bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding FDA Regulatory Requirements for Investigational New Drug Applications for Sponsor-Investigators
Authors: Holbein M. E. Blair
Published: May 2016

Clinical investigators invoke a number of specific regulatory requirements if their study includes use of a pharmaceutical agent. Studies using a drug that has not been approved by the Food and Drug Administration (FDA) or for indications not in the approved labeling may require filing an Investigational New Drug (IND) application with the FDA. If a study meets specific regulatory exemption criteria, then an IND may not be needed. Individual investigators may meet the FDA definition of a sponsor-investigator, in which case the application process is generally less complicated than for commercial sponsors, and this review addresses only this circumstance. Filing an IND requires completion of 3 sets of forms: 1 detailing the study (FDA Form 1571), 1 providing information about the investigator and study site (FDA Form 1572), and 1 certifying that the study is registered in the national database of clinical trials (FDA Form 3674). If the IND is approved, the study may begin 30 days after the FDA acknowledges receipt and assigns an IND. If the FDA requires additional information or if the study is placed on a “clinical hold,” the study must not proceed. While the IND is active, the investigator must also continue to meet a set of regulations for monitoring the study and reporting to the FDA.
Molecular Pathogenesis of Fragile X-Associated Tremor/Ataxia Syndrome
Authors: Raske Christopher , Hagerman Paul J.
Published: May 2016

Fragile X-associated tremor/ataxia syndrome is a late adult onset neurodegenerative disorder that affects individuals who carry a premutation CGG repeat expansion (55-200 CGG repeats) in the 5′ untranslated portion of the fragile X mental retardation 1 ( FMR1) gene. Affected individuals display cognitive decline, progressive intention tremor, gait ataxia, neuropathy, psychiatric symptoms, and parkinsonism; the severity of both clinical and neuropathological phenotypes is positively correlated with the extent of the CGG expansion. Overexpression of the expanded CGG repeat messenger RNA results in a direct gain-of-function cellular toxicity that is believed to form the pathogenic basis for fragile X-associated tremor/ataxia syndrome. This mechanism is entirely different from the mechanism giving rise to fragile X syndrome, which is due to transcriptional silencing and consequent loss of FMR1 protein. Much of the research in the field has focused on understanding the link between the pathogenic FMR1 messenger RNA and the potential proteins that interact with it.
Bridging Clinical Investigators and Statisticians: Writing the Statistical Methodology for a Research Proposal
Authors: Adams-Huet Beverley , Ahn Chul
Published: May 2016

Clinical investigators often find the thought of writing the statistical analysis plan daunting. Early collaboration between the clinical investigator and statistician can improve the study design and validity of the results by developing the statistical methodology that specifically addresses the research hypothesis. With the clinical investigator, a statistician often writes the statistical methods section that includes sample size and power analyses, randomization and blinding procedures, interim analysis, and data monitoring plans, in addition to the statistical analysis plan. To make this process less mysterious, we describe how the statistical methods section is developed in collaboration with a statistician.
Renal Complications in Oncohematologic Patients
Authors: Buemi Michele , Fazio Maria Rosaria , Bolignano Davide , Coppolino Giuseppe , Donato Valentina , Lacquaniti Antonio , Mondello Stefania , Buemi Antoine , Allegra Alessandro
Published: May 2016

The aim of the present paper was to review recent developments in the management of patients with acute kidney injury or chronic kidney disease occurring secondary to either cancer itself or its therapy, with a focus on infiltration of the renal parenchyma, myeloma, tumor lysis syndrome, glomerular disease, thrombotic microangiopathy, chemotherapy-associated thrombotic microangiopathy, biphosphonate-induced renal diseases, acute kidney injury, and chronic kidney disease after hematopoietic cell transplantation. Further studies are awaited because a better knowledge of renal complications, which frequently occur in patients with oncohematologic diseases, would be conducive to making an early diagnosis and providing prompt therapy.
International Outsourcing of Medical Research by High-Income Countries: Changes from 1995 to 2005
Authors: Belforti Raquel K. , Wall Michal Sarah , Lindenauer Peter K. , Pekow Penelope S. , Rothberg Michael B.
Published: May 2016

Background

Medical research outsourcing provides a financial benefit to those conducting research and financial incentives to the developing countries hosting the research. Little is known about how frequently outsourcing occurs or the type of research that is outsourced.

Methods

To document changes in medical research outsourcing over a 10-year period, we conducted a cross-sectional comparison of 3 medical journals: Lancet, The New England Journal of Medicine, and JAMA: The Journal of the American Medical Association in the last 6 months of 1995 and 2005. The main outcome measure was the 10-year change in proportion of studies including patients from low-income countries.

Findings

We reviewed 598 articles. During the 10-year period, the proportion of first authors from low-income countries increased from 3% to 6% ( P = 0.21), whereas studies with participants from low-income countries increased from 8% to 22% ( P = < 0.001). In 2005, compared with studies conducted exclusively in high-income countries, those including participants from low-income countries were more likely to be randomized trials (55% vs 35%, P = 0.004), to study medications (65% vs 34%, P < 0.001), to be funded by pharmaceutical companies (33% vs 21%, P = 0.05), and to involve pediatric populations (29% vs 8%, P < 0.001).

Interpretation

Outsourcing of medical research seems to be increasing. Additional studies are required to know if subjects from low-income countries are being adequately protected.
Clinicopathological Characteristics and Prognostic Factors of Asymptomatic IgA Nephropathy
Authors: Shen Pei-Cheng , He Li-Qun , Tang Ying , Wang Qing , Wang Wei , Li Jie
Published: May 2016

Aims

Many patients with immunoglobulin class A (IgA) nephropathy (IgAN) present with asymptomatic urinary abnormalities. The purpose of this study was to observe the clinicopathological characteristics and prognostic factors in asymptomatic IgAN.

