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1.  Glucocorticosteroids do not impact directly growth rate and biomass of Rhizopus arrhizus (syn. R. oryzae) in vitro 
Virulence  2015;6(5):441-443.
Glucocorticoid (GC) use is a common risk factor for invasive fungal infections. This is attributed to the complex dysregulation of immunity caused by GCs. However, studies have demonstrated increased growth with GC exposure for some molds, such as Aspergillus fumigatus and Exserohilum rostratum. No such data exist for Mucorales. Therefore, we investigated the influence of GC exposure on the growth of Rhizopus arrhizus (syn. R. oryzae) in different culture media and in different atmospheres. We measured continuous spore growth using spectrophotometry and biomass variations using XTT assay. We did not observe enhanced growth or biomass variation with any of the GCs regardless of the medium or conditions. These results support the existence of fungus-specific differences in the effect of GCs on fungal biology.
PMCID: PMC4601165  PMID: 25942104
biomass; corticosteroid; Rhizopus oryzae
2.  Alcohol Intake and Risk of Incident Psoriatic Arthritis in Women 
The Journal of rheumatology  2015;42(5):835-840.
Alcohol intake has been associated with an increased risk of psoriasis. However, the association between alcohol intake and risk of psoriatic arthritis (PsA) has been unclear. We evaluated the association between alcohol intake and risk of incident PsA in a large cohort of US women.
The present study included a total of 82,672 US women who provided repeated data on alcohol intake over the follow-up (1991–2005). Self-reported PsA was validated using psoriatic arthritis screening and evaluation (PASE) questionnaire. Cox proportional hazards models were used to estimate the age- and multivariate-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the PsA in association with alcohol intake.
We documented 141 incident PsA cases during 14 years (1,137,763 person-years) of follow-up. Compared to non-drinkers, the multivariate hazard ratios for PsA were 0.70 [95% confidence interval (CI): 0.48–1.01] for 0.1–14.9 g/d, 1.43 (95% CI: 0.67–3.08) for 15.0–29.9 g/d, and 4.45 (95% CI: 2.07–9.59) for ≥30.0 g/d of cumulative average alcohol intake. Risk estimates were generally consistent when using updated alcohol intake and baseline alcohol intake in 1991 as the exposures, and when the analysis was restricted to those who developed psoriasis during the follow-up.
Excessive alcohol intake was associated with an increased risk of incident PsA in a cohort of US women.
PMCID: PMC4600066  PMID: 25834201
alcohol; cohort study; psoriatic arthritis
3.  That’s not what you expect to do as a doctor, you know, you don’t expect your patients to die.” Death as a learning experience for undergraduate medical students 
BMC Medical Education  2016;16:108.
Experiencing the death of a patient can be one of the most challenging aspects of clinical medicine for medical students. Exploring what students' learn from this difficult experience may contribute to our understanding of how medical students become doctors, and provide insights into the role a medical school may play in this development. This research examined medical students' responses of being involved personally in the death of a patient.
Ten undergraduate medical students were followed through their three years of clinical medical education. A total of 53 individual semi-structured interviews were conducted. Grounded theory analysis was used to analyze the data.
Students illustrated a variety of experiences from the death of a patient. Three main themes from the analysis were derived: (i) Students’ reactions to death and their means of coping. Experiencing the death of a patient led to students feeling emotionally diminished, a decrease in empathy to cope with the emotional pain and seeking encouragement through the comfort of colleagues; (ii) Changing perceptions about the role of the doctor, the practice of medicine, and personal identity. This involved a change in students’ perceptions from an heroic curing view of the doctor’s role to a role of caring, shaped their view of death as a part of life rather than something traumatic, and resulted in them perceiving a change in identity including dampening their emotions; (iii) Professional environment, roles and responsibilities. Students began to experience the professional environment of the hospital by witnessing the ordinariness of death, understanding their role in formalizing the death of a patient, and beginning to feel responsible for patients.
Along with an integrative approach to facilitate students learning about death, we propose staff development targeting a working knowledge of the hidden curriculum. Knowledge of the hidden curriculum, along with the role staff play in exercising this influence, is vital in order to facilitate translating the distressing experiences students face into worthwhile learning experiences. Finally, we argue that student learning about death needs to include learning about the social organization and working life of clinical settings, an area currently omitted from many medical education curricula.
PMCID: PMC4832523  PMID: 27080014
Death and dying; Medical students; Undergraduate; End-of-life care; Hidden curriculum; Social organizations; Clinical settings
4.  Molecular imaging of atherosclerosis with nanoparticle-based fluorinated MRI contrast agents 
Nanomedicine (London, England)  2015;10(11):1817-1832.
