bluuebunny/crossref_metadata_2025 huggingface dataset:
Melanoma Risk in Relation to Use of Sunscreen or Other Sun Protection Methods
Authors: Lazovich DeAnn , Vogel Rachel Isaksson , Berwick Marianne , Weinstock Martin A. , Warshaw Erin M. , Anderson Kristin E.
Published: December 2011

Background: Epidemiologic evidence supporting sunscreen for melanoma prevention is limited to one small trial; case–control studies report conflicting results. Sunscreen usage patterns or alternative sun protection methods have rarely been studied in relation to melanoma.

Methods: In a population-based case–control study, participants (1,167 cases; 1,101 controls) reported for each decade year of age outdoor activity-related sunscreen use, sunscreen patterns (SPF15+, amount, skin coverage, reapplication, routine use), and use of other sun protection methods (like hats, long-sleeved shirts, staying in the shade). Scores were averaged across activities and/or decades; scores in the most recent two decades were used to classify individuals as non-, inconsistent- or optimal users. Adjusted mean score differences between cases and controls, and ORs and 95% CIs for melanoma among optimal-, inconsistent- versus nonusers were calculated.

Results: Mean scores for sunscreen, sunscreen patterns or other sun protection methods were low, but higher among controls than cases for SPF15+ sunscreen (P = 0.03) and other sun protection methods (P = 0.006). Adjusted ORs for optimal use of sunscreen and most sunscreen patterns were null or relatively weak, except for routine sunscreen (adjusted OR = 0.44, 95% CI: 0.23–0.86). Optimal use of other sun protection methods was inversely associated with melanoma (adjusted OR = 0.59, 95% CI: 0.44–0.78).

Conclusions: Optimal use of routine sunscreen or other sun protection methods were most strongly associated with decreased melanoma risk; results are limited by the small number of subjects who used sunscreen routinely and lack of specificity regarding other sun protection methods.

Impact: Both improving sunscreen practices and encouraging sun avoidance strategies may be important for melanoma prevention. Cancer Epidemiol Biomarkers Prev; 20(12); 2583–93. ©2011 AACR.
Cataract and Ovarian Carcinoma: Is the Vitamin D Hypothesis Alive?
Authors: Lurie Galina , Matsuno Rayna K. , Wilkens Lynne R. , Thompson Pamela J. , Ollberding Nicholas J. , Carney Michael E. , Goodman Marc T.
Published: December 2011

Background: The major health benefit of exposure to solar UV radiation is the production of vitamin D, which is implicated in protection against several human cancers, including ovarian carcinoma. On the other hand, solar UV radiation is a recognized risk factor for cataract.

Methods: This population-based case–control study of 709 women with primary invasive ovarian carcinoma and 1,101 controls examined the association of ovarian carcinoma risk with self-reported history of cataract as an indicator of high long-term exposure to UV radiation. ORs and 95% confidence intervals (CI) were estimated using multivariate logistic regression models.

Results: Among controls, older age (P < 0.0001), history of type 2 diabetes (P = 0.04), and skin cancer (P = 0.03) were significant cataract risk predictors. A history of cataract, reported by 14% of cases and 17% of controls, was significantly associated with a reduced ovarian carcinoma risk (OR = 0.6; 95% CI, 0.4–0.8; P = 0.002). No heterogeneity was observed by tumor histology, stage, grade, study site, body mass index, or other ovarian cancer risk factors (P > 0.16).

Conclusion: These findings add indirect evidence to the hypothesis that lifetime vitamin D exposure may be inversely associated with risk of ovarian carcinoma.

Impact: The study suggests some potential new avenues for research. Additional studies are needed to further investigate the potential behavioral and biologic factors that might influence association of cataract with ovarian cancer. Cancer Epidemiol Biomarkers Prev; 20(12); 2507–11. ©2011 AACR.
A Prospective Cohort Study of Coffee Consumption and Risk of Endometrial Cancer over a 26-Year Follow-Up
Authors: Je Youjin , Hankinson Susan E. , Tworoger Shelley S. , DeVivo Immaculata , Giovannucci Edward
Published: December 2011

Background: Coffee has been reported to lower levels of estrogen and insulin, two hormones implicated in endometrial carcinogenesis, but prospective data on the relation between coffee consumption and risk of endometrial cancer are limited.

Methods: We prospectively assessed coffee consumption in relation to endometrial cancer risk in the Nurses' Health Study (NHS) with 67,470 female participants aged 34 to 59 in 1980. Cumulative average coffee intake was calculated with all available questionnaires to assess long-term effects. Cox regression models were used to calculate incidence rate ratios (RR), controlling for other risk factors.

Results: Fewer than 4 cups of coffee per day were not associated with endometrial cancer risk. However, women who consumed 4 or more cups of coffee had 25% lower risk of endometrial cancer than those who consumed less than 1 cup per day (multivariable RR = 0.75; 95% CI = 0.57–0.97; Ptrend = 0.02). We found the similar association with caffeinated coffee consumption (RR for ≥4 vs. <1 cup/d = 0.70; 95% CI = 0.51–0.95). For decaffeinated coffee consumption, a suggestive inverse association was found among women who consumed 2 or more cups per day versus <1 cup/mo. Tea consumption was not associated with endometrial cancer risk.

Conclusions: These prospective data suggest that four or more cups of coffee per day are associated with a lower risk of endometrial cancer.