Methods

Eighty-six asymptomatic IgAN patients (49 males and 37 females) were investigated; 82 of them were followed up during a mean ± SD period of 66.7 ± 19.7 months.

Results

At biopsy, 18 patients (21%) presented with pure hematuria (HU), 29 patients (34%) presented with proteinuria alone (PU), and 39 patients (45%) presented concomitant hematuria and proteinuria with severe pathological lesions. Meanwhile, 16% and 26% had renal insufficiency and hypertension, respectively. Finally, urinary abnormalities of 15% of the patients disappeared, 25% of HU developed proteinuria, 47% of concomitant hematuria and proteinuria, and 32% of PU appeared to have increase of proteinuria, and 14% of PU developed hematuria. Fifteen (24%) of the patients with normal blood pressure initially became hypertensive and 18 (22%) of the patients with normal renal function initially developed renal insufficiency. Twenty-four patients (29%) had doubling of serum creatinine level, and 13 patients (16%) progressed to end-stage renal disease. Prednisone therapy and antihypertensive treatment significantly improved proteinuria and renal function deterioration. Hematuria, hypertension during follow-up, and tubulointerstitial lesions were independent risk factors predictive of the ultimate development of renal progression.

Conclusions

The renal outcome of asymptomatic IgAN is guarded. Hematuria, hypertension during follow-up, and tubulointerstitial lesions may be important markers to monitor renal progression in the course.
Changes in Gleason Scores for Prostate Cancer: What Should we Expect from a Measurement?
Authors: Ramos Jorge , Uchio Edward , Aslan Mihaela , Concato John
Published: May 2016

Background

Men diagnosed with prostate cancer receive therapy based on various clinical characteristics, including the Gleason score, a measurement (range, 2-10) describing a tumor's histological appearance. An upward shift has occurred in the distribution of Gleason scores during the past decade; this change was influenced by reports suggesting that lower scores (range, 2-4) should not be assigned to biopsy specimens.

Methods

We (1) compared Gleason scores from 1994-1995 and 2004-2005 at the same institution, (2) reviewed representative articles examining changes in Gleason scores during the last 2 decades, and (3) assessed the implications of a change in histological measurements.

Results

Among men diagnosed with prostate cancer at VA Connecticut, Gleason scores 2 to 4 were reported for 11.4% (19/167) of specimens in 1994-1995 but only 0.4% (1/260) of specimens in 2004-2005; this difference persisted after adjusting for age, clinical stage, and prostate-specific antigen ( P < 0.001). Similar results were evident in previous publications on this topic. A change in criteria for a clinical measurement may have unintended consequences, including problems of inconsistency across “time” and “place.”

Conclusions

Recent shifts in Gleason scores have led to fewer patients being diagnosed with low-grade prostate cancer; this change can have adverse impacts in clinical care and research.
Identification of Diagnostic Urinary Biomarkers for Acute Kidney Injury
Authors: Varghese Sanju A. , Powell Thomas B. , Janech Michael G. , Budisavljevic Milos N. , Stanislaus Romesh C. , Almeida Jonas S. , Arthur John M.
Published: May 2016

Acute kidney injury (AKI) is an important cause of death among hospitalized patients. The 2 most common causes of AKI are acute tubular necrosis (ATN) and prerenal azotemia (PRA). Appropriate diagnosis of the disease is important but often difficult. We analyzed urine proteins by 2-dimensional gel electrophoresis from 38 patients with AKI. Patients were randomly assigned to a training set, an internal test set, or an external validation set. Spot abundances were analyzed by artificial neural networks to identify biomarkers that differentiate between ATN and PRA. When the trained neural network algorithm was tested against the training data, it identified the diagnosis for 16 of 18 patients in the training set and all 10 patients in the internal test set. The accuracy was validated in the novel external set of patients where conditions of 9 of 10 patients were correctly diagnosed including 5 of 5 with ATN and 4 of 5 with PRA. Plasma retinol-binding protein was identified in 1 spot and a fragment of albumin and plasma retinol-binding protein in the other. These proteins are candidate markers for diagnostic assays of AKI.
The 5-Year Incidence of Type 2 Diabetes Mellitus in Women Older than 15 Years in Ankara, Turkey: A Population-Based Study
Authors: Maral Işıl , Tütüncü Neslihan Başçıl , Bakar Coşkun , Durukan Elif , Budakoğlu I.İrem , Özkan Seçil , Aycan Sefer , Aygün Remzi , Bumin Mehmet Ali
Published: May 2016

Background

Type 2 diabetes mellitus (DM) is a significant cause of morbidity and premature mortality especially in adults. In Turkey, there are few studies on DM incidence. This study aimed to determine the incidence of type 2 DM in women 15 years or older in Turkey.

Methods

This prospective cohort study was performed from December 2002 to May 2003. Preliminary population-based screening was performed in 1997 and 1998 on women 15 years or older living in 4 villages in the Gölbaşı, Ankara province. Five hundred sixty-three women who were considered nondiabetic in the first study comprised the population for the present study. Data collection was accomplished by using a questionnaire and randomly measuring the blood glucose levels of the women. The χ2 and Fisher exact tests were used to analyze the risk factors for DM.

Results

The 5-year incidences of type 2 DM, impaired glucose tolerance, and impaired fasting glucose were 2.3%, 0.4%, and 0.7%, respectively. The 5-year incidence of type 2 DM increased with age ( P < 0.05). The DM incidence was 6.2% in those with mixed-type hypertension and 4.0% in those with a body mass index of 30 kg/m2 or higher. At 5-year follow-up, age (≥35 years), hypertension, and body mass index (≥30 kg/m2) were the risk factors for incidence of abnormal glucose metabolism ( P < 0.05).

