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Primary And Secondary Intrusions In Double-Diffusively Stable Vertical Gradients, Julian A. Simeonov

Journal of Marine Research

The purpose of this paper is to show that molecularly-driven double-diffusive intrusions can produce significant lateral and vertical double-diffusive mixing even when the initial temperature and salinity are both stably stratified in the vertical. Assuming uniform density-compensated horizontal gradients and periodic disturbances, three-dimensional direct numerical simulations (DNS) for the fastest growing intrusion show that the latter equilibrates due to the generation of salt fingers which reduce the driving buoyancy pressure gradient. The DNS also provided statistical data for a new parameterization of the salt finger fluxes which includes the effects of shear and variable vertical gradients. This parameterization makes it …

Suffering Transfigured: Phenomenological Personalism In The Doctor-Patient Relationship, Keri Oxley

Yale Medicine Thesis Digital Library

From antiquity, one of the primary goals of medicine has been the alleviation of patients' suffering. Despite remarkable advances in modern science and technology, patients continue to experience suffering, which is frequently unnoticed and unaddressed by physicians.

Phenomenology incorporates an understanding of illness-as-lived, which provides the physician with a view more expansive than the purely biomedical model of disease. There exists a decisive gap between the way a physician thinks about disease and the way illness is experienced by the patient. As a result, there is a separation between the "lifeworlds" of the physician and patient. A fuller description of …

A Human Culture Model Of The Outer Blood-Retinal Barrier In Age-Related Macular Degeneration, Veena Rao

Yale Medicine Thesis Digital Library

In age-related macular degeneration (AMD), the outer blood-retinal barrier is exposed to various pathologic factors which can result in visual detriment. Two such stimuli include serum, as may be seen in neovascular AMD, and proinflammatory cytokines, which may be seen in neovascular and non-neovascular AMD. To examine effects of serum and cytokines in disease, we adapted an outer blood-retinal barrier culture model using human fetal retinal pigment epithelium (hfRPE) to investigate effects on tight junctions. Specifically, we focused on the claudin family and occludin tight junction proteins. HfRPE was cultured on filters in growth medium until quiescent monolayers were formed; …

Neural Systems Of Dysfluent Reading In Childhood: Anatomical And Functional Regions Of Interest, Ava Golchin

Yale Medicine Thesis Digital Library

Dyslexia is an unexpected difficulty in learning to read. Dyslexics experience difficulty parsing a written word's phonology. Although impairment of phonology is the cardinal feature of dyslexia, dyslexics may also be identified by slow, laborious, and inefficient reading of text (dysfluency). Dysfluent readers can be divided into those who have attained adequate skill in decoding, and those who lack both decoding accuracy and fluency. This study of 144 right handed children: (67 girls and 77 boys; ages 7-12 years, mean 9.0 years) is the first fMRI study to compare the neural pathways related to reading in dyslexics identified using dysfluency …

Medicine@Yale November/December 2011 Volume 7, Issue 5, Yale School Of Medicine Office Of Communications

Medicine@Yale - development newsletter

Medicine@Yale : advancing biomedical science, education and health care was a print and online newsletter which published news about academics, research and philanthropy for alumni, donors, faculty, students and the general public. It was initially published 6 times a year and then changed to a quarterly schedule. The first issue came out June/Jul. 2005. The final issue was published in May/June 2022, vol. 17, issue 1. Published by Yale School of Medicine, Office of Communications.