Impact: Drinking of coffee, given its widespread consumption, might be an additional strategy to reduce endometrial cancer risk. However, addition of substantial sugar and cream to coffee could offset any potential benefits. Cancer Epidemiol Biomarkers Prev; 20(12); 2487–95. ©2011 AACR.
Diabetes Mellitus Affects Biomechanical Properties of the Optic Nerve Head in the Rat
Authors: Terai Naim , Spoerl Eberhard , Haustein Michael , Hornykewycz Karin , Haentzschel Janek , Pillunat Lutz E.
Published: December 2011

Background: To investigate the effect of diabetes on the biomechanical behavior of the optic nerve head (ONH) and the peripapillary sclera (ppSc) in streptozocine-induced diabetic rats. Methods: Diabetes mellitus was induced in 20 Wistar rats using streptozocine. Twenty-five nondiabetic rats served as controls. Eyes were enucleated after 12 weeks and 2 strips of one eye were prepared containing ONH or ppSc. The stress-strain relation was measured in the stress range of 0.05–10 MPa using a biomaterial tester. Results: At 5% strain the stress of the ONH in diabetic rats was 897 ± 295 kPa and in the control group it was 671 ± 246 kPa; there was a significant difference between both groups (p = 0.011). The stress of the diabetic ppSc (574 ± 185 kPa) increased compared to that of the nondiabetic ppSc (477 ± 171 kPa), but this did not reach statistical significance (p = 0.174). The calculated tangent modulus at 5% strain was 11.79 MPa in the diabetic ONH and 8.77 MPa in the nondiabetic ONH; there was a significant difference between both groups (p = 0.006). The calculated tangent modulus at 5% strain was 7.17 MPa in the diabetic ppSc and 6.12 MPa in the nondiabetic ppSc, without a statistically significant difference (p = 0.09). Conclusion: In contrast to the ppSc, the ONH of diabetic rats showed a significant increase in stiffness compared to nondiabetic rats, which might be explained by nonenzymatic collagen cross-linking mediated by advanced glycation end products due to high blood glucose levels in diabetes. Further studies are needed to investigate if these biomechanical changes represent a detrimental risk factor for intraocular pressure regulation in diabetic glaucoma patients.
Altered MicroRNA Expression Profiles in Retinas with Diabetic Retinopathy
Authors: Wu Jin-hui , Gao Yu , Ren An-jing , Zhao Shi-hong , Zhong Ming , Peng Ya-jun , Shen Wei , Jing Ming , Liu Lin
Published: December 2011

Rats with streptozotocin (STZ)-induced diabetes were studied in order to identify abnormal microRNA (miRNA) expression profiles in diabetic retinopathy (DR) and to ascertain miRNAs associated with DR. Histopathologically, we observed characteristic features of DR in rats at 10 weeks after STZ injection. Investigation of miRNA expression profiles in the retinas of control and diabetic rats using miRNA microarrays revealed that many miRNAs were abnormally expressed in DR. On the basis of their fold changes and probability values, a total of 37 miRNAs were selected for further validation by real-time PCR analysis. The results showed that 11 miRNAs were significantly upregulated and 6 miRNAs were notably downregulated in DR. Furthermore, these changes in retinal miRNA expression levels paralleled the course of DR. Levels of miR-182, miR-96, miR-183, miR-211, miR-204, and miR-124 were significantly increased during the progress of DR, whereas miR-10b, miR-10a, miR-219-2-3p, miR-144, miR-338, and miR-199a-3p were significantly decreased. Our data indicate that the aberrant miRNA expression profiles in DR are associated with the development of DR. Modulation of retinal miRNA expression levels may provide a potential therapeutic strategy for DRs.
Use and Effectiveness of Intra-Aortic Balloon Pumps Among Patients Undergoing High Risk Percutaneous Coronary Intervention: Insights From the National Cardiovascular Data Registry
Authors: Curtis Jeptha P. , Rathore Saif S. , Wang Yongfei , Chen Jersey , Nallamothu Brahmajee K. , Krumholz Harlan M.
Published: December 2011

Background—

Intra-aortic balloon pumps (IABP) frequently are used to provide hemodynamic support during high risk percutaneous coronary intervention (PCI), but clinical evidence to support their use is mixed. We examined hospital variation in IABP use among high risk PCI patients, and determined the association of IABP use on mortality in this population.

Methods and Results—

We analyzed data submitted to the CathPCI Registry between January 2005 and December 2007. High risk PCI was defined as having at least 1 of the following features: unprotected left main artery as the target vessel, cardiogenic shock, severely depressed left ventricular function, or ST segment elevation myocardial infarction. Hospitals were categorized into quartiles by their proportional use of IABP. We examined differences in in-hospital mortality across hospital quartiles using a hierarchical logistic regression model to adjust for differences in patient and hospital characteristics across hospital quartiles of IABP use. IABPs were used in 18 990 (10.5%) of 181 599 high risk PCIs. Proportional use of IABP varied significantly across hospital quartiles: Q1, 0.0 to 6.5%; Q2, 6.6 to 9.2%; Q3, 9.3 to 14.1%; Q4, 14.2 to 40.0%. In multivariable analysis, after adjustment for differences in patient and hospital characteristics, in-hospital mortality was comparable across quartiles of hospital IABP usage (Q1, Ref; Q2, odds ratio 1.11, 95% CI 0.99–1.24; Q3, OR 1.03, 95% CI 0.92–1.15; Q4, OR 1.06, 95% CI 0.94–1.18).