As atherosclerosis remains one of the most prevalent causes of patient mortality, the ability to diagnose early signs of plaque rupture and thrombosis represents a significant clinical need. With recent advances in nanotechnology, it is now possible to image specific molecular processes noninvasively with MRI, using various types of nanoparticles as contrast agents. In the context of cardiovascular disease, it is possible to specifically deliver contrast agents to an epitope of interest for detecting vascular inflammatory processes, which serve as predecessors to atherosclerotic plaque development. Herein, we review various applications of nanotechnology in detecting atherosclerosis using MRI, with an emphasis on perfluorocarbon nanoparticles and fluorine imaging, along with theranostic prospects of nanotechnology in cardiovascular disease.
PMCID: PMC4483172  PMID: 26080701
atherosclerosis; contrast agent; inflammation; theranostics; thrombosis
5.  Effects of Calcium and Vitamin D3 on Transforming Growth Factors in Rectal Mucosa of Sporadic Colorectal Adenoma Patients: A Randomized Controlled Trial 
Molecular carcinogenesis  2013;54(4):270-280.
Transforming growth factor alpha (TGFα) and TGFβ1 are growth-promoting and -inhibiting autocrine/paracrine growth factors, respectively, that may (1) affect risk for colorectal cancer and (2) be modifiable by anti-proliferative exposures. The effects of supplemental calcium and vitamin D3 on these two markers in the normal-appearing colorectal mucosa in humans are unknown. We conducted a pilot, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial (n = 92; 23/treatment group) of calcium 2 g and/or vitamin D3 800 IU/d versus placebo over 6 mo. TGFα and TGFβ1 expression was measured in biopsies of normal-appearing rectal mucosa using automated immunohistochemistry and quantitative image analysis at baseline and 6-mo follow-up. In the calcium, vitamin D3, and calcium plus vitamin D3 groups relative to the placebo group (1) the mean overall expression of TGFβ1 increased by 14% (P = 0.25), 19% (P = 0.17), and 22% (P = 0.09); (2) the ratio of TGFα expression in the upper 40% (differentiation zone) to that in the lower 60% (proliferation zone) of the crypts decreased by 34% (P = 0.11), 31% (P = 0.22), and 26% (P = 0.33); and (3) the TGFα/TGFβ1 ratio in the upper 40% of the crypts decreased by 28% (P = 0.09), 14% (P = 0.41), and 22% (P = 0.24), respectively. These preliminary results, although not statistically significant, suggest that supplemental calcium and vitamin D3 may increase TGFβ1 expression and shift TGFα expression downward from the differentiation to the proliferation zone in the crypts in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, and support further investigation in a larger clinical trial.
PMCID: PMC4484733  PMID: 24166893
colorectal neoplasms; calcium; vitamin D3; transforming growth factor alpha (TGFα); transforming growth factor beta 1 (TGFβ1)
6.  Oral Disease Profiles in Chronic Graft versus Host Disease 
Journal of Dental Research  2015;94(4):547-554.
At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer’s tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will improve clinical diagnosis, observational research data collection, and the definitions of outcome measures in clinical trials.
PMCID: PMC4485216  PMID: 25740857
clinical research; oral medicine; autoimmune disease; salivary dysfunction; oral cGVHD; stem cell transplantation
7.  Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia 
Berndt, Sonja I. | Camp, Nicola J. | Skibola, Christine F. | Vijai, Joseph | Wang, Zhaoming | Gu, Jian | Nieters, Alexandra | Kelly, Rachel S. | Smedby, Karin E. | Monnereau, Alain | Cozen, Wendy | Cox, Angela | Wang, Sophia S. | Lan, Qing | Teras, Lauren R. | Machado, Moara | Yeager, Meredith | Brooks-Wilson, Angela R. | Hartge, Patricia | Purdue, Mark P. | Birmann, Brenda M. | Vajdic, Claire M. | Cocco, Pierluigi | Zhang, Yawei | Giles, Graham G. | Zeleniuch-Jacquotte, Anne | Lawrence, Charles | Montalvan, Rebecca | Burdett, Laurie | Hutchinson, Amy | Ye, Yuanqing | Call, Timothy G. | Shanafelt, Tait D. | Novak, Anne J. | Kay, Neil E. | Liebow, Mark | Cunningham, Julie M. | Allmer, Cristine | Hjalgrim, Henrik | Adami, Hans-Olov | Melbye, Mads | Glimelius, Bengt | Chang, Ellen T. | Glenn, Martha | Curtin, Karen | Cannon-Albright, Lisa A. | Diver, W Ryan | Link, Brian K. | Weiner, George J. | Conde, Lucia | Bracci, Paige M. | Riby, Jacques | Arnett, Donna K. | Zhi, Degui | Leach, Justin M. | Holly, Elizabeth A. | Jackson, Rebecca D. | Tinker, Lesley F. | Benavente, Yolanda | Sala, Núria | Casabonne, Delphine | Becker, Nikolaus | Boffetta, Paolo | Brennan, Paul | Foretova, Lenka | Maynadie, Marc | McKay, James | Staines, Anthony | Chaffee, Kari G. | Achenbach, Sara J. | Vachon, Celine M. | Goldin, Lynn R. | Strom, Sara S. | Leis, Jose F. | Weinberg, J. Brice | Caporaso, Neil E. | Norman, Aaron D. | De Roos, Anneclaire J. | Morton, Lindsay M. | Severson, Richard K. | Riboli, Elio | Vineis, Paolo | Kaaks, Rudolph | Masala, Giovanna | Weiderpass, Elisabete | Chirlaque, María- Dolores | Vermeulen, Roel C. H. | Travis, Ruth C. | Southey, Melissa C. | Milne, Roger L. | Albanes, Demetrius | Virtamo, Jarmo | Weinstein, Stephanie | Clavel, Jacqueline | Zheng, Tongzhang | Holford, Theodore R. | Villano, Danylo J. | Maria, Ann | Spinelli, John J. | Gascoyne, Randy D. | Connors, Joseph M. | Bertrand, Kimberly A. | Giovannucci, Edward | Kraft, Peter | Kricker, Anne | Turner, Jenny | Ennas, Maria Grazia | Ferri, Giovanni M. | Miligi, Lucia | Liang, Liming | Ma, Baoshan | Huang, Jinyan | Crouch, Simon | Park, Ju-Hyun | Chatterjee, Nilanjan | North, Kari E. | Snowden, John A. | Wright, Josh | Fraumeni, Joseph F. | Offit, Kenneth | Wu, Xifeng | de Sanjose, Silvia | Cerhan, James R. | Chanock, Stephen J. | Rothman, Nathaniel | Slager, Susan L.
Nature Communications  2016;7:10933.
Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P<5 × 10−7) for two additional new loci at 4q24 (rs10028805, BANK1, P=7.19 × 10−8) and 3p22.2 (rs1274963, CSRNP1, P=2.12 × 10−7). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.
Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.
PMCID: PMC4786871  PMID: 26956414
8.  Development and Investigation of a Site Selective Palladium-Catalyzed 1,4-Difunctionalization of Isoprene using Pyridine-Oxazoline Ligands 
Palladium-catalyzed 1,4-difunctionalizations of isoprene that produce skipped polyenes are reported. Complex isomeric product mixtures are possible as a result of the difficult-to-control migratory insertion of isoprene into a Pd-alkenyl bond, but good site selectivity has been achieved using easily accessible Pyrox ligands. Mechanistic studies suggest that the control of insertion is the result of the unique electronic asymmetry and steric properties of the ligand.
PMCID: PMC4334162  PMID: 25705367
9.  Phosphorylation and Cellular Function of the Human Rpa2 N-Terminus in the Budding Yeast Saccharomyces cerevisiae 
Experimental cell research  2014;331(1):183-199.
Maintenance of genome integrity is critical for proper cell growth. This occurs through accurate DNA replication and repair of DNA lesions. A key factor involved in both DNA replication and the DNA damage response is the heterotrimeric single-stranded DNA (ssDNA) binding complex Replication Protein A (RPA). Although the RPA complex appears to be structurally conserved throughout eukaryotes, the primary amino acid sequence of each subunit can vary considerably. Examination of sequence differences along with the functional interchangeability of orthologous RPA subunits or regions could provide insight into important regions and their functions. This might also allow for study in simpler systems. We determined that substitution of yeast Replication Factor A (RFA) with human RPA does not support yeast cell viability. Exchange of a single yeast RFA subunit with the corresponding human RPA subunit does not function due to lack of inter-species subunit interactions. Substitution of yeast Rfa2 with domains/regions of human Rpa2 important for Rpa2 function (i.e., the N-terminus and the loop 3–4 region) supports viability in yeast cells, and hybrid proteins containing human Rpa2 N-terminal phospho-mutations result in similar DNA damage phenotypes to analogous yeast Rfa2 N-terminal phospho-mutants. Finally, the human Rpa2 N-terminus (NT) fused to yeast Rfa2 is phosphorylated in a manner similar to human Rpa2 in human cells, indicating that conserved kinases recognize the human domain in yeast. The implication is that budding yeast represents a potential model system for studying not only human Rpa2 N-terminal phosphorylation, but also phosphorylation of Rpa2 N-termini from other eukaryotic organisms.