Trpa1 In Airway Inflammation, Maxwell Dominic Elia

Yale Medicine Thesis Digital Library

Asthma results from exposure to allergens and other airway irritants. While clinical treatment of the disease has recently expanded beyond simply β-agonists and inhaled steroids, recent strategies seeking to modulate the immune mechanisms of the disease have offered incomplete control of the disease. This study demonstrates a mechanistically novel component in the development of asthmatic inflammation mediated by sensory neurons within the lung parenchyma. Sensory neurons are rich in the transient receptor potential channel A1 (TRPA1), an ion channel activated by strong triggers of asthma, including cigarette smoke, chlorine, and hypochlorite. This project examines the role of TRPA1 in the …

Determining The Fate Of Bone Marrow Mononuclear Cells In Tissue Engineered Vascular Grafts Using Mri, Jamie Keiko Nicole Harrington

Yale Medicine Thesis Digital Library

The most widely used method of creating tissue engineered vascular grafts (TEVGs) for in vivo implantation consists of seeding autologous bone marrow cells (BMCs) onto biodegradable scaffolds. In this model of TEVG development it has traditionally been thought that stem cells and endothelial progenitor cells (EPCs) within the seeded bone marrow population gave rise to the cells of the neovessel. Recent work in our lab indicates that the seeded BMCs are not incorporated into the neovessel and are actually rapidly lost from the implanted scaffold. Here we show the feasibility of noninvasively monitoring this process by tracking ultrasmall superparamagnetic iron …

Bystander Attenuation Of Neuronal And Astrocyte Intercellular Communication By Murine Cytomegalovirus Infection Of Glia, Sze Chun Winson Ho

Yale Medicine Thesis Digital Library

Astrocytes are the first cells infected by murine cytomegalovirus (MCMV) in primary cultures of brain. These cells play key roles in intercellular signaling and neuronal development, and they modulate synaptic activity within the nervous system. Using ratiometric fura-2 digital calcium imaging of >8,000 neurons and glia, we found that MCMV-infected astrocytes showed an increase in intracellular basal calcium levels and an enhanced response to neuroactive substances, including glutamate and ATP, and to high potassium levels. Cultured neurons with no sign of MCMV infection showed attenuated synaptic signaling after infection of the underlying astrocyte substrate, and intercellular communication between astrocytes with …

Psychopathology In Adolescents With A History Of Foster Care, Scott Ronald Hunter

Yale Medicine Thesis Digital Library

Despite the enormous cost of the foster care system, high rates of psychopathology and homelessness among young-adult foster care alumni provide a stark reminder of the challenges faced by this vulnerable population. This study characterizes the effect of a history of foster care on psychopathology in a group of 39 adolescents that had exited foster care and were reunified with their biological mothers. A history of foster care was defined as out-of-home placement by child welfare for at least one month; median foster stay was 1.5 years and median age at placement was 8.5 years. A control group of 78 …

Bovine Aortic Arch: A Marker For The Development And Progression Of Thoracic Aortic Disease, Matthew Alan Hornick

Yale Medicine Thesis Digital Library

This study investigated the relationship between congenital bovine arch (BA) variant and thoracic aortic aneurysm (TAA), thoracic aortic expansion rate, bicuspid aortic valve (BAV), and aortic complications. We hypothesized that BA would be significantly associated with the presence and progression of thoracic aortic disease.

To determine prevalence of BA, we retrospectively reviewed thoracic CT and/or MRI scans of 616 patients with thoracic aortic disease and 844 patients without thoracic aortic disease (all from Yale-New Haven Hospital). In patients with thoracic aortic disease, we assessed accuracy of official radiology reports in citing BA, and reviewed all available hospital records to determine …

A 3'Utr Kras-Variant As A Biomarker Of Poor Outcome And Platinum Chemotherapy Resistance In Ovarian Cancer, Florence Keane

Yale Medicine Thesis Digital Library

Purpose: Ovarian cancer has a poor prognosis, yet pathologic and clinical data do not accurately predict which patients will ultimately succumb to their disease. We previously reported an association between rs61764370, a germline functional variant in the 3'UTR of the KRAS oncogene, and epithelial ovarian cancer (EOC) risk. Here we evaluate this variant as a biomarker of clinical outcome and chemotherapy resistance in EOC.