Conclusions—

IABP use varied significantly across hospitals for high risk PCI. However, this variation in IABP use was not associated with differences in in-hospital mortality.
Rates of Cardiac Catheterization Cancelation for ST-Segment Elevation Myocardial Infarction After Activation by Emergency Medical Services or Emergency Physicians
Authors: Garvey J. Lee , Monk Lisa , Granger Christopher B. , Studnek Jonathan R. , Roettig Mayme Lou , Corbett Claire C. , Jollis James G.
Published: December 2011

Background—

For patients with an acute ST-segment elevation myocardial infarction, cardiac catheterization laboratory (CCL) activation by emergency medical technicians or emergency physicians has been shown to substantially reduce treatment times. One drawback to this approach involves overtriage, whereby CCL staffs are activated for patients who ultimately do not require emergent coronary angiography or for patients who undergo angiography but are not found to have coronary artery occlusion.

Methods and Results—

We examined CCL activation at 14 primary angioplasty hospitals to determine the course of management, including the rate of inappropriate activation. Among 3973 activations (29% by emergency medical technicians, 71% by emergency physicians) between December 2008 and December 2009, appropriate CCL activations occurred for 3377 patients (85%), with 2598 patients (76.9% of appropriate activations) receiving primary percutaneous coronary intervention. Reasons for inappropriate activations (596 patients; 15%) included ECG reinterpretations (427 patients; 72%) or the fact that the patient was not a CCL candidate (169 patients; 28%). The rate of cancellation because of reinterpretation of emergency medical technicians' ECG (6% of all activations) was more common than for cancellation because of reinterpretation of emergency physicians' ECG (4.6%).

Conclusions—

This represents the first report of the rates of CCL cancellation for ST-segment elevation myocardial infarction system activation by emergency medical technicians and emergency physicians in a large group of hospitals organized within a statewide program. The high rate of coronary intervention and relatively low rate of inappropriate activation suggest that systematic CCL activation by emergency personnel on a broad scale is feasible and accurate, and these rates set a benchmark for ST-segment elevation myocardial infarction systems.
Walking the neighbourhood, seeing the small details of community life: Reflections from a photography walking tour
Authors: Fink Janet
Published: December 2011

This paper examines the value of photography walking tours for exploring meanings and experiences of community. The work is part of a larger visual research project which sought to examine the everyday lives of residents in a neighbourhood identified as ‘disadvantaged’, with the tour being organized as an opportunity for residents to identify what they valued about their local environment and what they considered to be problematic. The dynamics involved in gathering this photographic record are one element of the discussion as is analysis of the ways in which the participants constructed and re-constructed their sense of community through the different examples they selected for photographing. The paper is thus concerned with the ways in which visual data bring different insights to understandings of which practices, services and resources are embedded in meanings of community in working-class neighbourhoods and, in turn, how such data might have value for informing policy and practice about the experiences of inequality in contemporary England.
Declines in blood lead concentrations in clinically affected and unaffected cattle accidentally exposed to lead
Authors: Bischoff Karyn , Thompson Belinda , Erb Hollis N. , Higgins William P. , Ebel Joseph G. , Hillebrandt Joseph R.
Published: December 2011

Lead (Pb) poisoning remains a common cause of morbidity in dairy and beef cattle. Although Pb toxicosis is typically diagnosed in cattle with clinical signs of acute or subacute Pb poisoning, it has been hypothesized that subclinical chronic exposure of cattle to Pb, which often goes undiagnosed, poses more of a risk to the human consumer. There is not adequate information on Pb kinetics to determine when or if Pb-exposed cattle can safely enter the food chain. The objectives of the current study were to determine whether subclinical elevations in blood Pb (bPb) were present in cattle from herds where 1 or more individuals had clinical Pb poisoning and to determine the half-life (t1/2) of bPb in Pb-exposed cattle. Samples of blood were collected and analyzed for Pb from 126 cattle from 9 farms. Blood lead concentrations ranged from below the detection limit (2.50 µg/dl) to 423.0 µg/dl. Only 11 of the 94 cattle with detectable bPb had clinical signs such as diarrhea, blindness, bruxism, or seizures. When possible, cattle with detectable bPb had serial samples taken. The mean t1/2 calculated from 44 serially sampled cattle was 135 days (standard deviation: 125 days, range: 3–577 days). A source of Pb on the farm was determined for all but one herd.
Pulmonary arteriovenous malformation in two adult alpacas (Vicugna pacos)
Authors: Piripi Susan , Hustace Jaime , Carney Katelyn R. , Heidel Jerry R. , Löhr Christiane V.
Published: December 2011