Conclusions

The incidence of abnormal glucose metabolism in this study is in accord with that in the literature. Our results will contribute to our understanding of the incidence of DM in women in Turkey.
AIDS Awareness and Condom use among Patients in a High-HIV-Prevalence Area in Rural Northern Anhui, China
Authors: Mao Nai-Ling , Pan Hai-Feng , Lu Man-Man , Dai Se-Ying , Chen Gui-Mei , Tian Min , Huang Zhang-Jun , Ye Dong-Qing
Published: May 2016

The objective was to assess AIDS awareness and condom use in a rural northern Anhui area with a high HIV prevalence. One hundred two AIDS patients underwent a structured interview using a standard questionnaire. There were 51 female and 51 male patients, whose mean age was 46.27 ± 7.27 years and who had good knowledge of AIDS-related issues. More sexually active patients than those nonactive ones knew it more properly that AIDS was a blood-borne disease (100% vs 94.4%; P = 0.03). Significantly more female patients than male (62.7% vs 47.1%; P = 0.047) knew AIDS is incurable. Self-perceived risk was low, and only 84 respondents regarded the condom use as a common problem in their area. Two independent factors associated with a higher rate of condom use were the AIDS patients’ income level and their knowledge about condom use. There was statistically significance between the patients who regularly obtained free condoms and those who did not. The patients who bought condoms on their own initiative had a higher chance of using condoms than those who did not. In conclusion, despite a high level of awareness of HIV/AIDS issues, self-perceived risk was low, condom use was infrequent, and especially men continued to have multiple sexual partners.
Strategies for Vascularization of Polymer Scaffolds
Authors: Papavasiliou Georgia , Cheng Ming-Huei , Brey Eric M.
Published: May 2016

Biocompatible, degradable polymer scaffolds combined with cells or biological signals are being investigated as alternatives to traditional options for tissue reconstruction and transplantation. These approaches are already in clinical use as engineered tissues that enhance wound healing and skin regeneration. The continued enhancement of these material strategies is highly dependent on the ability to promote rapid and stable neovascularization (new blood vessel formation) within the scaffold. Whereas neovascularization therapies have shown some promise for the treatment of ischemic tissues, vascularization of polymer scaffolds in tissue engineering strategies provides a unique challenge owing to the volume and the complexity of the tissues targeted. In this article, we examine recent advances in research focused on promoting neovascularization in polymer scaffolds for tissue engineering applications. These approaches include the use of growth factors, cells, and novel surgical approaches to both enhance and control the nature of the vascular networks formed. The continued development of these approaches may lead to new tissue engineering strategies for the generation of skin and other tissues or organs.
Assessment of Serum Chromogranin-A as Prognostic Factor in High-Risk Prostate Cancer
Authors: Reis Leonardo O. , Vieira Larissa F.M. , Zani Emerson L. , Denardi Fernandes , de Oliveira Laurione C. , Ferreira Ubirajara
Published: May 2016

Purpose

The presence of neuroendocrine differentiation may play a key role in androgen-independent tumor progression. The prognostic significance of plasma chromogranin-A (CgA) was assessed in a series of consecutive patients with high-risk prostate cancer (PCa).

Patients and Methods

Twenty-three patients presenting high-risk PCa and 8 healthy individuals, as control group, had their blood samples collected to evaluate CgA, free and total prostate specific antigen, and free and total testosterone in a pilot study. The correlations of serum CgA levels with PSA, testosterone, Gleason score, number of foci of hypercaptation in bone scan, age, and outcomes were evaluated at baseline and after 12 months.

Results

Patients with PCa had significantly higher levels of plasma CgA (mean, 8.7; range, 1.9-73) than healthy patients (mean, 3.45; range, 0.6-5.6), P = 0.02. Analyzing only the patients group through correlation of the ranks, it was observed that CgA has low, insignificant correlations with PSA ( P = 0.07) and with metastatic extension ( P = 0.09). No association was found between the plasma CgA levels and the Gleason score ( P = 0.20), age ( P = 0.15), or disease progression ( P = 0.27).

Conclusion

The serum levels of CgA were significantly increased in the group with PCa compared with the healthy group. However, there were low correlations between serum CgA and known prognostic factors (such as total and free PSA, age, Gleason score, and bone metastases) or clinical deterioration. Although future studies are needed with larger samples and longer follow-up, the presented data envisage a limited role to serum CgA as high-risk PCa prognostic factor.
Systematic Review and Meta-Analysis of Immunosuppressant Therapy Clinical Trials in Membranous Lupus Nephritis
Authors: Swan Joshua T. , Riche Daniel M. , Riche Krista D. , Majithia Vikas
Published: May 2016

Purpose

We performed a systematic review and meta-analysis to compare response rates (complete remission plus partial remission) for nonsteroid immunosuppressant therapy to steroid-only immunosuppressant therapy in patients with membranous lupus nephritis.

Methods

A literature review was conducted from June 25, 2010 by querying PubMed, MEDLINE, and EMBASE databases. Inclusion criteria were trials containing remission data on patients with confirmed pure class V (Va and Vb) membranous lupus nephritis. The primary analysis evaluates response rates for regimens that contain at least one nonsteroid immunosuppressant therapy and steroid-only immunosuppressant therapy. A proportion meta-analysis using a DerSimonian-Laird random-effects model was performed. Data are reported as pooled proportions in percentages with 95% confidence intervals. Significant heterogeneity and/or bias were compensated for by trial exclusion.