PMCID: PMC4334453  PMID: 25499885
RPA; N-terminus; phosphorylation; DNA damage response
10.  Bariatric Surgery and Diabetes 
Diabetes Technology & Therapeutics  2015;17(Suppl 1):S-76-S-79.
PMCID: PMC4334459  PMID: 25679433
11.  Clinical features and outcomes of germline mutation BRCA1-linked versus sporadic ovarian cancer patients 
The role of germline mutations in BRCA1 and BRCA2 genes in the risk of the development of ovarian cancer is clinically well established. BRCA1/2 testing seems to have increasing role in clinical management in patients with advanced ovarian cancer who require treatment with poly(ADP-ribose) polymerase inhibitors.
Between 2002 – 2008, 125 consecutive patients with ovarian cancer were categorized as having three founder mutations in the BRCA1 gene in Poland as: 5382insC [exon 20], 4153delA [exon 11.17], and 300 T > G [exon 5]. PFS (progression free survival) and OS (overall survival) were determined by Kaplan-Meier analysis with log rank test, univariate comparisons, and multivariate regression analysis using Cox proportional hazards model.
Of the 125 patients, the founder mutations of BRCA1 were reported in 17 patients (13.6 %). The median OS was longer for BRCA mutated patients (not reached vs 35.6 months, p = 0.041). PFS was similar for both kinds of ovarian cancer. In multivariate analysis, age ≥70 years, suboptimal surgery, and BRCA1 wild type were poor prognostic factors. The BRCA1 mutation reduced the likelihood of death in ovarian cancer by 86 % (HR 0.14; CI: 0.032-0.650, p = 0.012).
In conclusion, we found better overall survival for ovarian cancer patients with BRCA1 germline mutations in comparison with patients without these mutations (sporadic) ovarian cancer. Thus, BRCA1 germline mutations appear to be an independent prognostic factor for ovarian cancer.
PMCID: PMC4706695  PMID: 26753012
Germline mutations of BRCA1; Ovarian cancer; Chemotherapy; Survival
12.  Time is (still) of the essence: quantifying the impact of emergency meningitis vaccination response in Katsina State, Nigeria 
International Health  2014;6(4):282-290.
In 2009, a large meningitis A epidemic affected a broad region of northern Nigeria and southern Niger, resulting in more than 75 000 cases and 4000 deaths. In collaboration with state and federal agencies, Médecins Sans Frontières (MSF) intervened with a large-scale vaccination campaign using polysaccharide vaccine. Here the authors analyze the impact (cases averted) of the vaccination response as a function of the timing and coverage achieved.
Phenomenological epidemic models were fitted to replicate meningitis surveillance data from the Nigerian Ministry of Health/WHO surveillance system and from reinforced surveillance conducted by MSF in both vaccinated and unvaccinated areas using a dynamic, state–space framework to account for under-reporting of cases.
The overall impact of the vaccination campaigns (reduction in meningitis cases) in Katsina State, northern Nigeria, ranged from 4% to 12%. At the local level, vaccination reduced cases by as much as 50% when campaigns were conducted early in the epidemic.
Reactive vaccination with polysaccharide vaccine during meningitis outbreaks can significantly reduce the case burden when conducted early and comprehensively. Introduction of the conjugate MenAfriVac vaccine has reduced rates of disease caused by serogroup A Neisseria meningitidis in the region. Despite this, reactive campaigns with polysaccharide vaccine remain a necessary and important tool for meningitis outbreak response.
PMCID: PMC4311152  PMID: 25193978
Meningitis surveillance; Neisseria meningitidis serogroup A; Nigeria; Polysaccharide vaccine; Vaccination outbreak response
13.  Proportional Hazards Model with Covariate Measurement Error and Instrumental Variables 
In biomedical studies, covariates with measurement error may occur in survival data. Existing approaches mostly require certain replications on the error-contaminated covariates, which may not be available in the data. In this paper, we develop a simple nonparametric correction approach for estimation of the regression parameters in the proportional hazards model using a subset of the sample where instrumental variables are observed. The instrumental variables are related to the covariates through a general nonparametric model, and no distributional assumptions are placed on the error and the underlying true covariates. We further propose a novel generalized methods of moments nonparametric correction estimator to improve the efficiency over the simple correction approach. The efficiency gain can be substantial when the calibration subsample is small compared to the whole sample. The estimators are shown to be consistent and asymptotically normal. Performance of the estimators is evaluated via simulation studies and by an application to data from an HIV clinical trial. Estimation of the baseline hazard function is not addressed.
