Showing papers in "Journal of Investigative Medicine in 2012"
TL;DR: Through analysis of in-depth interviews with members of highly successful research teams and others who did not meet their goals or ended because of conflicts, key elements that are critical for team success and effectiveness are identified.
Abstract: Interdisciplinary efforts are becoming more critical for scientific discovery and translational research efforts. Highly integrated and interactive research teams share a number of features that contribute to their success in developing and sustaining their efforts over time. Through analysis of in-depth interviews with members of highly successful research teams and others who did not meet their goals or ended because of conflicts, we identified key elements that are critical for team success and effectiveness. There is no debate that the scientific goal sits at the center of the collaborative effort. However, supporting features need to be in place to avoid the derailment of the team. Among the most important of these is trust: without trust, the team dynamic runs the risk of deteriorating over time. Other critical factors of which both leaders and participants need to be aware include developing a shared vision, strategically identifying team members and purposefully building the team, promoting disagreement while containing conflict, and setting clear expectations for sharing credit and authorship. Self-awareness and strong communication skills contribute greatly to effective leadership and management strategies of scientific teams. While all successful teams share the characteristic of effectively carrying out these activities, there is no single formula for execution with every leader exemplifying different strengths and weaknesses. Successful scientific collaborations have strong leaders who are self-aware and are mindful of the many elements critical for supporting the science at the center of the effort.
273 citations
TL;DR: It is hypothesize that the role of the immune system in tumor development and progression is tissue specific and it is hoped that better understanding of this process will lead to better treatments for this devastating disease.
Abstract: With the continued failures of both early diagnosis and treatment options for pancreatic cancer, it is now time to comprehensively evaluate the role of the immune system on the development and progression of pancreatic cancer. It is important to develop strategies that harness the molecules and cells of the immune system to treat this disease. This review will focus primarily on the role of immune cells in the development and progression of pancreatic ductal adenocarcinoma and to evaluate what is known about the interaction of immune cells with the tumor microenvironment and their role in tumor growth and metastasis. We will conclude with a brief discussion of therapy for pancreatic cancer and the potential role for immunotherapy. We hypothesize that the role of the immune system in tumor development and progression is tissue specific. Our hope is that better understanding of this process will lead to better treatments for this devastating disease.
116 citations
TL;DR: Elevation in serum TNF-α on post-SAH days 2 to 3 and global elevation of T NF-α over time are associated with poor outcome but not with angiographic vasospasm in this small cohort.
Abstract: Objective Subarachnoid hemorrhage (SAH) is associated with inflammation that may mediate poor outcome in SAH. We hypothesize that elevated serum tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) are associated with vasospasm and poor outcome in SAH. Methods In 52 consecutive SAH subjects, we compared TNF-α and IL-6 levels on post-SAH days 0 to 1, 2 to 3, 4 to 5, 6 to 8, and 10 to 14 with respect to vasospasm and to poor outcome at 3 and 6 months. Vasospasm was defined as more than 50% reduction in vessel caliber on angiography. Poor outcome was defined as modified Rankin score greater than 2. Results Elevated TNF-α on post-SAH days 2 to 3 was associated with poor 3-month outcome (P = 0.0004). Global elevation of TNF-α over time (post-SAH days 0–14) was independently associated with poor 3-month outcome after adjusting for Hunt-and-Hess grade and age (P = 0.02). Neither cross-sectional nor IL-6 levels over time were associated with outcome. Neither TNF-α nor IL-6 levels were associated with vasospasm. Conclusions Elevation in serum TNF-α on post-SAH days 2 to 3 and global elevation of TNF-α over time are associated with poor outcome but not with angiographic vasospasm in this small cohort. Future studies are needed to define the role of TNF-α in SAH-related brain injury and its potential as a SAH outcome biomarker.
70 citations
TL;DR: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of serum Tg after tryptic digestion of serum samples is described, which will permit the accurate determination of Tg levels even in patients with ATG.
Abstract: Thyroid cancer is the most common endocrine cancer in the United States. The primary treatment of thyroid cancer is partial or complete thyroidectomy in patients in whom the cancer is discovered preoperatively, and is often followed by radioactive iodine ablation. After the initial therapy, patients are followed up regularly, most commonly by measurement of serum thyroglobulin (Tg) levels and high-resolution neck ultrasound. As Tg is only produced within the thyroid gland, it has long been recognized as an excellent biomarker for the presence of residual disease after treatment. A number of immunoassays are in common use to measure serum Tg levels. Unfortunately, irrespective of which method is chosen, there is a major potential artifact, in that the presence of autoantibodies binding to Tg (ATG) may bias the results to the point where they are clinically unreliable. This article describes a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the measurement of serum Tg after tryptic digestion of serum samples. The method is compared to Tg analyses using both a Food and Drug Administration-approved immunometric assay (IMA) and a well-respected, clinically used radioimmunoassay. In the absence of ATG, the new LC-MS/MS assay demonstrates equivalency compared to the IMA. However, in ATG-positive patients, the IMA Tg results are lower than the LC-MS/MS assay and the radioimmunoassay Tg results are typically higher. These studies demonstrate the accuracy and validity of the measurement of Tg by LC-MS/MS. This assay will permit the accurate determination of Tg levels even in patients with ATG.