Patients and Methods: Four groups of EOC patients with complete clinical data were genotyped for the KRAS-variant and analyzed: Sporadic EOC patients (n=451); BRCA mutant EOC patients (n=79); EOC patients treated with neoadjuvant chemotherapy (n=122), and; …

Comparing Antipsychotic Treatments For Schizophrenia: A Health State Approach, Lewei Lin

Yale Medicine Thesis Digital Library

HYPOTHESIS/AIMS: Apply health state analysis to a large clinical trial dataset of patients with schizophrenia to provide added insights into clinical and quality of life characteristics. We also evaluated the hypothesis that there is no difference in the distribution of health states of patients across several antipsychotic medications. METHODS: This study was a secondary analysis of data from the CATIE trial, a multi-site double blind clinical trial of antipsychotic treatments for schizophrenia. We applied K-means clustering to the CATIE data, creating discrete clusters with symptom and side effect characteristics that were then validated using a panel of quality of life …

Role Of The Innate Immune Response In Tissue Engineered Vascular Graft Stenosis, Dane Mejias

Yale Medicine Thesis Digital Library

Tissue Engineered Vascular Grafts (TEVGs) hold great promise in advancing the field of pediatric cardiac surgery and other applications in which a vascular conduit is required. The first human clinical trial of these grafts indicated that stenosis was the primary mode of graft failure. Here, we investigate the role of the immune response in stenosis through a CB17 murine inferior vena cava interposition model. We demonstrate that this mouse model undergoes a dramatic stenotic response, and that this is nearly completely abolished in a SCID/bg immunodeficient variant (average luminal diameter (LD) WT: 0.071+/-0.035mm, SCID/bg: 0.804+/-0.039mm; P<0.001). SCID-only mice, which lack T- cells and B-cells, undergo stenosis with luminal diameters approaching those of wild type mice. The bg mutation is characterized by defects in natural killer (NK) cell and platelet dysfunction, and treatment of wild-type mice with either anti-platelet therapy (aspirin/clopidogrel) or an anti- natural killer cell antibody (NK 1.1) results in patency that is half of that achieved in the SCID/bg mouse (WT: 0.071+/-0.035mm, SCID/bg: 0.804+/-0.039mm, SCID: 0.137+/-0.032mm, Asp/Pla: 0.452+/-0.130mm, NKab: 0.356+/-0.151mm; P<0.001). We additionally show that SCID/bg mice show a blunted immune response to scaffold implantation, wheras wild-type mice show a dramatic initial burst of activity as demonstrated by macrophage number, mRNA, and cytokine levels. Implicating the initial innate immune response to the scaffold as a critical contributing factor in graft stenosis may provide a strategy for prognosis and therapy of future TEVGs.

Differences In Disease-Free Survival And Acute Toxcity Between African-American And Non-Latino White Men With Localized Prostate Cancer Treated With Intensity Modulated Radiation Therapy, Steven Oh

Yale Medicine Thesis Digital Library

Purpose

To determine whether differences exist in biochemical disease-free survival (BDFS) and acute toxicity between African-American (AA) and non-Latino white (NLW) men with prostate cancer treated with intensity modulated radiation therapy (IMRT).

Methods and Materials

Between January 2000 and January 2008, 129 AA and 591 NLW men with clinically localized prostate cancer were treated with IMRT. Median follow up was 26.6 months for both groups. Kaplan-Meier analysis was used to compute rates of biochemical disease free survival. Chi-square analysis was used to compute rates of acute toxicity.

Results

No difference was found in three year biochemical disease free survival (BDFS) …

Improving Prognostic Models In Breast Cancer With Biostatistical Analysis Of The Phosphatidyl Inositol 3-Kinase Pathway, Elliot Rapp

Yale Medicine Thesis Digital Library

IMPROVING PROGNOSTIC MODELS IN BREAST CANCER WITH BIOSTATISTICAL ANALYSIS OF THE PI3-KINASE PATHWAY.

Elliot James Rapp, Jena P. Giltnane, David L. Rimm, Annette Molinaro. Department of Biostatistics, Yale School of Public Health, Yale University School of Medicine, New Haven, CT.