PMCID: PMC4315262  PMID: 25663724
Generalized methods of moments; Nonparametric correction; Survival
14.  Research Training Among Pediatric Residency Programs – A National Assessment 
The Accreditation Council for Graduate Medical Education (ACGME) states that “residents should participate in scholarly activity.” However, there is little guidance for effectively integrating scholarly activity into residency. This study was conducted to understand how pediatric residency programs are meeting ACGME requirements and to identify characteristics of successful programs.
The authors conducted an on-line cross-sectional survey of all pediatric residency program directors in October 2012, assessing program characteristics, resident participation in scholarly activity, program infrastructure, barriers, and outcomes. Multivariate logistic regression was used to identify characteristics of programs in the top quartile for resident scholarly activity participation.
The response rate was 52.8% (105/199 programs). 78.6% (n=77) of programs required scholarly activity, although definitions were variable. When including only original research, systematic reviews or meta-analyses, and case reports or series with references, resident participation averaged 56% (range 0–100%). Characteristics associated with high participation programs included: 1) a scholarly activity requirement (odds ratio (OR) =5.5, 95% confidence interval (CI) 1.03–30.0); 2) program director belief that all residents should present work regionally or nationally (OR=4.7, 95% CI 1.5–15.1); and 3) mentorship by >25% of faculty (OR=3.6, CI 1.2–11.4). Only 47.1% (n=41) of program directors were satisfied with resident participation and only 30.7% (n=27) were satisfied with the quality of research training provided.
The results suggest resident scholarly activity experience is highly variable and suboptimal. Identifying characteristics of successful programs can improve the resident research training experience.
PMCID: PMC4315313  PMID: 25006705
15.  Red Blood Cells Induce Necroptosis of Lung Endothelial Cells and Increase Susceptibility to Lung Inflammation 
Rationale: Red blood cell (RBC) transfusions are associated with increased risk of acute respiratory distress syndrome (ARDS) in the critically ill, yet the mechanisms for enhanced susceptibility to ARDS conferred by RBC transfusions remain unknown.
Objectives: To determine the mechanisms of lung endothelial cell (EC) High Mobility Group Box 1 (HMGB1) release following exposure to RBCs and to determine whether RBC transfusion increases susceptibility to lung inflammation in vivo through release of the danger signal HMGB1.
Methods: In vitro studies examining human lung EC viability and HMGB1 release following exposure to allogenic RBCs were conducted under static conditions and using a microengineered model of RBC perfusion. The plasma from transfused and nontransfused patients with severe sepsis was examined for markers of cellular injury. A murine model of RBC transfusion followed by LPS administration was used to determine the effects of RBC transfusion and HMGB1 release on LPS-induced lung inflammation.
Measurements and Main Results: After incubation with RBCs, lung ECs underwent regulated necrotic cell death (necroptosis) and released the essential mediator of necroptosis, receptor-interacting serine/threonine-protein kinase 3 (RIP3), and HMGB1. RIP3 was detectable in the plasma of patients with severe sepsis, and was increased with blood transfusion and among nonsurvivors of sepsis. RBC transfusion sensitized mice to LPS-induced lung inflammation through release of the danger signal HMGB1.
Conclusions: RBC transfusion enhances susceptibility to lung inflammation through release of HMGB1 and induces necroptosis of lung EC. Necroptosis and subsequent danger signal release is a novel mechanism of injury following transfusion that may account for the increased risk of ARDS in critically ill transfused patients.
PMCID: PMC4315814  PMID: 25329368
RBC transfusion; necroptosis; endothelial; HMGB1; RIP3
Neuro-Oncology  2014;16(Suppl 5):v129.
BACKGROUND: Pituitary carcinomas (PC) are very uncommon, accounting for only 0.1 % of all pituitary tumors and representing a treatment challenge. Diagnosis is based on presence of intra- and/or extracranial metastases. PC is resistant to current treatment regimens, with a median overall survival of only 31 months. There is no standard treatment for PC, but maximal safe resection and radiation are performed when possible. Temozolomide (TEM)-based regimens are being used in progressive PC, but its effectiveness and the schedule/duration of treatment have not been established. The aim of this study is to report our experience with TEM in patients with progressive PC. METHODS: Three adult patients with progressive PC who were treated with TEM at MDACC between 01/2010-06/2014 were identified. Clinical and radiographic data were extracted from medical records. RESULTS: All three cases had prior history of pituitary macroadenoma. Clinical presentation of PC included visual field deficits, headaches and/or Cushing syndrome. Pathology revealed a mean Ki67 index of 11.5 % (0.4-24.2%) with positive p53 staining in one case. Cavernous sinus invasion was common and metastases involved lymph nodes, liver, bone and leptomeninges. Case 1 received a combined regimen consisting of capecitabine and TEM (CAPTEM). Case 2 was treated with standard-dose TEM, CAPTEM, and chemoradiation with TEM followed by TEM. Case 3 with dissemination to the bone and leptomeninges was initially treated with standard-dose TEM, followed by dose-dense TEM at progression. In the two patients who received chemoradiation with TEM for extracranial disease, the progression-free survival (PFS) was 15 and 17 months, whereas the PFS after TEM-only was 13 months. The median overall survival was 41 months, with all the patients still alive. CONCLUSION: TEM-based therapy seems to be an appropriate initial treatment for PC, prolonging the PFS and leading to tumor-stabilization.