65 citations
TL;DR: Low-serum 25(OH)D levels are associated with the severity of coronary artery stenosis and further studies are warranted to determine whether vitamin D supplementation could prevent progression of CAD.
Abstract: Background and Objectives Low-serum vitamin D levels have been associated with increased cardiovascular risk in the general population. We hypothesized that serum vitamin D levels would be inversely associated with inflammation and with severity of coronary atherosclerosis. We therefore investigated the link between serum vitamin D levels and (1) the extent of coronary artery disease (CAD) assessed by the Gensini score and (2) inflammatory parameters, including C-reactive protein and fibrinogen. Materials and Methods We measured 25-hydroxyvitamin D (25[OH]D) and inflammatory markers in 239 patients who underwent coronary angiography. We analyzed the relation between serum levels of 25(OH)D and inflammatory markers and angiographic severity of CAD. The Gensini lesion severity score was used for assessing the severity of coronary atherosclerosis. Results Vitamin D insufficiency was very common among our study population: 83% of the study population had levels less than 30 ng/mL. The Gensini score was negatively associated with serum vitamin D levels ( r = −0.416, P r = 0.209, P = 0.001), blood pressure ( r = 0.379, P r = 0.335, P r = 0.150, P = 0,021), and C-reactive protein levels ( r = 0.214, P = 0,001). After adjustments for traditional and nontraditional cardiovascular risk factors, vitamin D (B = −0,345, P Conclusions Low-serum 25(OH)D levels are associated with the severity of coronary artery stenosis. Further studies are warranted to determine whether vitamin D supplementation could prevent progression of CAD.
60 citations
TL;DR: The results indicate that IL-33 may contribute to the pathogenesis of chronic autoimmune diseases, such as systemic sclerosis, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus.
Abstract: Interleukin 33 (IL-33) is a newly described member of the IL-1 superfamily of cytokines. Through activation of the ST2 receptor, which is widely expressed particularly by helper T 2 cells and mast cells, IL-33 is involved in T-cell-mediated immune responses. Many previous studies have demonstrated that IL-33 may have a pleiotropic function in different diseases, and it could represent a novel target for the treatment of a range of diseases. Recent works have explored the role of IL-33 in chronic autoimmune diseases, such as systemic sclerosis, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus. These results indicate that IL-33 may contribute to the pathogenesis of chronic autoimmune diseases. Hence, in this review, we discuss the biological features of IL-33 and summarize recent advances on the role of IL-33 in the pathogenesis and treatment of autoimmune diseases.
59 citations
TL;DR: The purpose of this review was to acquaint practicing oncologists with the fundamental principles and pathways of steroid biosynthesis, to improve their understanding of how and why these drugs work, and to alert these physicians to potential problems related to the drugs’ mechanisms of action.
Abstract: In 2005, results from the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial ushered in a new era of endocrine therapy for hormone-responsive malignancies. This study demonstrated that, compared with tamoxifen (a selective estrogen receptor modulator), anastrozole (aromatase inhibitor [AI]) prolonged time to recurrence and disease-free survival for postmenopausal women with breast cancer. The advantage was even greater for those with estrogen receptor-positive (ER) tumors, and anastrozole was better tolerated than tamoxifen. Since then, AIs have become first-line adjuvant therapy for ER breast cancer in postmenopausal women.In late 2010, a trial comparing abiraterone acetate (a 17-hydroxylase/17,20-lyase [CYP17A1] inhibitor) plus prednisone versus prednisone alone in men with castration-resistant prostate cancer (CRPC) previously treated with docetaxel chemotherapy was terminated early because of the survival benefit in the abiraterone acetate arm. This result not only validated a new therapy for CRPC but also, with the antecedent phase I-II abiraterone studies, shattered our understanding of the molecular mechanisms underpinning CRPC development and progression.Aromatase inhibitors and CYP17A1 inhibitors will be widely used by oncologists, yet fellowship programs provide little training in steroid biosynthesis, compared with training in the biology of standard chemotherapies. Consequently, these drugs might be used without an appreciation of their caveats and pitfalls. The purpose of this review was to acquaint practicing oncologists with the fundamental principles and pathways of steroid biosynthesis, to improve their understanding of how and why these drugs work, and to alert these physicians to potential problems related to the drugs' mechanisms of action.
53 citations
TL;DR: Progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate, which effectively inhibits CYP17A1, blocks the synthesis of androgens, and extends the survival of men with CRPC.