Our hypothesis was that prognostic models for breast cancer that incorporate both clinical variables and biomarkers in the PI3 Kinase molecular pathway will improve upon the clinical models of TNM staging and the Nottingham Prognostic Index (NPI). Our specific aim was to develop models that misclassify fewer patients than TNM and NPI with the outcome of dead of disease at …

Optimal Tumor Sampling For Immunostaining Of Biomarkers In Breast Carcinoma, Juliana Tolles

Yale Medicine Thesis Digital Library

OPTIMAL TUMOR SAMPLING FOR IMMUNOSTAINING OF BIOMARKERS IN BREAST CARCINOMA. Juliana Tolles, Yalai Bai, Maria Baquero, Lyndsay N. Harris, David L. Rimm, Annette M. Molinaro. Division of Biostatistics, Yale University School of Public Health, New Haven, CT.

Biomarkers, such as estrogen receptor, are used to determine therapy and prognosis in breast carcinoma. Immunostaining assays of biomarker expression have a high rate of inaccuracy, for example estimates are as high as 20% for estrogen receptor. Biomarkers have been shown to be heterogeneously expressed in breast tumors and this heterogeneity may contribute to the inaccuracy of immunostaining assays. Currently, no evidence-based standards …

Prognostic Implications Of Patients With Mammographically Occult, Early Stage Breast Cancer, Tzu-I Jonathan Yang

Yale Medicine Thesis Digital Library

Purpose: To compare mammographically occult (MamOcc) and mammographically positive (MamPos) early-stage breast cancer patients treated with breast-conservation therapy (BCT), to analyze differences between the two cohorts.

Methods: The 2 cohorts were comprised of 214 MamOcc and 2168 MamPos patients treated with BCT. Chart reviews were conducted to assess mammogram reports and method of detection. All clinical-pathologic and outcome parameters were analyzed to detect differences between the two cohorts.

Results: Median follow-up was 7 years. There were no differences in final margins, T stage, nodal status, estrogen/progesterone receptor status, or "triple-negative" status. Significant differences included age at diagnosis (p < 0.0001), more positive family history (p = 0.0033), less HER-2+ disease (p = 0.0294), and 1° histology (p < 0.0001). At 10 years, the differences in overall survival, cause-specific survival, and distant relapse between the two groups did not differ significantly. The MamOcc cohort had more breast relapses (15% vs. 8%; p = 0.0357), but on multivariate analysis this difference was not significant (hazard ratio 1.0, 95% confidence interval 0.993-1.007, p = 0.9296). Breast relapses were more commonly not picked up on mammography in the MamOcc cohort (32% 12% p = 0.0136).

Conclusions: Our …

Pericyte, Neural Crest And Adipocyte Differentiation Markers: Support For A Novel Hypothesis For The Origin Of Hemangiomas, Laura Tom

Yale Medicine Thesis Digital Library

Introduction: Hemangiomas are the most common benign tumor of infancy. They are unique in that their behavioral course is well-described with a microvascular proliferative phase, quiescent phase and regressive fatty involuting phase. First, it is posited in this work that the cell of origin will have angiogenic and adipogenic properties, like the pericyte. Second, the predilection of the lesion to areas of embryologic fusions in the head and neck indicate that the neural crest may be involved. Previous research focused on the angiogenic characteristics of proliferating hemangiomas, this work is novel in that it investigates markers involved in adipogenesis. This …

Simulated Death: The Perceived Stress And Its Impact On Undergraduate Medical Education, Benjamin Zabar

Yale Medicine Thesis Digital Library

Simulated Death: The Perceived Stress And Its Impact On Undergraduate Medical Education

Benjamin Zabar, Kelly L Dodge, Basmah Safdar, Sanziana Roman, John Sather, Christopher Moore, Brian Biroscak, & Leigh V Evans. Yale Department of Emergency Medicine, Yale University School Of Medicine, New Haven CT.

Objectives: To determine perceived stress of medical students during simulated patient death, the impact of assigned role, and the effects on learning.