Two cases of pulmonary vascular anomaly in unrelated adult alpacas ( Vicugna pacos) are described. In the first case, a 9-year-old intact male alpaca presented at Oregon State University Veterinary Teaching Hospital with bilateral epistaxis and died the subsequent day following severe hemorrhage from the mouth and nostrils. At necropsy, a tortuous vascular lesion was identified in the right cranial lung lobe, associated with hemorrhage into airways. In the second case, a 2-year-old female alpaca presented with postpartum anorexia, opisthotonus, and recumbency. In this second case, a similar vascular lesion was identified in the right cranial lung lobe but without associated hemorrhage. Histopathological examination of the lesion in both cases revealed numerous dilated, irregular blood vessels with marked variation in wall thickness within vessels, surrounded by foci of extramedullary hematopoiesis. Diagnoses of locally extensive pulmonary vascular anomalies (arteriovenous malformations) were made.
Aberrant E-cadherin, β-catenin, and glial fibrillary acidic protein (GFAP) expression in canine choroid plexus tumors
Authors: Nentwig Alice , Higgins Robert J. , Francey Thierry , Doherr Marcus , Zurbriggen Andreas , Oevermann Anna
Published: December 2011

Expression of E-cadherin and β-catenin has been widely studied in various human and canine epithelial tumors and has been correlated with dedifferentiation, invasiveness, and metastasis. Choroid plexus tumors (CPTs) are of epithelial origin, and the most important prognostic factor in human medicine is the tumor grade. Limited information is available regarding E-cadherin and β-catenin expression in human CPTs, and no information is found in the veterinary literature. In the current study, 42 canine CPTs (19 choroid plexus papillomas and 23 choroid plexus carcinomas) were retrospectively reviewed, and the intensity and cellular staining pattern of E-cadherin and β-catenin were correlated with histological features, paying special attention to grade, invasion, and metastasis. In addition, cytokeratin and glial fibrillary acidic protein (GFAP) antibodies were evaluated as markers for canine CPTs. It was found that loss of E-cadherin and β-catenin expression was uncommon in canine CPTs. Rather, membranous expression of both molecules was increased in CPTs compared to normal choroid plexus (NCP), regardless of tumor grade. Additionally, aberrant cytoplasmic or nuclear expression of both E-cadherin and β-catenin was often observed in CPTs. GFAP was frequently expressed in CPTs in contrast to NCP. None of these parameters were correlated with malignancy, and therefore, do not appear to be useful for prognostic information. Nevertheless, a panel of antibodies including E-cadherin and GFAP might be useful to support the diagnosis of CPTs and help to differentiate them from other tumors, such as ependymomas and metastatic epithelial tumors.
Comparison of antemortem antimicrobial treatment regimens to antimicrobial susceptibility patterns of postmortem lung isolates from feedlot cattle with bronchopneumonia
Authors: Lamm Catherine G. , Love Brenda C. , Krehbiel Clint R. , Johnson Nicholas J. , Step Douglas L.
Published: December 2011

A retrospective study was performed to compare the treatment regimens in feedlot cattle that died with bovine respiratory disease (BRD) to the antimicrobial susceptibility patterns of the microorganisms isolated from lungs. Forty-three cattle submitted by the Willard Sparks Beef Research Center (WSBRC) to the Oklahoma Animal Disease Diagnostic Laboratory for postmortem examination during 2007 had bronchopneumonia (acute = 16, subacute = 5, or chronic = 22). Lungs from cattle were cultured aerobically (40 cattle) and for Mycoplasma spp. (34 cattle). Susceptibility panels were performed. At least 1 BRD pathogen ( Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, Mycoplasma bovis, or Arcanobacterium pyogenes) was isolated from 39 cattle, and 77% (30/39) had multiple organisms recovered. Mycoplasmal infections were common (25/34) and a major component of mixed infections (24/25). The majority (60%) of the M. haemolytica, P. multocida, and H. somni isolates were resistant to tetracycline. Most of the H. somni isolates (67%) were susceptible to tilmicosin (Ti), enrofloxacin (En), ceftiofur (Ce), and florfenicol, despite extensive treatment with Ti, En, and Ce (75% of isolates were from cattle that received each antimicrobial once). Most of the M. haemolytica (65%) and P. multocida (79%) isolates were susceptible to En and Ce, despite antemortem treatment of cattle with these antimicrobials. Hence, the current study reports a discrepancy between the antemortem treatment of clinical BRD and the susceptibility patterns of the bacteria isolated from lungs postmortem. Based on these findings, factors other than antimicrobial resistance are playing a role in the death of feedlot cattle with BRD.
Mean Platelet Volume Is Increased in Patients With Bicuspid Aortic Valve
Authors: Bilen Emine , Tanboga Ibrahim Halil , Kurt Mustafa , Kocak Umran , Ayhan Hüseyin , Durmaz Tahir , Bozkurt Engin
Published: December 2011

Background: It has been demonstrated that platelet activation occurs in patients with aortic stenosis. However, no study has assessed platelet activation in patients with a normally functioning bicuspid aortic valve (BAV). Therefore, we aimed to investigate relationship between platelet activation assessed by mean platelet volume (MPV) and normally functioning BAV. Methods: Thirty-nine patients with isolated BAV and 25 age- and gender-matched healthy participants were included in the study. Patients with more than mild aortic regurgitation and aortic velocity >2 m/s were excluded from the study. For the entire study population, MPV was measured using an automatic blood counter. Results: Compared to control group, MPV value was significantly higher in patients with BAV (8.6 ± 1.0 vs 8.0 ± 0.8, p: .01). In the correlation analysis, there was a significant correlation between MPV measures with aortic stiffness ( r: .32 and p: .01) and aortic elastic modulus ( r: .37 and p: .003). Conclusion: Our study results indicate that BAV is associated with elevated MPV values.
No room for reflexivity? Critical reflections following a systematic review of qualitative research
Authors: Newton Benjamin John , Rothlingova Zuzana , Gutteridge Robin , LeMarchand Karen , Raphael Jon Howard
Published: December 2011