Results

Twenty-four studies met inclusion criteria for meta-analysis, which yielded 34 groups of patients' data. Upon meta-analysis, the response rate for nonsteroid immunosuppressant therapy is higher than for steroids alone (81% [74%-87%] vs 60% [39%-79%]), even when compensating for significant heterogeneity and bias (76% [71%-81%] versus 60% [39%-79%]).

Conclusion

Nonsteroid immunosuppressant therapies in combination with steroids seem to be more effective than steroids alone for inducing partial or complete remission in patients with membranous lupus nephritis who have nephrotic proteinuria at baseline. This trial was not able to analyze adverse events, flares, relapses, or patient survival because of underreporting.
Assessment of Atrial Conduction Time in Patients with Systemic Lupus Erythematosus
Authors: Dogdu Orhan , Yarlioglues Mikail , Kaya Mehmet Gungor , Ardic Idris , Kilinc Yusuf , Elcik Deniz , Kelesoglu Saban , Akpek Mahmut , Sahin Omer , Cosgun Said , Oguzhan Nilufer , Oguzhan Abdurrahman
Published: May 2016

Objectives

Systemic lupus erythematosus (SLE) is an autoimmune disorder resulting in multisystemic inflammatory damage. Recent articles report that 20% to 30% of deaths in patients with SLE have cardiovascular origin. The aim of this study was to investigate the atrial conduction time in patients with SLE by using high-usefulness tissue Doppler echocardiography (TDI).

Methods

The study population included 56 patients with SLE (49 women; mean [SD] age, 46.2 [12.2] years, and mean [SD] disease duration, 30.7 [10.9] months) and 45 healthy subjects as control group (39 women; mean [SD] age, 45.8 [12.3] years). P-wave dispersion (PWD) was calculated by using 12-lead electrocardiogram. The timing of atrial contractions (PA) was measured as the interval between the onset of P wave on electrocardiogram and the beginning of A wave on TDI. Atrial electromechanical delay (EMD) was calculated from the lateral (PA lateral), septal (PA septal) mitral annulus, and lateral tricuspid annulus (PA tricuspid).

Results

Lateral mitral annulus and PA septal were significantly longer in the patients with SLE than in the control subjects (66.7 [15.9] vs 56.5 [13.7], P = 0.001, and 53.5 [15.0] vs 45.0 [15.1] milliseconds, P = 0.006, respectively). Interatrial (PA lateral − PA tricuspid) and intra-atrial (PA septal − PA tricuspid) EMD were significantly higher in SLE groups (25.5 [9.7] vs 19.9 [8.3], P = 0.003 and 13.3 [7.7] vs 8.4 [8.0] milliseconds, P = 0.002, respectively). Similarly, maximum P-wave duration and PWD were significantly longer in the patients with SLE than in the control subjects (104.9 [13.5] vs 98.1 [15.1], P = 0.021 and 24.6 [7.4] vs 20.0 [8.1] milliseconds, P = 0.004, respectively). There were significant positive correlations between the disease duration and interatrial EMD ( r = 0.611, P < 0.001) and intra-atrial EMD ( r = 0.565, P < 0.001). Positive correlation was also present between the disease duration and PWD ( r = 0.457, P < 0.001).

Conclusion

Atrial EMD is prolonged in patients with SLE. We have also shown that PWD, intra-atrial EMD, and interatrial EMD were significantly correlated with disease duration. This study calls attention to the following: the measurement of atrial conduction time may be clinically helpful in the definition of cardiac involvement.
Crossing the Chasm: Information Technology to Biomedical Informatics
Authors: Fahy Brenda G. , Balke C. William , Umberger Gloria H. , Talbert Jeffery , Canales Denise Niles , Steltenkamp Carol L. , Conigliaro Joseph
Published: May 2016

Accelerating the translation of new scientific discoveries to improve human health and disease management is the overall goal of a series of initiatives integrated in the National Institutes of Health (NIH) “Roadmap for Medical Research.” The Clinical and Translational Science Award (CTSA) program is, arguably, the most visible component of the NIH Roadmap providing resources to institutions to transform their clinical and translational research enterprises along the goals of the Roadmap. The CTSA program emphasizes biomedical informatics as a critical component for the accomplishment of the NIH's translational objectives. To be optimally effective, emerging biomedical informatics programs must link with the information technology platforms of the enterprise clinical operations within academic health centers.

This report details one academic health center's transdisciplinary initiative to create an integrated academic discipline of biomedical informatics through the development of its infrastructure for clinical and translational science infrastructure and response to the CTSA mechanism. This approach required a detailed informatics strategy to accomplish these goals. This transdisciplinary initiative was the impetus for creation of a specialized biomedical informatics core, the Center for Biomedical Informatics (CBI). Development of the CBI codified the need to incorporate medical informatics including quality and safety informatics and enterprise clinical information systems within the CBI. This article describes the steps taken to develop the biomedical informatics infrastructure, its integration with clinical systems at one academic health center, successes achieved, and barriers encountered during these efforts.
Lower Fetuin-A Predicts Angiographic Impaired Reperfusion and Mortality in ST-Elevation Myocardial Infarction
Authors: Basar Nurcan , Sen Nihat , Kanat Selcuk , Ozlu Mehmet Fatih , Ozcan Firat , Cay Serkan , Erden Gonul , Cagli Kumral Ergun , Yildirimkaya Metin , Maden Orhan , Covic Adrian , Kanbay Mehmet
Published: May 2016

Aims

Fetuin-A is an anti-inflammatory negative acute-phase glycoprotein, synthesized by the liver. In this study, we aimed to investigate the effects of admission fetuin-A levels on coronary and myocardial blood flow and short- and long-term prognosis in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention.