Methods: This was a prospective, single blinded, randomized cross over study of third year medical students who participated in a 12 week simulation course using a high fidelity mannequin (Laerdal SimMan®) during a required …

Development Of A Nanoparticulate Drug Delivery Vehicle For Retinoic Acid, Noah Capurso

Yale Medicine Thesis Digital Library

Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models including Th17 mediated diseases. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating …

Development Of A Viral Vaccine Vector Expressing A P. Falciparum Erythrocyte Membrane Protein Domain To Target Severe Malaria, Sara Eve Crager

Yale Medicine Thesis Digital Library

There are an estimated 300-500 million cases of malaria every year, resulting in approximately 2 million deaths. Malaria mortality occurs primarily in children under the age of five, and is resultant from the development of severe malaria. Attempts to control P. falciparum malaria face rapidly escalating levels of resistance on two fronts: the parasite to anti-malarial drugs, and the mosquito vector to insecticides. Despite current prevention efforts, the global incidence of malaria continues to rise and there is a clear and urgent need for a malaria vaccine. Malaria vaccine efforts thus far have been largely unsuccessful in eliciting robust and …

Effects Of Antiphospholipid Antibodies On Trophoblast-Mediated Angiogenesis And Vascular Remodeling, Tamara Carroll

Yale Medicine Thesis Digital Library

EFFECTS OF ANTIPHOSPHOLIPID ANTIBODIES ON TROPHOBLAST-MEDIATED ANGIOGENESIS AND VASCULAR REMODELING

Tamara Y. Carroll, Melissa Mulla and Vikki M. Abrahams. Section of Reproductive Immunology, Department of Obstetrics and Gynecology, Yale University, School of Medicine, New Haven, CT.

Women with antiphospholipid antibody syndrome (APS) are at increased risk for miscarriage and preeclampsia, which are associated with diminished trophoblast invasion and limited spiral artery transformation. Antiphospholipid antibodies (aPL) specifically target the placenta by binding trophoblast beta₂glycoprotein I (&beta₂GPI). Thus, we determined whether aPLs alter trophoblast angiogenic factor production, endothelial tube formation, and trophoblast-endothelial cell interactions, and evaluated the effect …

Investigating The Influence Of Langerhans Cells On Keratinocyte Proliferative Response To Chemical And Ultraviolet B (Uvb) Exposure, Kseniya Golubets

Yale Medicine Thesis Digital Library

Initially, the Girardi lab demonstrated that LC facilitate chemical carcinogenesis by showing lower levels of proliferation in LC-deficient (Langerin-diptheria toxin A transgenic) mice relative to LC-intact littermate controls. Thus, we sought to explore the breadth of potential influences of LC on keratinocyte responses (hypertrophy, apoptosis, and clonal expansion) in two classic models of carcinogenesis (chemical and UVB), by using immunohistochemical (IHC) and immunofluorescent (IF) methods of cell identification. At baseline, LC-deficient compared to LC-intact mouse skin showed comparable proliferation levels as measured by Ki-67 IHC (13.6±2.6 vs 12.7±2.8 Ki-67+ cells, NS) and epidermal thickness (7.9±1.8 vs 6.9±2.8 micrometers, NS). After …

High-Resolution Characterization Of The Leukemic Cutaneous T-Cell Lymphoma Genome, William Lin

Yale Medicine Thesis Digital Library

Cutaneous T cell lymphoma (CTCL) is a heterogenous disease that can progress to leukemic involvement and is lethal in advanced stages. Toward a better understanding of the pathogenesis and identification of novel therapeutic targets in this malignancy of CD4+ T cells, we conducted an integrative high-resolution genomic analysis combining DNA and mRNA data, along with clinical information, from 24 CTCL patients with blood involvement. We further performed a consensus analysis, totaling 108 samples, that confirms and narrows key loci to produce one of the most comprehensive views of the CTCL genome to date. The most significant regions of alteration are …

Evaluation Of Need And Feasibility Of Tuberculosis Screening In Buprenorphine Treatment Programs, Ryan Schwarz

Yale Medicine Thesis Digital Library

Background: Buprenorphine's availability in primary care settings offers increased access to treatment and linkage to primary care for opioid-dependent patients. Currently, tuberculin skin testing (TST) is recommended for patients enrolling in methadone maintenance treatment (MMT), but not for those enrolling in buprenorphine maintenance treatment (BMT).