We conducted a systematic search of qualitative research into the individual’s experience of chronic low back pain. Two reviewers independently read through 740 unique abstracts. Inter-rater reliability was fair. The final sample comprised 19 articles which we critiqued using the Critical Appraisal Skills Programme checklist. This article focuses on the critical appraisal. Limitations include a lack of an adequate rationale for the theoretical framework, a lack of an account for the decisions made across recruitment and data collection, and a lack of reflexivity. Finally we discuss and offer recommendations for reflexivity and the explication of qualitative methodology in research articles.
A critical analysis of US cultural policy in the global film market
Authors: Jin Dal Yong
Published: December 2011

By emphasizing contextualization between the film industry and government cultural policies in association with FTAs, this article historically examines the set of social relations and the interplay of power between the US and other countries (mainly non-western), as well as between the commercial interests of Hollywood and the critical political ideology of domestic film industries. It analyses whether the US, supported and lobbied by Hollywood, has hampered cultural diversity and sovereignty in other countries, particularly through the use of FTAs in the midst of neoliberal globalization. The article maps out how the US government has intensified its state power in the global cultural market. It articulates the consequences of FTAs in the realm of culture in several countries in order to determine the crucial influence of FTAs on domestic film and cultural markets. It is not an easy task to establish an exact correlation between FTAs and the deleterious consequences of signing FTAs for domestic film industries, therefore, the article discusses the more general, causal relationship between FTAs and consequences in domestic film industries.
Is Thrombophilia Testing Useful?
Authors: Middeldorp Saskia
Published: December 2011

Thrombophilia is found in many patients presenting with venous thromboembolism (VTE). However, whether the results of such tests help in the clinical management of such patients has not been determined. Thrombophilia testing in asymptomatic relatives may be useful in families with antithrombin, protein C, or protein S deficiency or homozygosity for factor V Leiden, but is limited to women who intend to become pregnant or who would like to use oral contraceptives. Careful counseling with knowledge of absolute risks helps patients in making an informed decision in which their own preferences can be taken into account. Observational studies show that patients who have had VTE and have thrombophilia are at most at a slightly increased risk for recurrence. In an observational study, the risk of recurrent VTE in patients who had been tested for inherited thrombophilia was not lower than in patients who had not been tested. In the absence of trials comparing routine and prolonged anticoagulant treatment in patients testing positive for thrombophilia, testing for such defects to prolong anticoagulant therapy cannot be justified. Diagnosing antiphospholipid syndrome (APS) in women with recurrent miscarriage usually leads to treatment with aspirin and low-molecular-weight heparin (LMWH), although the evidence to support this treatment is limited. Because testing for thrombophilia serves a limited purpose, this test should not be performed on a routine basis.
Approach to Hemophagocytic Syndromes
Authors: Weitzman Sheila
Published: December 2011

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory condition. It may occur as a primary (genetic) condition due to mutations in genes important in the cytolytic secretory pathway that cause perforin and granzymes to induce apoptosis in target cells. Primary HLH is divided into familial HLH (FHLH1-5), in which HLH is the only manifestation of disease, and other genetic causes in which HLH is one of several clinical manifestations. The identical clinical findings may arise secondary to infectious, rheumatologic, malignant, or metabolic conditions. Whether primary or secondary, HLH therapy needs to be instituted promptly to prevent irreversible tissue damage. It is helpful to think of HLH as the severe end of the spectrum of hyperinflammatory disorders when the immune system starts to damage host tissues (immunopathology). Therefore, no single clinical feature alone is diagnostic for HLH, and it is important that the entire clinical presentation be considered in making the diagnosis. This article contains a discussion of the genetic background, clinical presentation, diagnostic dilemmas, and features that are helpful in making the diagnosis of HLH, along with a discussion of common problems in its management.
Management of Essential Thrombocythemia
Authors: Cervantes Francisco
Published: December 2011

Essential thrombocythemia (ET) is a Philadelphia chromosome (Ph)–negative myeloproliferative neoplasm (MPN) characterized by thrombocytosis and megakaryocytic hyperplasia of the bone marrow, with presence of the JAK2 V617F mutation in 50%-60% of patients. ET evolves to myelofibrosis in a minority of cases, whereas transformation to acute leukemia is rare and increases in association with the use of certain therapies. Survival of ET patients does not substantially differ from that of the general population. However, important morbidity is derived from vascular complications, including thrombosis, microvascular disturbances, and bleeding. Because of this, treatment of ET must be aimed at preventing thrombosis and bleeding without increasing the risk of transformation of the disease. Patients are considered at high risk of thrombosis if they are older than 60 years or have a previous history of thrombosis and at high risk of bleeding if platelet counts are > 1500 × 109/L. Patients with low-risk ET are usually managed with low-dose aspirin, whereas treatment of high-risk ET is based on the use of cytoreductive therapy, with hydroxyurea as the drug of choice and IFN-α being reserved for young patients or pregnant women. For patients resistant or intolerant to hydroxyurea, anagrelide is recommended as second-line therapy. Strict control of coexistent cardiovascular risk factors is mandatory for all patients. The role in ET therapy of new drugs such as pegylated IFN or the JAK2 inhibitors is currently under investigation.
Genomics of AML: Clinical Applications of Next-Generation Sequencing
Authors: Welch John S. , Link Daniel C.
Published: December 2011