Methods and Results

One hundred eighty consecutive patients admitted with diagnosis of STEMI and 55 healthy age- and sex-matched volunteer controls were enrolled in the study. Patients with STEMI were divided into 2 groups in respect to thrombolysis in myocardial infarction myocardial perfusion grade after primary PCI: with thrombolysis in myocardial infarction myocardial perfusion grade 0-1-2 and thrombolysis in myocardial infarction myocardial perfusion grade 3. Serum levels of fetuin-A were lower in patients with STEMI than in the healthy group subjects. In-hospital and 1-year deaths were significantly higher in patients from the abnormal perfusion group. In-hospital major adverse cardiac event (MACE) and 1-year follow-up MACE also were significantly higher in patients from the abnormal perfusion group. The receiver-operating characteristic analysis indicated an optimal cut point of less than 200 μg/mL, which detects 1-year mortality with a negative predictive value of 95%. The 1-year mortality rate and 1-year MACE were significantly higher in patients with low fetuin-A level as compared with those with high fetuin-A level.

Conclusions

Because low-admission fetuin-A levels are associated with impaired coronary flow in STEMI patients undergoing primary percutaneous coronary intervention, admission fetuin-A level detection may be helpful in identifying the patients at a greater risk of poor coronary blood flow and worse short- and long-term prognosis.
Blockage of TNF-α by Infliximab Reduces CCL2 and CCR2 Levels in Patients with Rheumatoid Arthritis
Authors: Xia Liping , Lu Jing , Xiao Weiguo
Published: May 2016

Objectives

To investigate the mechanism in vivo for the regulation of inflammation of patients with RA by infliximab, we measured serum levels of chemokine ligand (CCL) 2, CCL3, CXCL8, and expression of CCL2 receptor chemokine receptor (CCR) 2 on CD4+ T cells from patients with rheumatoid arthritis (RA).

Methods

Forty-four patients with were enrolled in our study. Twenty-four patients received infliximab combined with methotrexate. Twenty patients received methotrexate alone. Serum levels of the chemokines CCL2, CCL3, and CXCL8 were quantified using commercial enzyme-linked immunosorbent assay kits. Flow cytometry was used to analyze the expression of CCR2 on CD4+ T cells.

Results

The mean CCL2 levels in the infliximab-treated patients decreased significantly from 885.20 ± 323.52 pg/mL at pretreatment to 454.65 ± 185.03 pg/mL ( P < 0.05) at 30 weeks after the initial treatment. Fluorescence density of CCR2 expression on CD4+ T cells were significantly reduced after infliximab treatment.

Conclusions

CCL2/CCR2 system in patients with active RA may be sensitive to anti-tumor necrosis factor-α therapy and suggest that CCL2 plays a crucial role in the pathogenesis of RA. CCR2 may be an important target for therapy in RA.
APOA4 Polymorphism as a Risk Factor for Unfavorable Lipid Serum Profile and Depression: A Cross-Sectional Study
Authors: Ota Vanessa Kiyomi , Chen Elizabeth Suchi , Ejchel Tatiana Flank , Furuya Tatiane Katsue , Mazzotti Diego Robles , Cendoroglo Maysa Seabra , Ramos Luiz Roberto , Araujo Lara Quirino , Burbano Rommel Rodriguez , de Arruda Cardoso Smith Marília
Published: May 2016

Introduction

APOA1/C3/A4/A5 gene cluster is closely involved in lipid metabolism, and its polymorphisms have been associated with coronary heart disease and lipid plasma levels. Here, we aimed to investigate associations of APOC3 (3238C>G, −482C>T, 1100C>T) and APOA4 (Gln360His, Thr347Ser) polymorphisms in 382 individuals from a cohort of a Longitudinal Brazilian Elderly Study with major age-related morbidities and with lipid and protein serum levels.

Materials and Methods

The whole sample was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Descriptive statistics, logistic regression analysis, Student t test, deviation from Hardy-Weinberg, Bonferroni correction for multiple testing, and haplotype analyses were performed.

Results

Although APOC3 1100T allele carriers presented lower triglyceride and very low density lipoprotein levels than non-T carriers, these associations disappeared after Bonferroni correction ( P > 0.05). Moreover, APOA4 360His allele was associated with depression ( P = 0.03), increased triglyceride ( P = 0.035) and very low density lipoprotein ( P = 0.035) levels, and reduced HDL levels ( P = 0.0005). Haplotype analyses found an association between His/C/C haplotype (Gln360His/−482C>T/1100C>T) with depression, but this result was due to Gln360His polymorphism.

Conclusions

Our data suggest that 360His allele might be a risk factor for depression and unfavorable lipid profile and depression for elderly people in the Brazilian population.
Prostaglandin I2 Analogs Suppress Tumor Necrosis Factor α Production and the Maturation of Human Monocyte-Derived Dendritic Cells
Authors: Yeh Ching-Hui , Kuo Chang-Hung , Yang San-Nan , Huang Ming-Yii , Wu Hsaing-Chi , Wang Hsing-Pi , Kuo Thai-Hung , Hung Chih-Hsing
Published: May 2016

Background

Dendritic cells (DCs) are professional antigen-presenting cells and have critical roles in regulating immune responses. Prostaglandin I2 (PGI2) analogs are considered to be potential treatments for asthma. However, the effect of PGI2 analogs on human monocyte-derived DCs (MDDCs) is still not clearly understood.

