ETIOLOGIC AND CLINICAL FACTORS WHICH DIFFERENTIATE PATIENTS WITH CHROMOSOMAL ABNORMALITIES FROM DIPLOID PATIENTS IN ACUTE NONLYMPHOCYTIC LEUKEMIA

Tumor-specific chromosomal abnormalities have been demonstrated in bone marrow of approximately 50% of newly diagnosed acute nonlymphocytic (ANLL) patients. This study examined two hypotheses: (1) Aneuploid (AA) patients are diagnosed later in the course of their disease than diploid (NN) patients; and (2) AA patients are more likely to have been exposed to environmental agents. Of 324 patients eligible for study, environmental exposure data were obtained for 236 (73%) of them. No evidence was found to suggest that AA patients had more advanced disease than NN patients. Aneuploid patients were more likely than NN patients to: (a) report treatment with cytotoxic drugs for a prior medical condition (odds ratio, adjusted for age, sex and other exposures (OR) = 4.25, 95% confidence intervals, 1.38 to 13.17); (b) smoke cigarettes, OR = 1.82 (1.02, 3.26) and (c) drink alcoholic beverages, OR = 1.91 (1.05, 3.48). No statistically significant associations between aneuploidy and occupational exposures were present, OR = 3.59 (0.76, 17.13). Problems in interpreting these ORs are discussed. ^

BIOCHEMICAL CHARACTERIZATION AND CLINICAL SIGNIFICANCE OF COAGULASE-NEGATIVE STAPHYLOCOCCI

Although coagulase-negative staphylococci (C-NS) have been implicated in certain human infections, they are generally regarded as contaminants and their clinical significance is questioned. To assess their role as pathogens, 205 isolates of C-NS from wounds, and body fluids (blood, urine, pleural and peritoneal fluids, etc.) were studied. Patient's charts were reviewed and using strict criteria a determination was made regarding the clinical significance of these isolates. The organisms were then identified using the scheme of Kloos and Schleifer to determine if certain species of C-NS were associated with specific infections. S. epidermidis sensu stricto accounted for 81% of the C-NS isolated; the frequency of other species was S. haemolyticus (6%), S. hominis (5%), S. capitis (4%), S. warneri (3%), and others (1%). Only two isolates were novobiocin resistant; neither was identified as S. saprophyticus. Using these criteria, 22% of C-NS were considered to be clinically significant and the majority of these (93%) were due to S. epidermidis. The most common source of the clinically relevant C-NS isolates was from wounds. These data suggest that identifying C-NS species other than S. epidermidis may be of limited value in predicting clinical significance.^ In addition, selected pathogenic and non-pathogenic strains of C-NS were compared for their ability to adhere to human cells in vitro. Although the results were not conclusive, it appeared that pathogenic C-NS adhered more avidly than non-pathogenic C-NS to buccal cells. Experiments with HeLa cells showed no difference between pathogenic and non-pathogenic C-NS in adherence abilities. ^

Genetic variants in the mammalian target of rapamycin (mTOR) signaling pathway as predictors of survival and clinical response in women with ovarian cancer

Background. The mTOR pathway is commonly altered in human tumors and promotes cell survival and proliferation. Preliminary evidence suggests this pathway's involvement in chemoresistance to platinum and taxanes, first line therapy for epithelial ovarian cancer. A pathway-based approach was used to identify individual germline single nucleotide polymorphisms (SNPs) and cumulative effects of multiple genetic variants in mTOR pathway genes and their association with clinical outcome in women with ovarian cancer. ^ Methods. The case-series was restricted to 319 non-Hispanic white women with high grade ovarian cancer treated with surgery and platinum-based chemotherapy. 135 SNPs in 20 representative genes in the mTOR pathway were genotyped. Hazard ratios (HRs) for death and Odds ratios (ORs) for failure to respond to primary therapy were estimated for each SNP using the multivariate Cox proportional hazards model and multivariate logistic regression model, respectively, while adjusting for age, stage, histology and treatment sequence. A survival tree analysis of SNPs with a statistically significant association (p<0.05) was performed to identify higher order gene-gene interactions and their association with overall survival. ^ Results. There was no statistically significant difference in survival by tumor histology or treatment regimen. The median survival for the cohort was 48.3 months. Seven SNPs were significantly associated with decreased survival. Compared to those with no unfavorable genotypes, the HR for death increased significantly with the increasing number of unfavorable genotypes and women in the highest risk category had HR of 4.06 (95% CI 2.29–7.21). The survival tree analysis also identified patients with different survival patterns based on their genetic profiles. 13 SNPs on five different genes were found to be significantly associated with a treatment response, defined as no evidence of disease after completion of primary therapy. Rare homozygous genotype of SNP rs6973428 showed a 5.5-fold increased risk compared to the wild type carrying genotypes. In the cumulative effect analysis, the highest risk group (individuals with ≥8 unfavorable genotypes) was significantly less likely to respond to chemotherapy (OR=8.40, 95% CI 3.10–22.75) compared to the low risk group (≤4 unfavorable genotypes). ^ Conclusions. A pathway-based approach can demonstrate cumulative effects of multiple genetic variants on clinical response to chemotherapy and survival. Therapy targeting the mTOR pathway may modify outcome in select patients.^