Abstract: The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor (AR), as well as the availability of endogenous AR agonists. Originating from the gonads, testosterone is released into circulation and is converted by steroid-5α-reductase in prostate cancer to 5α-dihydrotestosterone (DHT), potently activating AR and driving tumor progression. Advanced prostate cancer is initially treated with gonadal testosterone depletion, which suppresses this cascade of events and typically leads to a treatment response. Eventually, resistance to testosterone deprivation occurs with "castration-resistant" prostate cancer (CRPC) and is driven by the intratumoral synthesis of DHT. The generation of DHT occurs in large part from adrenal 19-carbon precursor steroids, which are dependent on expression of CYP17A1. Although the path from adrenal precursor steroids to DHT was generally thought to require 5α-reduction of testosterone, recent data suggest that it instead involves conversion from Δ-androstenedione by steroid-5α-reductase isoenzyme-1 to 5α-androstanedione, followed by subsequent conversion to DHT. The 5α-androstanedione pathway to DHT therefore bypasses testosterone entirely. Abiraterone acetate effectively inhibits CYP17A1, blocks the synthesis of androgens, and extends the survival of men with CRPC. Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate.
41 citations
TL;DR: CXCL12 levels in SF of knee OA patients were significantly correlated with disease severity evaluated by KL grading criteria, however, there were no significant differences in the serum CXCL 12 levels between patients with different KL grades.
Abstract: Objective Inflammation is implicated to be involved in the pathogenesis of osteoarthritis (OA). CXCL12, also known as stromal cell-derived factor, is the unique identified natural ligand of the G-protein-coupled receptor CXCR4 and exhibits both homeostatic and proinflammatory functions. This study aims to determine whether CXCL12 levels in serum and synovial fluid (SF) of patients with knee OA are correlated with the disease severity. Methods This study consisted of 252 patients with knee OA and 144 healthy controls. The radiological grading of OA in the knee was performed according to the Kellgren-Lawrence grading system. CXCL12 levels in serum and SF were measured by enzyme-linked immunosorbent assay. Results Higher levels of serum CXCL12 were found in knee OA patients compared with healthy controls. The CXCL12 levels in SF of knee OA patients with KL grade 4 were significantly elevated compared with those with KL grades 2 and 3. Furthermore, knee OA patients with KL grade 3 had significantly higher SF levels of CXCL12 compared with those with KL grade 2. CXCL12 levels in SF of knee OA patients were significantly correlated with disease severity evaluated by KL grading criteria. However, there were no significant differences in the serum CXCL12 levels between patients with different KL grades. Conclusion CXCL12 levels in SF were closely related to the radiographic severity of OA. CXCL12 levels in SF may be an alternative biomarker for the progression of OA.
41 citations
TL;DR: The challenges in using the currently available animal models for translational research, particularly for developing potentially new drugs for human disease, coupled with the difficulties in toxicity prediction have led some researchers to develop a scoring system for translatability.
Abstract: Translation of scientific discoveries into meaningful human applications, particularly novel therapies of human diseases, requires development of suitable animal models. Experimental approaches to test new drugs in preclinical phases often necessitated animal models that not only replicate human disease in etiopathogenesis and pathobiology but also biomarkers development and toxicity prediction. Whereas the transgenic and knockout techniques have revolutionized manipulation of rodents and other species to get greater insights into human disease pathogenesis, we are far from generating ideal animal models of most human disease states. The challenges in using the currently available animal models for translational research, particularly for developing potentially new drugs for human disease, coupled with the difficulties in toxicity prediction have led some researchers to develop a scoring system for translatability. These aspects and the challenges in selecting an animal model among those that are available to study human disease pathobiology and drug development are the topics covered in this detailed review.
41 citations
TL;DR: Obesity and metabolic syndrome were associated with strikingly elevated risk for diabetes in subjects with intermediate hyperglycemia, and this seemingly justifies intensive clinical intervention for prevention of both diabetes and cardiovascular disease.
Abstract: Background To determine risk for type 2 diabetes in subjects with fasting glucose levels in the ranges of normoglycemia, mild hyperglycemia, and intermediate hyperglycemia and to assess the effect of obesity and metabolic syndrome on this risk. Subjects and Methods Incidence of type 2 diabetes mellitus was evaluated in 28,209 relatively healthy subjects participating in the Cooper Center Longitudinal Study. They were included in the study if they had more than 1 fasting plasma glucose measurement, anthropometry, and other parameters of interest. Three subgroups were identified: normoglycemic ( Results Thirty-one percent of men and 15.9% of women had mild hyperglycemia and 11.9% of men and 3.6% of women had intermediate hyperglycemia. Yearly conversion rates to diabetes were low in individuals with normoglycemia and mild hyperglycemia but were strikingly higher in those with intermediate hyperglycemia. In subjects with intermediate hyperglycemia, presence of obesity and/or metabolic syndrome doubled conversion rates to diabetes. Conclusions This study showed a marked difference in outcomes in subjects with mild and intermediate hyperglycemia. Moreover, obesity and metabolic syndrome were associated with strikingly elevated risk for diabetes in subjects with intermediate hyperglycemia. Thus intermediate hyperglycemia plus obesity/metabolic syndrome seemingly justifies intensive clinical intervention for prevention of both diabetes and cardiovascular disease.