Methods

Human MDDCs were pretreated with iloprost and treprostinil (2 PGI2 analogs) or forskolin (an adenyl cyclase activator) before lipopolysaccharide (LPS) stimulation. In some cases, I prostanoid (IP) receptor and E prostanoid receptor antagonists were added before the PGI2 analog treatment. tumor necrosis factor α (TNF-α) was measured by enzyme-linked immunosorbent assay. The expression of costimulatory molecules was assessed by flow cytometry. T-cell polarization function was investigated by measuring interferon γ, interleukin 13 (IL-13), and IL-17A production by T cells cocultured with iloprost-treated MDDCs.

Results

Iloprost and treprostinil suppressed LPS-induced TNF-α expression in MDDCs. This effect could be reversed by an IP receptor antagonist, CAY10449, but not by E prostanoid receptor antagonists. Forskolin conferred a similar effect. Iloprost suppressed the LPS-induced expression of costimulatory molecules, including CD80, CD86, CD40, and HLA-DR. Iloprost-treated MDDCs increased IL-17A production by T cells.

Conclusions

Prostaglandin I2 analogs may exert anti-inflammatory effects by suppressing TNF-α expression via the IP receptor-cyclic adenosine monophosphate pathways and by inhibiting the expression of costimulatory molecules in human MDDCs.
Evidence for the Role of Inadequate Vitamin D in Asthma Severity among Children
Authors: Staple Lauren E. , Teach Stephen J.
Published: May 2016

Asthma is the most common chronic pediatric medical condition in the United States and accounts for significant morbidity, particularly among minority and disadvantaged populations. Hypovitaminosis D is also highly prevalent throughout the developed world, and many of the risk factors for hypovitaminosis D and asthma are the same. Several recent observational studies have documented a correlation between asthma severity and vitamin D levels; however, there is no strong evidence for causality yet. Until trials of vitamin D supplementation among children with asthma are performed, the role of low levels of vitamin D in causing asthma morbidity will remain unclear.
Quantitative Assessment of Wilms Tumor 1 (WT1) Gene Transcripts in Egyptian Acute Lymphoblastic Leukemia Patients
Authors: Ali Sadek Hoda , El-Metnawey Wafaa Hassan , Shaheen Iman Abdel-Mohsen , Korshied Mervat Mamdouh , Mohamed Azza Sobieh
Published: May 2016

Background

Accurate assessment of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL) patients after initial chemotherapy is essential to evaluate the efficacy of therapeutic regimens. Wilms tumor 1 ( WT1) is a pan-leukemic marker used for identification of the leukemic clone rather than the use of individual specific molecular aberration of ALL.

Methods

Using a real-time quantitative polymerase chain reaction, bone marrow samples from 41 newly diagnosed Egyptian ALL patients; 22 adults and 19 children were examined for WT1 expression. After induction therapy, WT1 expression was reestimated in 20 ALL patients.

Results

WT1 was overexpressed in adult and pediatric ALL patients (95.4% and 89.4%, respectively). WT1 expression at diagnosis had no statistically significant impact on disease-free survival of patients ( P = 0.054). However, WT1 expression increased after induction chemotherapy in the 3 pediatric patients who had relapse.

Conclusions

WT1 is a leukemia-associated molecular marker that may be used for the diagnosis and for monitoring clinical progress in ALL; it also can be used as a molecular target for adoptive immunotherapy.
Effects of Coronary Angiography and Femoral Arterial Access on Endothelial Functions
Authors: Tulmaç Murat , Özer Nurtaç , Şimşek Vedat , Doğru Mehmet Tolga , Ebinç Haksun
Published: May 2016

Background

Impairment of endothelial function is an independent predictor of coronary events. The aim of this study was to clarify the influence of arterial access and coronary angiography on endothelial function.

Methods

Eighteen patients with stable angina pectoris who underwent coronary angiography were included in this study. Brachial artery flow-mediated dilatation of patients was measured before angiography, after femoral arterial sheath insertion, and after coronary angiography.

Results

Of 18 patients, 11 had angiographically apparent atherosclerosis. Flow-mediated dilatation after femoral arterial sheath insertion (mean ± SD, 6.62% ± 3.87%) was found to be significantly lower than either before (10.62% ± 5.18%) or after coronary angiography (11.66% ± 5.30%; P = 0.007 and P = 0.001, respectively). Basal and postangiographic flow-mediated dilatation values were similar. Flow-mediated dilatation significantly decreased after sheath insertion in the group with angiographically normal coronary arteries (14.47% ± 4.34% vs 5.98 ± 4.00%, respectively; P = 0.006), whereas the difference was not significant in patients with CAD (8.17% ± 4.16% vs 7.03% ± 3.92%, respectively).

Conclusions

Coronary angiography did not result in endothelial vasomotor dysfunction. Femoral arterial sheath insertion during coronary angiography was associated with a short-lived endothelial dysfunction. Larger studies are needed to interpret the effect of coronary atherosclerosis on attenuation of endothelial response against arterial wall injury.
Respiratory Impairment and Mortality in Older Persons: A Novel Spirometric Approach
Authors: Vaz Fragoso Carlos A. , Gill Thomas M. , McAvay Gail , Yaggi Henry Klar , Van Ness Peter H. , Concato John
Published: May 2016

Background

The Lambda-Mu-Sigma (LMS) method calculates the lower limit of normal for spirometric measures of pulmonary function as the fifth percentile of the distribution of z scores, suitably accounting for age-related changes in pulmonary function. Extending prior work, and to assess whether the LMS method is clinically valid when evaluating respiratory impairment in the elderly, our current objective was to evaluate the association of LMS-defined respiratory impairment (airflow limitation and restrictive pattern) with all-cause mortality and respiratory symptoms (chronic bronchitis, dyspnea, or wheezing) in older persons.

Methods

Spirometric data and outcome data on white participants aged 65 to 80 years were obtained from the Third National Health and Nutrition Examination Survey (NHANES-III, n = 1497) and the Cardiovascular Health Study (CHS, n = 3583). Multivariable analyses determined the corresponding associations, adjusting for important covariates.