In the past decade, a series of technological advances have revolutionized our ability to interrogate cancer genomes, culminating in whole-genome sequencing, which provides genome-wide coverage at a single base-pair resolution. As sequencing technologies improve and costs decrease, it is likely that whole-genome sequencing of cancer cells will become commonplace in the diagnostic workup of patients with acute myelogenous leukemia (AML) and other cancers. The unprecedented molecular characterization provided by whole-genome sequencing offers the potential for an individualized approach to treatment in AML, bringing us one step closer to personalized medicine. In this chapter, we discuss how next-generation sequencing is being used to study cancer genomes. Recent publications of whole-genome sequencing in AML are reviewed and current limitations of whole-genome sequencing are examined, as well as current and potential future clinical applications of whole-genome sequencing.
Pediatric Acute Leukemia Therapies Informed by Molecular Analysis of High-Risk Disease
Authors: Winter Stuart S.
Published: December 2011

The acute leukemias are the most common cancer of children, adolescents, and young adults. These diseases are characterized by a tremendous variability in clinical course, prompting a continuing search for accurate predictors of outcome. Using algorithms based on clinical features at presentation, response to therapy, and several molecular analyses, some patients are diagnosed with features of high-risk disease and comparatively greater risk for relapse. Molecular analyses of patients with high-risk acute leukemias have resulted in an improved understanding of how dysregulated cellular signaling can affect resistance to conventional therapy. Whereas exciting discoveries continue to be made in the identification of relevant molecular biomarkers and targeted therapies, the challenges and opportunities associated with these findings remain to be clearly defined in future clinical trials.
What To Do When You Suspect an Inherited Platelet Disorder
Authors: Lambert Michele P.
Published: December 2011

Inherited platelet disorders (IPDs) comprise a heterogenous group of diseases that include defects in platelet function and disordered megakaryopoiesis. Some IPDs overlap as both defects in function and thrombopoiesis, resulting in both altered aggregation and/or secretion and thrombocytopenia. This review examines the key features of the presentation of IPDs in children and adults and presents a diagnostic algorithm for the evaluation of these patients. In addition, recent advances in our understanding of the pathophysiology of platelet disorders are addressed, with attention given to some of the novel genetic associations. Finally, treatment options and future therapies are briefly discussed.
What is the Evidence for the Use of Immunomodulatory Agents to Eradicate Inhibitory Antibodies in Patients with Severe Hemophilia A Who Have Previously Failed to Respond to Immune Tolerance Induction?
Authors: Callaghan Michael U. , Fogarty Patrick F.
Published: December 2011

An 18-year-old man has severe hemophilia A that has been complicated by a high-titer inhibitory antibody (peak 170 BU/mL). He had previously failed a trial of immune tolerance induction (ITI) using daily high-dose (100 units/kg/d) factor VIII (FVIII) for 20 months and would like to know if immunomodulatory agents, with or without another course of ITI, might eradicate the inhibitor.
Secondary Prevention of Overt Strokes in Sickle Cell Disease: Therapeutic Strategies and Efficacy
Authors: DeBaun Michael R.
Published: December 2011

Overt strokes, previously one of the most common neurological complications in sickle cell disease (SCD), have become far less frequent with routine transcranial Doppler (TCD) assessment followed by regular blood transfusion therapy. Nevertheless, children and adults with SCD continue to have overt strokes, and in the foreseeable future will continue to require secondary prevention of strokes. With the exception of the most recently completed “Stroke With Transfusions Changing to Hydroxyurea” Trial (SWiTCH; NCT00122980), randomized trials providing best evidence for long-term management of overt strokes in SCD is lacking. Instead of randomized clinical trials, a series of observational and single-arm studies have predominated. This review assesses the best available evidence for acute and chronic management of overt stroke and the efficacy of regular blood transfusion therapy, hydroxyurea therapy, and hematopoietic stem cell transplantation (HSCT), including matched sibling donor and unrelated HSCT.
Targeted Therapeutic Strategies for Fetal Hemoglobin Induction
Authors: Sankaran Vijay G.
Published: December 2011

Increased levels of fetal hemoglobin (HbF) can ameliorate the severity of the β-hemoglobin disorders, sickle cell disease (SCD) and β-thalassemia, which are major sources of morbidity and mortality worldwide. As a result, there has been a longstanding interest in developing therapeutic approaches for inducing HbF. For more than 3 decades, the majority of HbF inducers developed were based on empiric observations and have had limited success. Recently, human genetic approaches have provided insight into previously unappreciated regulators of the fetal-to-adult hemoglobin switch and HbF silencing, revealing molecular targets to induce HbF. This article reviews these developments and discusses how molecules including BCL11A, KLF1, MYB, SOX6, miRNAs 15a and 16-1, and histone deacetylase 1 and 2 (HDAC1/2) could be important targets for HbF induction in humans. The current understanding of how these molecules function and the benefits and drawbacks of each of these potential therapeutic targets are also examined. The identification of these regulators of HbF expression is extremely promising and suggests that rationally designed approaches targeting the very mechanisms mediating this switching process could lead to better, less toxic, and more effective strategies for HbF induction.
Diamond Blackfan Anemia
Authors: Ball Sarah
Published: December 2011