TL;DR: This review summarizes the current state of knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo and indicates multiple lines of evidence indicate a role for cholesterol in AD.
Abstract: Alzheimer disease (AD) is an age-related neurodegenerative disorder that manifests as a progressive loss of memory and deterioration of higher cognitive functions. Alzheimer disease is characterized by accumulation in the brain of the β-amyloid peptide generated by β- and γ-secretase processing of amyloid precursor protein. Epidemiological studies have linked elevated plasma cholesterol and lipoprotein levels in midlife with AD development. Cholesterol-fed animal models exhibit neuropathologic features of AD including accumulation of β-amyloid peptide. Specific isoforms of the cholesterol transporter apolipoprotein E are associated with susceptibility to AD. Although multiple lines of evidence indicate a role for cholesterol in AD, the exact impact and mechanisms involved remain largely unknown. This review summarizes the current state of our knowledge of the influence of cholesterol and lipid pathways in AD pathogenesis in vitro and in vivo.
TL;DR: Raising awareness to career-related aspects of team science will help individuals (particularly trainees and junior faculty) take steps to align their excitement and participation with the success of both the team and their personal career advancement.
Abstract: Academic institutions and researchers are becoming increasingly involved in translational research to spur innovation in addressing many complex biomedical and societal problems and in response to the focus of the National Institutes of Health and other funders. One approach to translational research is to develop interdisciplinary research teams. By bringing together collaborators with diverse research backgrounds and perspectives, these teams seek to blend their science and the workings of the scientists to push beyond the limits of current research.While team science promises individual and team benefits in creating and implementing innovations, its increased complexity poses challenges. In particular, because academic career advancement commonly focuses on individual achievement, team science might differentially impact early stage researchers. The need to be recognized for individual accomplishments to move forward in an academic career may give rise to research team conflicts. Raising awareness to career-related aspects of team science will help individuals (particularly trainees and junior faculty) take steps to align their excitement and participation with the success of both the team and their personal career advancement.
TL;DR: The activity of PON and ARE were significantly decreased, and oxidative stress was increased in patients with SH, indicating increased oxidative damage in SH.
Abstract: Introduction In subclinical hypothyroidism (SH), serum lipid and lipoprotein concentrations are frequently changed. Compared with the healthy population, the levels of oxidized low-density lipoprotein cholesterol are higher, and the levels of high-density lipoprotein cholesterol are lower. In patients with SH, the mechanism of atherosclerosis may beattributed to the lipid abnormalities. There is evidence showing that oxidation plays an important role during the process of atherosclerosis. Inthis study, we evaluated the activity of paraoxonase (PON) and arylesterase (ARE) in patients with SH and investigated their relation with oxidative stress. Methods The study enrolled 25 patients with SH and 20 sex- and age-matched healthy controls. The patient group and the control group were compared in terms of the activity of PON and ARE and the oxidative stress index. Results Between 2 groups, no significant difference was found in terms of age, sex, serum levels of total cholesterol, low-density lipoprotein, and high-density lipoprotein. In the SH group, the activity of PON was significantly lower than that observed in the control group (P Conclusions The activity of PON and ARE were significantly decreased, and oxidative stress was increased in patients with SH. Lower activities of these 2 biomarkers indicate increased oxidative damage in SH. Atherosclerosis in SH can be attributed to increased oxidative stress.
TL;DR: The targeting of the trafficking of 2 key BBB proteins, P-glycoprotein and occludin, is presented as a novel, reversible means of optimizing central nervous system drug delivery.
Abstract: The blood-brain barrier (BBB) is a physical and metabolic barrier that separates the central nervous system from the peripheral circulation. Central nervous system drug delivery across the BBB is challenging, primarily because of the physical restriction of paracellular diffusion between the endothelial cells that comprise the microvessels of the BBB and the activity of efflux transporters that quickly expel back into the capillary lumen a wide variety of xenobiotics. Therapeutic manipulation of protein trafficking is emerging as a novel means of modulating protein function, and in this minireview, the targeting of the trafficking of 2 key BBB proteins, P-glycoprotein and occludin, is presented as a novel, reversible means of optimizing central nervous system drug delivery.
TL;DR: The high expression of CD200 in B-cell CLL and hairy cell leukemia could open the option for targeted immune (anti-CD200) therapy and could be added to the BCLPD routine panels.