Results

In the NHANES-III and CHS populations, respectively, LMS-defined airflow limitation had adjusted hazard ratios (95% confidence interval) of 1.64 (1.28-2.11) and 1.69 (1.48-1.92) for mortality; adjusted odds ratios for respiratory symptoms were 2.71 (1.92-3.83) and 2.63 (2.11-3.27). The LMS-defined restrictive pattern was also significantly associated with mortality (adjusted hazard ratios of 1.98 [1.54-2.53] and 1.68 [1.44-1.95]), as well as with respiratory symptoms (adjusted odds ratios of 1.55 [1.03-2.34] and 1.37 [1.07-1.75]) in NHANES-III and CHS, respectively.

Conclusions

The LMS-defined airflow limitation and restrictive pattern confers a significantly increased risk of death and likelihood of having respiratory symptoms. These results support the use of LMS-derived spirometric z scores as a basis for evaluating respiratory impairment in older persons.
Relationship of Blood Pressure to Heart Rate in Isolated Systolic Hypertension
Authors: Goldberger Jeffrey J. , Jacobson Jason T.
Published: May 2016

Background

Patients with isolated systolic hypertension (ISH) have been noted to be less responsive to β-blockers than patients with essential hypertension (HTN). The purpose of this study was to determine the relationship between blood pressure (BP) and heart rate in ISH.

Methods

A total of 619 patients underwent 24-hour ambulatory BP monitoring. Patients were grouped as normal, HTN, or ISH. Clinical characteristics, mean BPs, and mean heart rate were compared between the groups.

Results

Two hundred seventy-one patients had normal BP, 98 had HTN, and 90 had ISH. Antihypertensives were used in 37% with normal BP, 51% with HTN, and 58% with ISH. The pulse pressure was highest for ISH (67 [10] mm Hg), followed by HTN (59 [12] mm Hg) and normal BP (49 [7] mm Hg; P < 0.0001). Heart rate in ISH was 71 [10] beats per minute; slower than that for normal BP (73 [11] beats per minute; P = 0.0464) and HTN (78 [12] beats per minute; P < 0.0001). There was a positive relationship between diastolic BP and heart rate. In ISH, there was a negative relationship between systolic BP and heart rate (slope = −0.18; r = 0.24; P = 0.0209) and a positive relationship between diastolic BP and heart rate (slope = 0.19; r = 0.33; P = 0.0015).

Conclusions

The noted relationship of heart rate to systolic BP and pulse pressure may in part explain the lower efficacy of β-blockers in patients with ISH. The rate-lowering effects of these medications may result in an increase in systolic and pulse pressures.
Implementation and Impact of a Consensus Diagnostic and Management Algorithm for Complicated Pneumonia in Children
Authors: Pillai Dinesh , Song Xiaoyan , Pastor William , Ottolini Mary , Powell David , Wiedermann Bernhard L. , DeBiasi Roberta L.
Published: May 2016

Introduction

Variable treatment exists for children with bacterial pneumonia complications such as pleural effusion and empyema. Subspecialists at an urban academic tertiary children's hospital created a literature-based diagnosis and management algorithm for complicated pneumonia in children. We proposed that algorithm implementation would reduce use of computed tomography (CT) for diagnosis of pleural infection, thereby decreasing radiation exposure, without increased adverse outcomes.

Materials and Methods

A cross-sectional study was undertaken in children (3 months to 20 years old) with principal or secondary diagnosis codes for empyema and/or pleural effusion in conjunction with bacterial pneumonia. Study cohorts consisted of subjects admitted 15 months before (cohort 1, n = 83) and after (cohort 2, n = 87) algorithm implementation. Data were collected using clinical and financial data systems. Imaging studies and procedures were identified using Current Procedural Terminology codes. Statistical analysis included χ2 test, linear and ordinal regression, and analysis of variance.

Results

Age ( P = 0.56), sex ( P = 0.30), diagnoses ( P = 0.12), and severity level ( P = 0.84) were similar between cohorts. There was a significant decrease in CT use in cohort 2 (cohort 1, 60% vs cohort 2, 17.2%; P = 0.001) and reduction in readmission rate (7.7% vs 0%; P = 0.01) and video-assisted thoracoscopic surgery procedures (44.6% vs 28.7; P = 0.03), without concomitant increases in vancomycin use (34.9% vs 34.5%; P = 0.95) or hospital length of stay (6.4 vs 7.6 days; P = 0.4). Among patients who received video-assisted thoracoscopic surgery drainage (n = 57), there were no significant differences between cohorts in median time from admission to video-assisted thoracoscopic surgery (2 days; P = 0.29) or median duration of chest tube drainage (3 vs 4 days; P = 0.10). There was a statistically nonsignificant trend for higher rate of pathogen identification in cohort 2 (cohort 1, 33% vs cohort 2, 54.1%; P = 0.12); Streptococcus pneumonia was the most commonly identified pathogen in both cohorts (37.5% vs 27%; P = 0.23).

Discussion

Implementation of an institutional complicated pneumonia management algorithm reduced CT scan use/radiation exposure, VATS procedures, and readmission rate in children with a diagnosis of pleural infection, without associated increases in length of stay or vancomycin use. This algorithm provides the framework for future prospective quality improvement studies in pediatric patients with complicated pneumonia.
HER2 Codon 655 G-Allele is Associated with Reductions in Plasma High-Density Lipoprotein Levels in Breast Cancer Patients Treated with Tamoxifen
Authors: Chang Nai-Wen , Chen Dar-Ren , Chen Fei-Na , Lin Chingju , Wu Chen-Teng
Published: May 2016

Background

Retrospective studies have revealed that overexpression of the epidermal growth factor receptor ErbB-2 (HER2) reduced the efficacy of tamoxifen therapy, which is associated with an increased risk for cardiovascular events. The aim of this study was to evaluate the effects of the HER2 I655V polymorphism (ATC/isoleucine to GTC/valine) on lipid profiles after tamoxifen treatment.

