwest region of the USA (aOR 0.7, 95% CI 0.6 to 0.7) were associated with reduced mortality. The incidence of HRS in hospitalized patients with CLD increased during 2002–2012. HRS is associated with significant mortality and morbidity in these patients.
Prevalence and molecular characterisation of Giardia duodenalis in calves with diarrhoea
Authors: Lee S. H. , VanBik D. , Kim H. Y. , Cho A. , Kim J. W. , Byun J. W. , Oem J. K. , Oh S. I. , Kwak D.
Published: May 2016

The aim of this study was to investigate the prevalence of Giardia duodenalis in diarrhoeal faeces from calves that were reared in Korea using PCR and ELISA. Diarrhoeal faecal samples were collected from 590 calves (<3 months old) throughout the country from November 2013 through March 2015. Data were analysed according to the region of collection, season, and type of diarrhoea. Of the 590 collected faecal samples, 77 (13.1 per cent) and 78 (13.2 per cent; true prevalence 9.1 per cent) tested positive by PCR and ELISA, respectively. The results from both testing methods were in agreement in 501 (84.9 per cent) samples, with a κ value of 0.34, which suggests fair agreement. The PCR results showed a higher prevalence in summer and in cases of haemorrhagic diarrhoea (P<0.05), while the ELISA results showed a lower prevalence in cases of pasty diarrhoea (P<0.05). Phylogenetic analysis of the β‐giardin gene sequences of G duodenalis showed that the sequences detected in this study belonged to assemblage E, which is specific to cattle and livestock. The higher prevalence of giardiasis in calves with haemorrhagic diarrhoea found in this study differed from previous studies. Therefore, researchers and veterinarians should be aware of the possible involvement of giardiasis in haemorrhagic diarrhoea.
Genome‐wide association study of periweaning failure‐to‐thrive syndrome (PFTS) in pigs
Authors: Zanella R. , Morés N. , Morés M. A. Z. , Peixoto J. O. , Zanella E. L. , Ciacci‐Zanella J. R. , Ibelli A. M. G. , Gava D. , Cantão M. E. , Ledur M. C.
Published: May 2016

Porcine periweaning‐failure‐to‐thrive syndrome (PFTS) is a condition that affects newly weaned piglets. It is characterised by a progressive debilitation leading to death, in the absence of infectious, nutritional, management or environmental factors. In this study, we present the first report of PFTS in South America and the results of a genome‐wide association study to identify the genetic markers associated with the appearance of this condition in a crossbred swine population. Four chromosomal regions were associated with PFTS predisposition, one located on SSCX, one on SSC8, and the two other regions on SSC14. Regions on SSC8 and SSC14 harbour important functional candidate genes involved in human depression and might have an important role in PFTS. Our findings contribute to the increasing knowledge about this syndrome, which has been investigated since 2007, and to the identification of the aetiology of this disease.
Long-term compositional changes following partial disturbance revealed by the resurvey of logging concession limits in the northern temperate forest of eastern Canada
Authors: Danneyrolles Victor , Arseneault Dominique , Bergeron Yves
Published: May 2016

Land use changes that are linked to European settlement of North America have transformed northeastern temperate forest landscapes. Many studies report a regional increase of young early-successional forests due to high disturbance rates since the preindustrial era (fire, land clearing, and clear-cuts). In this study, we document specific compositional changes to present-day mature forest landscapes, which have only been managed with partial cutting (high-grading and diameter-limit cuts) since the preindustrial era in southwestern Quebec. We resurveyed 108 forest observations that were extracted from logbooks of former logging concession limits (surveyed between 1870 and 1890). Results highlight an increase in mid- to late-successional shade-tolerant taxa (Betula alleghaniensis Britton, Thuja occidentalis L., Acer saccharum Marsh.) at the expense of preindustrial dominant conifers (Abies balsamea (L.) Mill., Pinus strobus L.). Former logging activities and spruce budworm (Choristoneura fumiferana Clemens) outbreaks appear to be the main drivers of these changes, which were also strongly structured across the topographic gradient. To some extent, these results highlight the relevance of partial cutting management, as it has allowed long-term maintenance of a mid- to late-successional forest composition, while also pointing the need for P. strobus restoration. We conclude that by allowing site-specific comparisons, the resurvey of historical observations greatly improve the analytical strengths of historical reconstruction.