Abstract: Background Flow cytometry immunophenotyping (FCIP) is used for rapid, specific diagnosis of B-chronic lymphoproliferative disorders (BCLPDs). However, cases may deviate from the typical immunophenotype; therefore, there is a need for adding new marker(s) for differentiating BCLPDs. Lately, few researches highlighted CD200 expression in some BCLPDs. Our aim was to evaluate CD200 expression in different BCLPDs and whether adding CD200 to BCLPD-FCIP routine panels could improve the ability of their differential diagnosis. Methods We evaluated CD200 expression in 49 BCLPD patients and 26 age- and sex-matched control subjects. Flow cytometry immunophenotyping first panel included CD5, CD19, sIg, CD23, CD22, CD79b, and FMC7; for BCLPDs other than chronic lymphocytic leukemia (CLL) and mantle cell lymphoma, CD11c, CD103, CD25, and CD10 were evaluated. Results Using tricolor FCIP, CD200 showed high bright expression on CD5/19-positive clone in all B-CLL patients (100%), with a mean of 94% (SD, 11%); in the 2 cases of hairy cell leukemia, CD200 was brightly expressed on 96% and 99% of cells. In all other BCLPDs including mantle cell lymphoma, follicular lymphoma and splenic marginal zone lymphoma, CD200 expression (on CD19/22-positive cells) was less than 20% with a mean of 10% (SD, 8%) and a dim pattern. CD200 expression was significantly higher in CLL compared with non-Hodgkin lymphoma groups (P Conclusions Evaluating CD200 expression has a great impact on accurate BCLPDs diagnosis and could be added to the BCLPD routine panels. The high expression of CD200 in B-cell CLL and hairy cell leukemia could open the option for targeted immune (anti-CD200) therapy.
TL;DR: In this paper, the authors demonstrate omentin-1 levels in serum and synovial fluid (SF) of patients with knee osteoarthritis and investigate their correlation with radiographic disease severity.
Abstract: Objective The purpose of this study was to demonstrate omentin-1 levels in serum and synovial fluid (SF) of patients with knee osteoarthritis (OA) and to investigate their correlation with radiographic disease severity. Methods One hundred and ninety-seven patients with OA and 65 sex- and age-matched healthy controls were enrolled in this study. The radiographic disease severity of OA was assessed by the Kellgren- Lawrence (KL) grading system. The omentin-1 levels in serum and SF were determined by enzyme-linked immunosorbent assay. Results There were no significant differences in serum omentin-1 levels between patients with OA and healthy controls (P > 0.05). There were also no significant differences in serum omentin-1 levels among patients with OA with different KL grades (P > 0.05). However, SF omentin-1 levels decreased significantly as the KL grades increased (KL grade 4 Conclusions Synovial fluid omentin-1 levels showed an independent and negative correlation with radiographic severity of the disease in patients with knee OA. Omentin-1 in SF might serve as a potential biomarker for reflecting the degenerative process of primary knee OA.
TL;DR: Visceral fat measured with BIA is an easily applicable and useful method for identifying people with MetS and the best cutoff values were higher than 12% for men and higher than 9% for women.
Abstract: Objective Central obesity is a prerequisite for the diagnosis of metabolic syndrome (MetS). Precise measurement of visceral fat by bioelectrical impedance analysis (BIA) has been validated. The aim of this study was to investigate the diagnostic performance of BIA in MetS and validate the best cutoff in a large adult cohort. Materials and Methods The study was performed on the MELEN Study cohort—a prospectively designed survey on the prevalence of cardiometabolic risk factors in Turkish adults. The final cohort consisted of 2219 participants. Weight and visceral body composition were measured without shoes in light indoor clothes using a bioimpedance analyzer (Omron BF 510; Omron Corp, Kyoto, Japan). Plasma concentrations of cholesterol, insulin, fasting triglycerides, high-density lipoprotein cholesterol, glucose, and other biochemical variables were measured. The diagnostic performance of visceral fat measurement by BIA in patients with MetS was assessed. Results Metabolic syndrome was detected in 751 participants (520 women and 231 men with a mean age of 55 [12] years; 34% of the whole study population). Total body fat and visceral fat levels were higher in subjects with MetS. Correlation analyses showed that there were significant correlations between anthropometric and BIA measurements. Receiver operating curve characteristics of visceral adiposity revealed the best cutoff values as greater than 12% for men and greater than 9% for women. The diagnostic performance was good in both sexes (the sensitivity/specificity and area-under-the-curve values were 76%/75% and 0.83 for men and 83%/67% and 0.81 for women, respectively). Conclusions Visceral fat measured with BIA is an easily applicable and useful method for identifying people with MetS. The best cutoff values were higher than 12% for men and higher than 9% for women.
TL;DR: High NGAL levels may be associated with poor prognosis after PCI in patients with STEMI, and further studies with larger numbers of patients and longer follow-up are required to evaluate the usefulness of plasma NGAL level for predicting prognosis of STEMI.