PMCID: PMC4218266
Neuro-Oncology  2014;16(Suppl 5):v129-v130.
INTRODUCTION: Meningiomas are common intracranial neoplasms with variability in their clinical presentation, biological behavior and response to treatment. PURPOSE: The aim of this study was to identify factors that predict the biological behaviour of meningiomas and patients' postsurgical outcome. METHODOLOGY: We retrospectively reviewed 415 meningiomas cases who had undergone surgical resection at Toronto Western Hospital between January 2007 to June 2013. Our cohort consisted of 162 males and 253 females. We reviewed clinical, radiological, and pathological reports, and collected the following data for statistical analysis: patients' sex, age, tumor grade-location, presence of peritumoral edema prior to surgical resection, tumors' largest diameter as a clinical measure of tumor size and history of radiation. All analyses were performed using IBM SPSS 20.0. RESULTS: The incidence of peritumoral edema was significantly higher in males (75%) than in females patients (52%) (p = 0.007). Meningioma location was associated with presence of edema (p < 0.001): olfactory meningiomas showed the highest incidence of edema (71.4%) followed by convexity meningiomas (62%), and sphenoid wing meningiomas (72%) (p < 0.001). Tumors with larger diameters (4.3cm vs. 3.5cm) were likely to have peritumoral edema (p = 0.001). The history of radiation was significantly correlated with peritumoral brain edema (76.4%, p = 0.003). The presence of residual tumor after surgical resection was more likely in meningiomas with higher grades; residual tumor was most common in grade III meningioma (75%) followed by grade II (29.3%), and grade I (17.7%) (p = 0.008). In radiation induced meningiomas the incidence of residual was 41.1%. Also, the grade of tumor was significantly correlated with the incidence of recurrence; grade III meningiomas showed the highest incidence of recurrence (50%) followed by grade II (19.5%) and grade I (4.1%) (p < 0.001). CONCLUSION: The present study demonstrates that specific demographic, radiologic, and pathologic characteristics are significant predictors of tumor response to therapy, tumor recurrence and overall patient outcome.
PMCID: PMC4218269
Neuro-Oncology  2014;16(Suppl 5):v130.
INTRODUCTION: Primary central nervous system angiosarcoma is a very rare malignancy, with only 22 cases reported in the literature for the past 26 years. CLINICAL PRESENTATION: A 60-year old Filipino woman, housewife, presented with 1 week history of difficulty performing daily mathematical equations, difficulty reading words, and difficulty writing. On neurologic exam, patient was found to be oriented to person, place, and time. There was note of dyscalculia, agraphia, and right-left disorientation. There were no finger agnosia, agraphesthesia, astereognosia, nor apraxia. Cranial MRI showed a 4 x 4 x 4.1 cm mass at the left parietal lobe. Total excision of the mass done and biopsy revealed angiosarcoma of the brain. Thorough search for another systemic lesion failed to show any other angiosarcomatous lesion. The patient refused any further radiotherapy or chemotherapy. DISCUSSION: Soft tissue sarcomas comprise a small percent 1% of the malignant neoplasms, and of which only 0.5% comprise the primary brain OR spine sarcoma. In the review of literature that we did, of the 22 reported cases, the tumor was commonly located supratentorially (9/22), affecting middle to late ages with 3:1 male to female ratio. It is an aggressive tumor with a <2-year (range of survival is 4months – 3 ½ years) survival independent of the age, location, or whether chemotherapy or radiotherapy was given. As with the best of our knowledge, there has been no recorded case of angiosarcoma which presented with Gerstmann syndrome in the literature. CONCLUSION: We described the first reported case of primary CNS angiosarcoma in the Philippines and the 23rd worldwide. We also described the first case of angiosarcoma which presented with Gerstmann syndrome. Due to the rarity of this disease, much is still yet to be known in its risk factors, definitive treatment, and prognosis.