TAZ AS A REGULATOR OF MESENCHYMAL TRANSFORMATION AND CLINICAL AGGRESSIVENESS IN GLIOMAS

Glioblastoma multiforme (GBM) is an aggressive, high grade brain tumor. Microarray studies have shown a subset of GBMs with a mesenchymal gene signature. This subset is associated with poor clinical outcome and resistance to treatment. To establish the molecular drivers of this mesenchymal transition, we correlated transcription factor expression to the mesenchymal signature and identified transcriptional co-activator with PDZ-binding motif (TAZ) to be highly associated with the mesenchymal shift. High TAZ expression correlated with worse clinical outcome and higher grade. These data led to the hypothesis that TAZ is critical to the mesenchymal transition and aggressive clinical behavior seen in GBM. We investigated the expression of TAZ, its binding partner TEAD, and the mesenchymal marker FN1 in human gliomas. Western analyses demonstrated increased expression of TAZ, TEAD4, and FN1 in GBM relative to lower grade gliomas. We also identified CpG islands in the TAZ promoter that are methylated in most lower grade gliomas, but not in GBMs. TAZ-methylated glioma stem cell (GSC) lines treated with a demethylation agent showed an increase in mRNA and protein TAZ expression; therefore, methylation may be another novel way TAZ is regulated since TAZ is epigenetically silenced in tumors with a better clinical outcome. To further characterize the role of TAZ in gliomagenesis, we stably silenced or over-expressed TAZ in GSCs. Silencing of TAZ decreased invasion, self-renewal, mesenchymal protein expression, and tumor-initiating capacity. Over-expression of TAZ led to an increase in invasion, mesenchymal protein expression, mesenchymal differentiation, and tumor-initiating ability. These actions are dependent on TAZ interacting with TEAD since all these effects were abrogated with TAZ could not bind to TEAD. We also show that TAZ and TEAD directly bind to mesenchymal gene promoters. Thus, TAZ-TEAD interaction is critically important in the mesenchymal shift and in the aggressive clinical behavior of GBM. We identified TAZ as a regulator of the mesenchymal transition in gliomas. TAZ could be used as a biomarker to both estimate prognosis and stratify patients into clinically relevant subgroups. Since mesenchymal transition is correlated to tumor aggressiveness, strategies to target and inhibit TAZ-TEAD and the downstream gene targets may be warranted in alternative treatment.

A study of nutrition promotion in and consumer nutrition environments of hospitals