Abstract: Objectives This study investigated the prognostic value of neutrophil gelatinase–associated lipocalin (NGAL) in patients with ST-segment elevation myocardial infarction (STEMI). Background Neutrophil gelatinase–associated lipocalin is a promising biomarker for acute kidney injury. Recently, it was concluded that NGAL may be used beyond the boundaries of renal physiopathology. It was found to be an important factor indirectly contributing to the inflammatory processes. Little is known regarding its predictive role in STEMI. Methods One hundred six consecutive patients who underwent percutaneous coronary intervention (PCI) for STEMI and control group consisted of age- and sex-matched 60 consecutive patients with chest pain admitted to the hospital for elective PCI. According to median NGAL level, patients were classified into high- and low-NGAL groups. Results Neutrophil gelatinase–associated lipocalin levels were higher in patients with STEMI compared to the elective PCI group subjects. Inhospital and 1-year mortality rates were found to be significantly greater in patients with high NGAL. In addition, inhospital and 1-year major adverse cardiovascular event rates were significantly greater in the high-NGAL group, compared to the low NGAL group. High NGAL level on admission was a significant predictor for long-term mortality and major adverse cardiovascular events. The receiver operating characteristics curve analysis further illustrated that NGAL level on admission is a strong indicator of mortality, with an area under the curve of 0.76 (95% confidence interval, 0.62–0.89). Conclusions High NGAL levels may be associated with poor prognosis after PCI in patients with STEMI. However, further studies with larger numbers of patients and longer follow-up are required to evaluate the usefulness of plasma NGAL level for predicting prognosis of STEMI.
TL;DR: Investigating the cross-sectional association between serum adipocyte fatty acid–binding protein (A-FABP) level and diagnosis or severity of obstructive sleep apnea syndrome (OSAS) and some echocardiographic indices related with cardiac dysfunction found increased A-FabP levels in patients with OSAS, which were correlated significantly with left ventricular mass index and MPI.
Abstract: Objective To investigate the cross-sectional association between serum adipocyte fatty acid–binding protein (A-FABP) level and diagnosis or severity of obstructive sleep apnea syndrome (OSAS) and some echocardiographic indices related with cardiac dysfunction. Methods In this study, plasma A-FABP and high-sensitivity C-reactive protein concentrations were measured, and echocardiography was performed in subjects without any cardiac or pulmonary disease who were referred for evaluation of OSAS. According to the apnea-hypopnea index (AHI), subjects were classified into 3 groups: control group (AHI AHI ≥ 5; n = 30), and severe OSAS (AHI ≥ 30; n = 31). Results Levels of A-FABP were significantly different between the groups (P Conclusions Increased A-FABP levels were found in the patients with OSAS, which were correlated significantly with left ventricular mass index and MPI. Further prospective studies are needed to clarify whether increased serum A-FABP level is a marker or a potential mechanism for left ventricular involvement in patients with OSAS.
TL;DR: In this paper, it has been shown that adipose tissue fibrosis is also enhanced in obese humans and rodents along with inflammatory responses, and suppression of adipose tissues fibrosis shows improved insulin sensitivity in rodent models.
Abstract: Obesity is one of the most serious pandemic health problems in modern society and the predisposing factor for the type 2 diabetes mellitus. Chronic low-grade inflammation mediates the pathogenesis of insulin resistance in obese humans and rodents, and white adipose tissue is one of major tissues to modulate inflammation. Obese humans and rodents show dynamic changes of immunocellular compositions in white adipose tissue to induce inflammatory responses. Innate and adaptive immune responses mainly mediated by macrophages and T cells contribute insulin resistance. Recently, it has been shown that adipose tissue fibrosis is also enhanced in obese humans and rodents along with inflammatory responses, and suppression of adipose tissue fibrosis shows improved insulin sensitivity in rodent models, suggesting that adipose tissue fibrosis is involved in insulin resistance.
TL;DR: Clostridium difficile infection is associated with significantly worse outcomes in hospitalized patients with ESRD, and CDI was independently associated with greater mortality and higher charges.
Abstract: Objective To investigate the association of Clostridium difficile infection (CDI) with the outcomes of hospitalized patients with end-stage renal disease (ESRD). Methods We extracted all adult cases with a discharge diagnosis of ESRD or CDI from the United States Nationwide Inpatient Sample 2009 database. Outcome variables (mortality, length of hospital stay [LOS], and hospitalization charges), demographic information, and comorbidity data were collected. Data were evaluated by univariate and multiple regression analyses. Results We identified 184,139 cases with ESRD of which 2.8% had CDI. Comparison of patients with ESRD + CDI to those with only ESRD revealed in-hospital mortality (13.2% vs 5.3%; P Conclusions Clostridium difficile infection is associated with significantly worse outcomes in hospitalized patients with ESRD.
TL;DR: The concept of chemokines (RANTES) as mediators of liver cell injury in HCV infection is supported and MDA and NO levels might be used as monitoring markers for oxidative stress in hepatitis C infection.