PMCID: PMC4218270
Neuro-Oncology  2014;16(Suppl 5):v130.
BACKGROUND: Isolated primary leptomeningeal primitive neuroectodermal tumor (PNET) without intraparenchymal lesion is very rare and to-date few case reports have been published. We report a rare case of leptomeningeal PNET and highlight its neuroimaging features, outcome and literature review. DESIGN AND METHODS: A medline search was conducted for queries including “Children”, “PNET”, leptomeningeal involvement”. Relevant papers were selected for review. CASE REPORT: A 5-year-old female presented with 4-month history of continuous vomiting and repeated headache. CT scan demonstrated communicating hydrocephalus. External ventricular drain was place to relieve the intracranial pressure. An MRI of the brain and the spine showed diffuse leptomeningeal infiltration of the brain and the spinal cord with contrast enhancement. Lumbar cerebrospinal fluid analysis revealed elevated protein but no malignant cells. Pathology of the leptomeningeal biopsywas consistent with neuroepithelial neoplasm. Immunohistochemical stains revealed tumor cells strongly positive for synaptophysin and CD56, retained INI-1, but negative for CD99. Cytogenetical analysis revealed absence of EWS translocation and a diagnosis of primary leptomeningeal PNET was established. Patient received radiation therapy with 36 Gy to the craniospinal axis, concomitantly with vincristine and carboplatin . Follow-up brain and spine MRI showed near complete resolution of the leptomeningeal disease. Family opted not to pursue any therapy and she remains alive with residual disease 8 months since diagnosis. DISCUSSION: Leptomeningeal PNET carries poor prognosis with most patients succumbing to their disease. There are seven case reports in the literature with dismal outcome with survival range from 2 weeks to thirteen months post diagnosis .Rarity of this clinical entity had hindered profiling therapeutic guidelines. Prospective studies are needed to understand if the elusive molecular biology of this rare disease differs from other central PNET. This could help in strategizing optimal therapy and provide a meaningful improvement in the survival of these children.
PMCID: PMC4218271
20.  Examining construct and predictive validity of the Health-IT Usability Evaluation Scale: confirmatory factor analysis and structural equation modeling results 
In a previous study, we developed the Health Information Technology Usability Evaluation Scale (Health-ITUES), which is designed to support customization at the item level. Such customization matches the specific tasks/expectations of a health IT system while retaining comparability at the construct level, and provides evidence of its factorial validity and internal consistency reliability through exploratory factor analysis.
In this study, we advanced the development of Health-ITUES to examine its construct validity and predictive validity.
The health IT system studied was a web-based communication system that supported nurse staffing and scheduling. Using Health-ITUES, we conducted a cross-sectional study to evaluate users’ perception toward the web-based communication system after system implementation. We examined Health-ITUES's construct validity through first and second order confirmatory factor analysis (CFA), and its predictive validity via structural equation modeling (SEM).
The sample comprised 541 staff nurses in two healthcare organizations. The CFA (n=165) showed that a general usability factor accounted for 78.1%, 93.4%, 51.0%, and 39.9% of the explained variance in ‘Quality of Work Life’, ‘Perceived Usefulness’, ‘Perceived Ease of Use’, and ‘User Control’, respectively. The SEM (n=541) supported the predictive validity of Health-ITUES, explaining 64% of the variance in intention for system use.
The results of CFA and SEM provide additional evidence for the construct and predictive validity of Health-ITUES. The customizability of Health-ITUES has the potential to support comparisons at the construct level, while allowing variation at the item level. We also illustrate application of Health-ITUES across stages of system development.
PMCID: PMC4173162  PMID: 24567081
usability; technology acceptance; scale development; factor analysis; structural equation modeling
21.  Caudal Anesthesia for Open Bladder Surgery in High-Risk Adolescent With Scoliosis and Neural Tube Defect 
PMCID: PMC4604290  PMID: 26478864
Anesthesia; Caudal; Adolescent; Meningomyelocele; Scoliosis
22.  Solomon's Wisdom 
Breastfeeding Medicine  2014;9(6):279-280.
PMCID: PMC4074737  PMID: 24967947
23.  Impact of Breastfeeding Self-Efficacy and Sociocultural Factors on Early Breastfeeding in an Urban, Predominantly Dominican Community 
Breastfeeding Medicine  2014;9(6):301-307.
Background: Latinas have high breastfeeding initiation rates that decrease significantly in the first postpartum months. Little is known about the effects of self-efficacy and sociocultural factors on early breastfeeding among low-income Latinas. This study quantifies early breastfeeding rates and identifies factors associated with breastfeeding at 4–6 weeks postpartum in our community.