Methods

Thirty-four women diagnosed with breast cancer were recruited in the study and followed up for 6 months. The presence of the HER2 I655V polymorphism and fasting plasma lipid profiles before and after tamoxifen treatment were determined for each subject for the duration of the study.

Results

In response to tamoxifen therapy, we found that plasma total cholesterol (TC, P = 0.041), low-density lipoprotein-cholesterol (LDL-C, P < 0.001), and high-density lipoprotein-cholesterol (HDL-C, P = 0.012) levels decreased significantly in the A-allele (AA genotype) carriers compared with the baseline measurements. Plasma LDL-C ( P < 0.001) and HDL-C ( P < 0.001) levels decreased significantly, and the TC/HDL-C ( P = 0.027) ratio increased significantly in the G-allele (AG/GG genotypes) carriers. According to the repeated-measures analysis, G-allele carriers had a lower ratio of LDL-C/HDL-C than A-allele carriers did ( P = 0.016). Notably, G-allele carriers had a greater reduction in HDL-C concentration than A-allele carriers ( P = 0.039; G-allele, −12.4 ± 6.8 mg/dL vs A-allele, −5.6 ± 9.5 mg/dL).

Conclusions

This study shows that the HER2 codon 655 G-allele was associated with a larger reduction in plasma HDL-C levels in breast cancer patients under tamoxifen therapy. Therefore, we suggest that the polymorphism of HER2 655 codon should be considered for the prevention of cardiovascular events in breast cancer patients after tamoxifen therapy.
Levels of Blood Periostin Decrease after Acute Myocardial Infarction and are Negatively Associated with Ventricular Function after 3 Months
Authors: Cheng Chi-Wen , Wang Chao-Hung , Lee Ju-Fang , Kuo Li-Tang , Cherng Wen-Jin
Published: May 2016

Background

A recent study showed that periostin (PN) induced reentry of differentiated cardiomyocytes into the cell cycle and improved heart function after acute myocardial infarction (AMI). This study sought to investigate whether PN levels increase after AMI and whether they provide prognostic value.

Methods and Results

We recruited 123 patients: 45 with AMI, 45 with stable coronary artery disease (CAD), and 33 healthy controls (CON). Blood PN and N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels were measured. Echocardiography was repeated 3 months after AMI. In the AMI group, the PN levels 1.3 ± 1.2 days after AMI were significantly lower than those in the CAD and CON groups (175 ± 60, 245 ± 68, and 232 ± 63 ng/mL, respectively, P = 0.001). The NT-pro-BNP levels were significantly higher in the AMI group, compared to the CON and CAD groups (10.07 ± 28.2 [median, 0.70] vs 0.08 ± 0.06 [median, 0.05] and 1.1 ± 4.2 [median, 0.09] ng/mL, respectively; P = 0.02). The PN levels further decreased 8 ± 2 days after AMI (from 175 ± 60 to 143 ± 57 ng/mL; P = 0.003). However, NT-pro-BNP levels did not significantly change. With respect to the echocardiographic parameters 3 months after AMI, the PN levels measured before discharge were negatively associated with the left ventricular ejection fraction ( rs = −0.50; P = 0.001), end diastolic ( rs = 0.42; P = 0.009) and systolic ( rs = 0.46; P = 0.004) diameters. The NT-pro-BNP levels were not significantly correlated with these parameters.

Conclusion

Acute myocardial infarction is associated with a decrease in blood PN levels, and PN concentrations predict cardiac function 3 months after AMI.
Influence of Upper and Lower Body Adipose Tissue on Insulin Sensitivity in South Asian Men
Authors: Balakrishnan Preetha , Grundy Scott M. , Islam Arsalla , Dunn Fredrick , Vega Gloria Lena
Published: May 2016

Background

South Asians have a high prevalence of insulin resistance, which predisposes to type 2 diabetes.

Rationale

In the current study, we examined whether insulin sensitivity in South Asian men and men of European descent (Europids) relates to truncal and lower body fat, number of adipocytes, and cell size distribution.

Results

Fifteen South Asian men and 15 Europid young men with comparable body mass indexes completed assessments of insulin sensitivity, body composition analysis by dual-energy x-ray absorptiometry, and measurement of adipocyte cellularity in the subcutaneous abdominal (truncal) and gluteal (lower body) adipose tissue. The South Asians and the Europids had similar total body fat and fat contents in truncal and lower body regions. Compared to the Europids, the South Asians had a greater insulin resistance shown by fasting insulin, area-under-the-curve for postprandial insulin, oral glucose insulin sensitivity, homeostatic model assessment of insulin resistance, β-cell index, and triglyceride-to-high-density lipoprotein ratio. The South Asians had similar number of adipocytes to the Europids, but the South Asians had significantly higher ratios of small-to-larger adipocytes. The South Asians further had a higher fraction of very large adipocytes. In both South Asians and Europids, truncal fat was positively associated with insulin resistance. In the South Asians but not in the Europids, lower body fat was associated with severity of insulin resistance.

Conclusions

The results suggest first, a higher ratio of small-to-larger adipocytes in the South Asians consistent with a lesser lipid storage capacity of adipose tissue; and second, the positive association of lower body fat with insulin resistance in the South Asians implies that fat in their lower body worsens insulin resistance. This association was not observed in the Europids.