Abstract: Background Chronic infection with hepatitis C virus (HCV) is associated with failures of T-cell–mediated immune clearance and with abnormal B-cell growth and activation. Hepatitis C virus infection is characterized by a systemic oxidative stress that is most likely caused by a combination of chronic inflammation, iron overload, liver damage, and proteins encoded by HCV. After a viral infection, multiple proinflammatory mediators contribute to recruitment of immune cells to the liver and to the generation of an antiviral immune response. Recent publications mark chemokines and their receptors as key players in leukocyte recirculation through the inflamed liver. Materials and Methods The present study involved 75 male subjects, divided into 2 groups: group 1 (n = 30), control group; group 2 (n = 45), patients with chronic HCV. For all subjects, the following investigations were performed: estimation of the levels of bilirubin, albumin, prothrombin concentration, glycosylated hemoglobin, creatinine, α-fetoprotein, HCV RNA, and activities of alanine and aspartate transaminases as well as alkaline phosphatase. In addition, regulated on activation normal T cell expressed and secreted (RANTES), tumor necrosis factor alpha, malondialdehyde (MDA) and nitric oxide (NO) were assessed. Plasma HCV-RNA concentration (viral load) was determined by real-time polymerase chain reaction (PCR) StepOne system using Applied Biosystem. Complete blood picture was assayed using Abbott Cell-Dyn 3700 hematology analyzer. Results There were significant increases of the levels of RANTES, tumor necrosis factor alpha, MDA, and NO in HCV-infected patients compared with the control group (P Conclusion The data support the concept of chemokines (RANTES) as mediators of liver cell injury in HCV infection. In addition, MDA and NO levels might be used as monitoring markers for oxidative stress in hepatitis C infection.
TL;DR: Sex differences in CVD incidence and risk among diabetics, sex differences in physical activity behaviors, cardiovascular abnormalities and impaired exercise capacity in women living with diabetes, and the effects of exercise on prevention and treatment of CVD in diabetic women are reviewed.
Abstract: Diabetes currently affects approximately 14% of the US population, and cardiovascular disease (CVD) is a leading cause of morbidity and mortality in those with diabetes. Although in the general population women are at lower risk than men for CVD, women have a disproportionately greater increase in risk for CVD than do men in the context of diabetes. Physical activity is considered a cornerstone in the prevention and treatment of CVD and its risk factors, but greater barriers to physical activity may exist for women with diabetes compared to their male counterparts. In this article, we review sex differences in CVD incidence and risk among diabetics, sex differences in physical activity behaviors, cardiovascular abnormalities and impaired exercise capacity in women living with diabetes, and the effects of exercise on prevention and treatment of CVD in diabetic women. Finally, we discuss future research needed to clarify potential sex differences in the cardiovascular effects of diabetes and to establish ways to reduce the barriers to exercise in women with diabetes.
TL;DR: High-density lipoprotein cholesterol (HDL-C) promotes cholesterol efflux from macrophage foam cells in atheroma plaques and has anti-inflammatory and endothelium-protective properties, but it is found that low HDL-C frequency was more frequent in the poor CCC group than the good C CC group, and HDL- C was a predictor of CCC.
Abstract: Introduction High-density lipoprotein cholesterol (HDL-C) promotes cholesterol efflux from macrophage foam cells in atheroma plaques. In addition, HDL-C has anti-inflammatory and endothelium-protective properties. Despite that the only prerequisite for collateral development is shown to be the degree of coronary artery stenosis, there are significant differences even among patients with a similar degree of coronary artery disease. Objective We designed this study to investigate a possible association between HDL-C and coronary collateral circulation (CCC). Materials and Methods All study participants had at least one occluded major coronary artery. Demographic, clinical, and laboratory data were obtained from patients’ medical records. To classify CCC, we used Rentrop classification. The patients were then classified as having poor CCC (Rentrop grades 0–1) or good CCC (Rentrop grades 2–3). We performed t test and the χ 2 test in comparing groups and multivariate logistics regression analysis to determine the predictors of CCC. The study population consisted of 151 patients (mean age, 63.7 ± 9 years; 76.2% male). Results Forty-nine patients had poor CCC and 102 patients had good CCC. The proportion of previous myocardial infarctions, serum triglycerides, and low HDL-C levels were more frequent in the poor CCC group ( P = 0.026, P = 0.015, and P B = 1.456; P Conclusion We found that low HDL-C frequency was more frequent in the poor CCC group than the good CCC group, and HDL-C was a predictor of CCC.
TL;DR: 3 proteins, namely, PAI-RBP1, C1orf142, and COTL1, which were differentially expressed in NSCLC cell lines with different metastatic potential are identified by using 2-dimensional electrophoresis proteomics analysis.