Subjects and Methods: Mothers were recruited from a newborn clinic (NBC) in the first postpartum week. Questionnaires in the NBC and 4–6 weeks later assessed feeding practices, breastfeeding self-efficacy, and sociocultural factors. Feeding practices in the well baby nursery (WBN) were obtained by chart review. A scale from “1” (exclusive formula feeding) to “5” (exclusive breastfeeding) characterized feeding practices. Paired-sample t tests assessed change in feeding practices, and regression analysis assessed the impact of factors on breastfeeding at 4–6 weeks.
Results: We interviewed 209 women: 86.1% Latina, 47.3% foreign-born, and 94.2% Medicaid-recipients. Breastfeeding increased from WBN to NBC (2.6±1.2 to 2.9±1.4; p<0.05) and then decreased by 4–6 weeks (2.9±1.4 to 2.5±1.44; p<0.05), without significant change between WBN and 4–6 weeks. Higher levels of education [β=0.21 (0.08, 0.56)], breastfeeding a previous child for ≥6 months [β=0.35 (0.57, 1.8)], foreign birth [β=0.2 (0.06, 1.07)], and higher breastfeeding self-efficacy scores [β=0.38 (0.02, 0.05)] were associated with more breastfeeding. Higher breastfeeding self-efficacy scores were associated with exclusive breastfeeding [adjusted odds ratio=1.18 (1.05, 1.32)].
Conclusions: Breastfeeding self-efficacy was the sole, modifiable factor associated with exclusive breastfeeding. Efforts to improve breastfeeding self-efficacy may serve to support breastfeeding in this population.
PMCID: PMC4074742  PMID: 24902047
24.  Lactation Stage-Related Expression of Sialylated and Fucosylated Glycotopes of Human Milk α-1-Acid Glycoprotein 
Breastfeeding Medicine  2014;9(6):313-319.
Background: Because terminal sugars of α-1-acid glycoprotein (AGP) are reported to be involved in anti-inflammatory and immunomodulatory processes, their expressions might have an influence on the proper function of immune system of newborns. Here, relative amounts of sialylated and fucosylated glycotopes on human milk AGP over normal lactation were investigated.
Materials and Methods: AGP concentration and relative amounts of its sialylated and fucosylated glycovariants were analyzed in early colostrum, colostrum, and transitional and mature milk samples of 127 healthy mothers by lectin–AGP enzyme-linked immunosorbent assay using α2,3- and α2,6-sialic acid and α1,2-, α1,3-, and α1,6-fucose specific biotinylated Maackia amurensis, Sambucus nigra, Ulex europaeus, Tetragonolobus purpureus, and Lens culinaris lectins, respectively.
Results: AGP concentration in human milk was about 30 times lower than in plasma of lactating mothers and decreased gradually over lactation. Milk AGP showed significantly higher expression of sialylated and fucosylated glycotopes in comparison with those of plasma AGP. Milk AGP glycovariants containing α2,6-sialylated and α1,6- and α1,2-fucosylated glycotopes showed the highest relative amounts in early colostrums. With progression of lactation, the expressions of glycotopes α1,2-fucosylated decreased starting from Day 4 and those of α2,6-sialylated and α1,6-fucosylated from Day 8 of lactation, whereas the level of α2,3-sialyl-glycotope was almost constant over 45 days of lactation. In contrast, the expression of α1,3-linked fucose on AGP was low in colostrums and significantly higher in transitional and mature milk.
Conclusions: The relative amounts of sialylated and fucosylated glycovariants of human hindmilk AGP significantly varied between Days 2 and 45 of normal lactation.
PMCID: PMC4074750  PMID: 24892765
25.  Knowledge and Beliefs About Breastfeeding Are Not Determinants for Successful Breastfeeding 
Breastfeeding Medicine  2014;9(6):308-312.
A cross-sectional prospective study was performed to assess knowledge and attitude toward breastfeeding among mothers in a tertiary hospital in Malaysia and its influence on their breastfeeding practices. Two hundred thirteen women who had delivered healthy babies at term were enrolled. A structured questionnaire containing demographic data and the Iowa Infant Feeding Attitude Score were used, followed by a telephone interview after 8 weeks to determine the feeding outcome. Women of Malay ethnicity with higher education level who had received breastfeeding counseling had a significantly more favorable attitude toward breastfeeding. Ethnicity was found to be a significant determinant in the success of breastfeeding, whereas returning to work was a major reason for discontinuing breastfeeding. In ensuring a successful breastfeeding practice, apart from knowledge and attitude, issues surrounding culture and traditions as well as improving deliverance of readily available support should be addressed.
PMCID: PMC4074751  PMID: 24893127

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