Dietary intake is a complex, health-related behavior, and although individual-level theoretical models explain some variation in dietary intake, comprehensive theoretical models such as the ecological framework describe the multiple levels which influence diet-related behaviors. Thus, the ecological framework is a preferred model for designing comprehensive nutrition interventions. While ecological-based nutrition interventions have been described, little work has focused on interventions in the hospital setting. Because hospitals are considered the hallmarks of health, it might seem that hospitals would regularly engage in worksite nutrition promotion; however, recent publications and other anecdotal evidence have indicated otherwise. The first paper of this dissertation systematically reviewed the scientific literature between 1996 and 2012 and identified 13 outcome evaluation trials for hospital-based worksite nutrition interventions. Of these 13 interventions, only one intervention targeted three of the four levels of the ecological framework and no intervention targeted all four levels. Only half of the interventions targeted the physical environment of hospitals, thus warranting more investigation into this specific level of the ecological framework in this setting. ^ A critical type of nutrition-related physical environments is the consumer nutrition environment. Although other tools measure the consumer nutrition environments of stores and restaurants, no tool specifically measured the consumer nutrition environments of hospitals until the CDC developed the Healthy Hospital Environment Scan for Cafeterias, Vending Machines, and Gift Shops (HHES-CVG). The HHES-CVG, a tool which measures the consumer nutrition environments of hospital cafeterias, vending machines, and gifts shops, was released in November 2011, and in the second paper of this dissertation, the reliability of this tool was investigated. Two trained raters visited 39 hospitals across Southern California between February and May 2012, and based on analyses of the raters' findings, the HHES-CVG exhibited strong reliability metrics (inter-observer agreement between 74 and 100%, and an intraclass correlation coefficient of 0.961 for the overall nutrition composite score). Because the HHES-CVG was found to be a reliable tool, the third paper of this dissertation presented HHES-CVG results from the 39 hospitals. Overall, hospitals only scored about one-fourth of the total possible points for the nutrition composite score, indicating that most facilities do not have acceptable consumer nutrition environments. Some of the best practices observed in cafeterias were significantly associated with having a large facility and with having a contracted foodservice operation, but overall nutrition composite score was not associated with any specific facility or operation type. ^ The dissertation concluded that much work is needed in order to improve the consumer nutrition environments of hospitals. Practitioners and healthcare administrators should consider starting with ecological-based interventions addressing all levels including the physical environment.^

Abortion and Clinical Practice. Abortion Review Papers from the bpas conference: London, 25 - 26 June 2008

The groundbreaking bpas conference The Future of Abortion: Controversies and Care brought together clinicians, academics, policymakers and advocates from the UK, Europe and the USA for a discussion about all aspects of abortion provision. Taking place during a critical Parliamentary debate about the UK abortion law, the conference generated great excitement and presented a number of important research findings and policy suggestions.In order to maximise the strides made by The Future of Abortion conference in taking forward an international, interdisciplinary discussion, Abortion Review is producing a series of special editions in which we have published edited transcripts of the presentations. In this third edition, Abortion and Clinical Practice, the presentations examine developments in abortion research and practice, and what these might indicate for the kind of abortion service that should be provided.

Personalidad, género y vulnerabilidad a la depresión :(Women and vulnerability to depression : some personality and clinical factors)

En este trabajo se exploraron relaciones existentes entre las características de personalidad, género y la presencia de depresión, siguiendo la linea de investigación de Carrillo, Rojo y Staats (2004). Se intentó encontrar perfiles de personalidad caracterizados por determinados rasgos que fueran significativamente distintos entre hombres y mujeres y que a su vez se asociaran a una mayor presencia de síntomas depresivos. Esto se llevó a cabo en dos muestras de distintos países y culturas por separado: Chile (N= 448, 257 varones (57.37%) y 190 mujeres (42.41%), y un rango etario de 17-65) y España (N = 578, 196 varones (33.9%) y 381 mujeres (65,9%), y un rango etario de 17-67 ), con el propósito de aportar evidencia respecto de cómo afecta la cultura, como factor ambiental, en la conformación de la personalidad a partir de repertorios de aprendizajes. Orientado a eso en el presente trabajo se intentó buscar asociaciones significativas entre las dimensiones de Personalidad propuestas por Eysenk (1975), en el EPQ y EPQ-R, por los factores de Personalidad de los Cinco grandes a partir del NEO PI y del NEO PI-R (Costa y McCrae, 1985, citado en Carrillo et al. 2004) y otras variables clínicas, como rasgos de personalidad esquizotipicos, frecuencia e intensidad de emociones, habilidades sociales y sintomatología clínica. Las características de personalidad se compararon en función del género y finalmente se analizó si las diferencias de personalidad pudieron predecir depresión a partir del Beck Depression Inventory, (Beck, Rush, Shaw y Emery, 1979)...