Abstract: Human non–small cell lung cancer (NSCLC) is one of the most common malignancies in the modern world Its recurrence is mainly due to its ability to invade and metastasize However, the precise mechanism for tumor development and metastasis is still not fully understood To shed light on the development of lung cancer, the human giant cell lung carcinoma cell lines 95D with high metastatic potential and 95C with low metastatic potential were selected in this study The 2 cell lines originated from the same parental cell and share a similar genetic background In the current study, we identified 3 differentially expressed proteins in 95C and 95D cell lines, namely, PAI-RBP1, C1orf142, and COTL1, by using 2-dimensional electrophoresis proteomics analysis We found that PAI-RBP1 and C1orf142 expression levels were higher in 95D than in 95C cells, whereas COTL1 expression level was lower in 95D when compared to 95C cells We also confirmed these results by reverse transcription–polymerase chain reaction and immunoblotting analyses The messenger RNA and protein levels of PAI-RBP1 and C1orf142 were much higher in 95D than in 95C cells, and COTL1 expression level was lower in 95D than in 95C cells The PAI-RBP1 expression was assessed by immunohistochemistry in 70 NSCLC and 7 normal lung tissue samples from patients PAI-RBP1 expression level was higher in tumor tissues (positive staining in 871% of cases [61/70]) than in normal tissues (positive staining in 143% of cases [1/7]) In conclusion, by studying protein expression in NSCLC cell lines with high and low metastasis as well as in human lung cancer tissues, we have identified 3 proteins, namely, PAI-RBP1, C1orf142, and COTL1, which were differentially expressed in NSCLC cell lines with different metastatic potential In addition, we also found that PAI-RBP1 might contribute to NSCLC development
TL;DR: Excess ATII accumulates in the heart, thereby promoting myocyte hypertrophy, fibroblast proliferation, interstitial accumulation of collagen, and microvessel disease, which contributes to cardiac abnormalities and elevated cardiovascular mortality in patients with CKD.
Abstract: Angiotensin II (ATII), the biologically active product of the renin-angiotensin system (RAS), is involved in modulation of left ventricular (LV) structure and function in chronic kidney disease (CKD). Because the RAS system is overactive in CKD, excess ATII accumulates in the heart, thereby promoting myocyte hypertrophy, fibroblast proliferation, interstitial accumulation of collagen, and microvessel disease. These cardiac abnormalities are further enhanced by a possible interaction between enhanced RAS activity and hypercalcemia, hyperphosphatemia and secondary hyperparathyroidism, and vitamin D deficiency. The ATII-associated stimulation of aldosterone production from the adrenal gland and the increase in activity of the sympathetic system in CKD, further contribute to LV abnormalities. Myocardial structural changes are major determinants of an increase in myocardial stiffness, leading to LV diastolic and systolic function impairment, and clinical congestive heart failure. Other complications include cardiac conduction disturbances, QT prolongation, and arrhythmias, which all contribute to elevated cardiovascular mortality in patients with CKD.
TL;DR: A significant proportion of patients referred to a tertiary pain clinic were found to fulfill the ACR criteria for classification of FMS and thus exhibit an important element of central pain.
Abstract: Background Fibromyalgia syndrome (FMS), the prototypical central pain augmentation syndrome, is characterized by widespread pain and tenderness. Although patients referred to tertiary care pain clinics are recognized as suffering from chronic pain, they are generally considered to have pain attributable to discrete peripheral, nociceptive, or neuropathic etiology. The purpose of the current study was to assess the prevalence of FMS among consecutive patients referred to a tertiary pain clinic and to evaluate the contribution of central pain to the clinical impact upon such patients. Methods Eighty-five consecutive patients (38 were male, and 47 were female) attending a pain clinic were assessed for the presence of FMS. The presence of FMS was determined according to the 1990 American College of Rheumatology (ACR) classification criteria. Quality of life and physical functioning were assessed, utilizing a structured questionnaire. Results The ACR criteria for the classification of FMS were fulfilled by 41.2% of patients. Patients fulfilling FMS criteria ranked significantly lower on all domains of the SF-36, including general health, physical functioning, role limitation due to physical and emotional problems, vitality, social functioning, bodily pain, and mental health. Composite physical and mental health scores were significantly lower among patients fulfilling ACR FMS criteria. Patients fulfilling the ACR criteria for FMS felt significantly more tenderness, based on the mean number of tender points and the mean tenderness threshold, when compared with patients not fulfilling the ACR FMS criteria. Conclusions A significant proportion of patients referred to a tertiary pain clinic were found to fulfill the ACR criteria for classification of FMS and thus exhibit an important element of central pain. Central pain augmentation should be actively searched for and therapeutically addressed in the evaluation and management of all patients with chronic pain.
TL;DR: A higher ratio of small-to-larger adipocytes in the South Asians consistent with a lesser lipid storage capacity of adipose tissue implies that fat in their lower body worsens insulin resistance.
Abstract: 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.
TL;DR: This article addresses current challenges facing pharmaceutical and biopharmaceutical developers, including the expiration of patents on many high-revenue–generating products, increasing competition in the marketplace, low public support, high regulatory hurdles, and the increasing time, cost, and risk of new product development.
Abstract: This article addresses current challenges facing pharmaceutical and biopharmaceutical developers, including the expiration of patents on many high-revenue-generating products, increasing competition in the marketplace, low public support, high regulatory hurdles, and the increasing time, cost, and risk of new product development. To meet these challenges, drug developers are looking to new models of innovation to improve efficiency, lower risk, and increase output. These new models include codevelopment agreements with small companies, multicompany consortia, and strategic partnerships with academic research centers. In the United States and the European Union, the government is supporting these efforts by creating incentives for academic centers to foster translational research and become more "commercially minded". The goal for all stakeholders is to reduce the barriers to product development and bring new medicines to market in a timely and cost-efficient manner.