Mutations affecting genes encoding ribosomal proteins cause Diamond Blackfan anemia (DBA), a rare congenital syndrome associated with physical anomalies, short stature, red cell aplasia, and an increased risk of malignancy. p53 activation has been identified as a key component in the pathophysiology of DBA after cellular and molecular studies of knockdown cellular and animal models of DBA and other disorders affecting ribosomal assembly or function. Other potential mechanisms that warrant further investigation include impaired translation as the result of ribosomal insufficiency, which may be ameliorated by leucine supplementation, and alternative splicing leading to reduced expression of a cytoplasmic heme exporter, the human homolog of the receptor for feline leukemia virus C (FVLCR). However, the molecular basis for the characteristic steroid responsiveness of the erythroid failure in DBA remains unknown. This review explores the clinical and therapeutic implications of the current state of knowledge and delineates important but as-yet-unanswered questions.
Aggressive B-Cell Lymphomas: A Review of New and Old Entities in the WHO Classification
Authors: Jaffe Elaine S. , Pittaluga Stefania
Published: December 2011

Aggressive B-cell lymphomas are clinically and pathologically diverse and reflect multiple pathways of transformation. The 2008 World Health Organization (WHO) classification reflects this complexity with the addition of several new entities and variants. Whereas MYC translocations have long been associated with Burkitt lymphoma (BL), deregulation of MYC has been shown to occur in other aggressive B-cell lymphomas, most often as a secondary event. Lymphomas with translocations of both MYC and BCL2 are highly aggressive tumors, with a high failure rate with most treatment protocols. These “double-hit” lymphomas are now separately delineated in the WHO classification as B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and BL. A MYC translocation is also found uncommonly in DLBCL, but the clinical consequences of this in the absence of a double hit are not yet fully delineated. Most recently, MYC translocations have been identified as a common secondary event in plasma cell neoplasms, seen in approximately 50% of plasmablastic lymphoma. Another area that has received recent attention is the spectrum of EBV-driven B-cell proliferations in patients without iatrogenic or congenital immunosuppression; most of these occur in patients of advanced age and include the EBV-positive large B-cell lymphomas of the elderly.
Therapies for Peripheral T-Cell Lymphomas
Authors: Savage Kerry J.
Published: December 2011

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of disorders that, for the most part, are associated with a very poor prognosis. The standard therapy for PTCLs is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or a comparable CHOP-like regimen that incorporates anthracyclines. With the exception of anaplastic lymphoma kinase–positive anaplastic large cell lymphoma (ALK+ ALCL), the cure rate for PTCLs with CHOP is low, and limited evidence suggests that anthracyclines do not improve the prognosis. However, there is no compelling evidence that any other regimen or approach is superior. It remains challenging to compare alternative therapies or treatment strategies with CHOP because the majority of data are retrospective and include diverse patient populations. Recently, prospective studies have been initiated exclusively for PTCL, and in some, select histologic subtypes are evaluated in an effort to remove heterogeneity. Encouragingly, there have been several new therapies emerging with activity in PTCLs and exciting novel combinations under consideration that will hopefully move the field forward and improve outcome in this challenging group of diseases.
Unraveling Mechanisms Regulating Systemic Iron Homeostasis
Authors: Finberg Karin E.
Published: December 2011

Systemic iron balance must be tightly regulated to prevent the deleterious effects of iron deficiency and iron overload. Hepcidin, a circulating hormone that is synthesized by the liver, has emerged as a key regulator of systemic iron homeostasis. Hepcidin inhibits the absorption of dietary iron from the intestine and the release of iron derived from red blood cells from macrophages. Therefore, variation in hepcidin levels modifies the total amount of iron stored in the body and the availability of iron for erythropoiesis. The production of hepcidin by the liver is modulated by multiple physiological stimuli, including iron loading, inflammation, and erythropoietic activity. Investigation of the functions of the gene products mutated in inherited iron disorders using tissue-culture systems and animal models has provided valuable insights into the mechanisms by which these hepcidin responses are mediated. This review focuses on recent advances in our understanding of the molecular mechanisms underlying the regulation of systemic iron homeostasis.
The Clinical Relevance of Response Variability to Antiplatelet Therapy
Authors: Cattaneo Marco
Published: December 2011

Interindividual variability in the pharmacological response to antiplatelet drugs has been reported in some studies. Suboptimal response to aspirin, as determined by specific tests (serum thromboxane B2), appears to be rare and in most cases is caused by poor compliance. In contrast, studies using specific tests to measure the pharmacological effect of clopidogrel showed a wide variability of responses, with a significant number of subjects (approximately one-third) who were very poor responders. Interindividual differences in the extent of metabolism of clopidogrel to its active metabolite is the most plausible mechanism for the observed interindividual variability in platelet inhibition. Tailored treatment based on laboratory monitoring of platelet function has been proposed as a solution to poor responsiveness to clopidogrel. However, we still need to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness before monitoring clopidogrel therapy can be recommended in clinical practice.
High-dose melphalan and peripheral blood stem cell transplantation for light-chain amyloidosis with cardiac involvement
Authors: Madan Sumit , Kumar Shaji K. , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Buadi Francis K. , Dingli David , Rajkumar S. Vincent , Hogan William J. , Leung Nelson , Grogan Martha , Gertz Morie A.
Published: December 2011