Intercultural Communication Between Forensic and Clinical Psychologists

While working in clinical and forensic psychology settings, a communication difficulty between the two professions became apparent. Forensic psychologists often appeared cold and callous from the clinical psychologist’s perspective, while clinical psychologists often appeared naïve or too client centered from the forensic psychologist’s perspective. I wondered if viewing each subfield of psychology as a culture could facilitate better communication through intercultural communication. Guided by Intercultural Communication in Contexts (Martin & Nakayama, 2010) in approaching intercultural communication between the two professions, I explored factors contributing to each profession’s cultural identities. Once this was established, I attempted to explore the different ways each culture could communicate more effectively. By recognizing and utilizing the strengths from each profession and understanding the possible pitfalls of one’s own, we may become competent in intercultural communication

Estimation of the Central Corneal Power in Keratoconus: Theoretical and Clinical Assessment of the Error of the Keratometric Approach

Purpose: The aim of this study was to analyze theoretically the errors in the central corneal power calculation in eyes with keratoconus when a keratometric index (nk) is used and to clinically confirm the errors induced by this approach. Methods: Differences (DPc) between central corneal power estimation with the classical nk (Pk) and with the Gaussian equation (PGauss c ) in eyes with keratoconus were simulated and evaluated theoretically, considering the potential range of variation of the central radius of curvature of the anterior (r1c) and posterior (r2c) corneal surfaces. Further, these differences were also studied in a clinical sample including 44 keratoconic eyes (27 patients, age range: 14–73 years). The clinical agreement between Pk and PGauss c (true net power) obtained with a Scheimpflug photography–based topographer was evaluated in such eyes. Results: For nk = 1.3375, an overestimation was observed in most cases in the theoretical simulations, with DPc ranging from an underestimation of 20.1 diopters (D) (r1c = 7.9 mm and r2c = 8.2 mm) to an overestimation of 4.3 D (r1c = 4.7 mm and r2c = 3.1 mm). Clinically, Pk always overestimated the PGauss c given by the topography system in a range between 0.5 and 2.5 D (P , 0.01). The mean clinical DPc was 1.48 D, with limits of agreement of 0.71 and 2.25 D. A very strong statistically significant correlation was found between DPc and r2c (r = 20.93, P , 0.01). Conclusions: The use of a single value for nk for the calculation of corneal power is imprecise in keratoconus and can lead to significant clinical errors.

Clinical utility of ocular residual astigmatism and topographic disparity vector indexes in subclinical and clinical keratoconus

Purpose. We aimed to characterize the distribution of the vector parameters ocular residual astigmatism (ORA) and topography disparity (TD) in a sample of clinical and subclinical keratoconus eyes, and to evaluate their diagnostic value to discriminate between these conditions and healthy corneas. Methods. This study comprised a total of 43 keratoconic eyes (27 patients, 17–73 years) (keratoconus group), 11 subclinical keratoconus eyes (eight patients, 11–54 years) (subclinical keratoconus group) and 101 healthy eyes (101 patients, 15–64 years) (control group). In all cases, a complete corneal analysis was performed using a Scheimpflug photography-based topography system. Anterior corneal topographic data was imported from it to the iASSORT software (ASSORT Pty. Ltd), which allowed the calculation of ORA and TD. Results. Mean magnitude of the ORA was 3.23 ± 2.38, 1.16 ± 0.50 and 0.79 ± 0.43 D in the keratoconus, subclinical keratoconus and control groups, respectively (p < 0.001). Mean magnitude of the TD was 9.04 ± 8.08, 2.69 ± 2.42 and 0.89 ± 0.50 D in the keratoconus, subclinical keratoconus and control groups, respectively (p < 0.001). Good diagnostic performance of ORA (cutoff point: 1.21 D, sensitivity 83.7 %, specificity 87.1 %) and TD (cutoff point: 1.64 D, sensitivity 93.3 %, specificity 92.1 %) was found for the detection of keratoconus. The diagnostic ability of these parameters for the detection of subclinical keratoconus was more limited (ORA: cutoff 1.17 D, sensitivity 60.0 %, specificity 84.2 %; TD: cutoff 1.29 D, sensitivity 80.0 %, specificity 80.2 %). Conclusion. The vector parameters ORA and TD are able to discriminate with good levels of precision between keratoconus and healthy corneas. For the detection of subclinical keratoconus, only TD seems to be valid.