High-dose melphalan (HDM) plus stem cell transplantation is an effective treatment for light-chain amyloidosis (AL), but is associated with high treatment-related mortality in patients with cardiac involvement. We studied 187 patients with cardiac involvement with AL who underwent HDM between 1996 and 2008. The median age was 57 years and the median time from diagnosis to HDM was 3.6 months. Half of the patients received reduced-dose melphalan (100-160 mg/m2). The median overall survival (OS) was 66 months, 54 months from diagnosis and HDM, respectively, and 91 patients (49%) were alive at the last follow-up 52 months (median) from HDM. Thirty patients (16%) died within 100 days of transplantation; only low serum albumin predicted early deaths. Overall, hematologic response (HR) and cardiac responses were seen in 66% and 41% of patients, respectively. The median OS for patients with and without HR was not reached and 22 months, respectively (P < .01); and for those with any decrease and no decrease in N-terminal-pro-brain natriuretic peptide was not reached and 26 months, respectively (P < .01). In multivariate analysis of baseline factors, only reduced-dose melphalan predicted shorter OS. HDM is feasible in patients with cardiac amyloidosis, and achievement of HR and organ response is associated with improved survival.
Transcriptional analysis of late ripening stages of grapevine berry
Authors: Guillaumie Sabine , Fouquet Romain , Kappel Christian , Camps Céline , Terrier Nancy , Moncomble Dominique , Dunlevy Jake D , Davies Christopher , Boss Paul K , Delrot Serge
Published: December 2011

Background

The composition of grapevine berry at harvest is a major determinant of wine quality. Optimal oenological maturity of berries is characterized by a high sugar/acidity ratio, high anthocyanin content in the skin, and low astringency. However, harvest time is still mostly determined empirically, based on crude biochemical composition and berry tasting. In this context, it is interesting to identify genes that are expressed/repressed specifically at the late stages of ripening and which may be used as indicators of maturity.

Results

Whole bunches and berries sorted by density were collected in vineyard on Chardonnay (white cultivar) grapevines for two consecutive years at three stages of ripening (7-days before harvest (TH-7), harvest (TH), and 10-days after harvest (TH+10)). Microvinification and sensory analysis indicate that the quality of the wines made from the whole bunches collected at TH-7, TH and TH+10 differed, TH providing the highest quality wines.

In parallel, gene expression was studied with Qiagen/Operon microarrays using two types of samples, i.e. whole bunches and berries sorted by density. Only 12 genes were consistently up- or down-regulated in whole bunches and density sorted berries for the two years studied in Chardonnay. 52 genes were differentially expressed between the TH-7 and TH samples. In order to determine whether these genes followed a similar pattern of expression during the late stages of berry ripening in a red cultivar, nine genes were selected for RT-PCR analysis with Cabernet Sauvignon grown under two different temperature regimes affecting the precocity of ripening. The expression profiles and their relationship to ripening were confirmed in Cabernet Sauvignon for seven genes, encoding a carotenoid cleavage dioxygenase, a galactinol synthase, a late embryogenesis abundant protein, a dirigent-like protein, a histidine kinase receptor, a valencene synthase and a putative S-adenosyl-L-methionine:salicylic acid carboxyl methyltransferase.

Conclusions

This set of up- and down-regulated genes characterize the late stages of berry ripening in the two cultivars studied, and are indirectly linked to wine quality. They might be used directly or indirectly to design immunological, biochemical or molecular tools aimed at the determination of optimal ripening in these cultivars.
Arsenic, cadmium and neuron specific enolase (ENO2, γ-enolase) expression in breast cancer
Authors: Soh Maureen A , Garrett Scott H , Somji Seema , Dunlevy Jane R , Zhou Xu Dong , Sens Mary Ann , Bathula Chandra S , Allen Christina , Sens Donald A
Published: December 2011

Background

Neuron specific enolase (ENO2, γ-enolase) has been used as a biomarker to help identify neuroendocrine differentiation in breast cancer. The goal of the present study was to determine if ENO2 expression in the breast epithelial cell is influenced by the environmental pollutants, arsenite and cadmium. Acute and chronic exposure of MCF-10A cells to As+3and Cd+2sufficient to allow colony formation in soft agar, was used to determine if ENO2 expression was altered by these pollutants.

Results

It was shown that both As+3and Cd+2exposure caused significant increases in ENO2 expression under conditions of both acute and chronic exposure. In contrast, ENO1, the major glycolytic enolase in non-muscle and neuronal cells, was largely unaffected by exposure to either As+3or Cd+2. Localization studies showed that ENO2 in the MCF-10A cells transformed by As+3or Cd+2had both a cytoplasmic and nuclear localization. In contrast, ENO1 was localized to the cytoplasm. ENO2 localized to the cytoplasm was found to co-localized with ENO1.

Conclusion

The results are the first to show that ENO2 expression in breast epithelial cells is induced by acute and chronic exposure to As+3or Cd+2. The findings also suggest a possible link between As+3and Cd+2exposure and neuroendocrine differentiation in tumors. Overall, the results suggest that ENO2 might be developed as a biomarker indicating acute and/or chronic environmental exposure of the breast epithelial cell to As+3and Cd+2.