Objectives: To compare TST screening results in enrollees in BMT and MMT programs and assess the correlates of TST positivity among these subjects.

Methods: A cross-sectional analysis of a retrospective cohort study was conducted to compare concurrent TST results among contemporaneously matched groups of MMT and BMT patients in the same community.

Results: TST positivity …

Effects Of Surface Quasi-Geostrophic Turbulence On Phytoplankton Competition And Coexistence, Coralie Perruche, Pascal Rivière, Guillaume Lapeyre, Xavier Carton, Philippe Pondaven

Journal of Marine Research

This paper aims at studying numerically the competition between two mutually exclusive phytoplankton species in a fully-turbulent field consisting of interacting mesoscale and submesoscale structures. A simple NPPZD ecosystem model is embedded in a Surface Quasi-Geostrophic model which is able to reproduce frontogenesis and the associated nutrient vertical pump. The two simulated phytoplankton species differ by their size and their affinity for nutrients. In this study, we rationalize the role played by eddies and filaments in the distribution of the two phytoplankton species. We show that the SQG dynamics are responsible for the coexistence of the two phytoplankton species on …

Modeling The Evolution Of Intrathermocline Lenses In The Atlantic Ocean, B. N. Filyushkin, M. A. Sokolovskiy

Journal of Marine Research

The existence of a tongue of Mediterranean Water (MW) at the depths of 500–1500 m is a characteristic feature of the hydrological regime in the northeastern part of the Atlantic Ocean. Anticyclonic eddies filled with MW (meddies or lenses) are observed in this region. They are identified via their high temperature and salinity anomalies, which compensate in density, yielding nearly homogeneous meddy cores. The analysis of historical observations has showed that approximately 100 lenses can exist simultaneously in this part of the ocean. High concentration of large water volumes (>4000 km³ each) can be found both in the …

Modeling Of The M2 Surface And Internal Tides And Their Seasonal Variability In The Arctic Ocean: Dynamics, Energetics And Tidally Induced Diapycnal Diffusion, B. A. Kagan, E. V. Sofina, A. A. Timofeev

Journal of Marine Research

Modeling results for the M₂ surface and internal tides in the Arctic Ocean (AO) are presented. These incorporate the data on tidal dynamics and energetics and tidally induced diapycnal diffusion. A modified version of the 3D finite-element hydrostatic model QUODDY-4 is used as a basis for modeling. It is shown that the predicted surface tide differs slightly from that obtained from other tidal models, whereas the internal tidal waves (ITW) are less than those in oceans of moderate and low latitudes. It also appears that ITW themselves belong to the family of trapped waves. This finding, together with the …

On Trend Analysis In Climatic Time Series, With Application To Surface Temperature, Victor Privalsky, Marina Fortus, Vladimir Komchatov, Eugene Borisov

Journal of Marine Research

The deletion of a trend as an initial step in the analysis of climatic time series may result in the elimination of low-frequency components which constitute an integral part of climatic variability. An example is given here showing that linear trend deletion from the time series of the World Ocean annual sea-surface temperature (1850–2009) reduces the low-frequency (from 0.02 year^–1 to 0.001 year–¹) part of the time series spectrum by ∼40% to 80% thus severely distorting the spectrum of climate. As an additional result, it is shown that the current warming can be explained in full within …

The Arrested Agulhas Retroflection, Doron Nof, Volodymyr Zharkov, Joseph Ortiz, Nathan Paldor, Wilton Arruda, Eric Chassignet

Journal of Marine Research

Paleoceanographic proxy data indicate that the Agulhas leakage into the South Atlantic was dramatically reduced during glacial times. In our former papers, we suggested that this was due to a northward shift of the zero wind stress curl that, in turn, forced the retroflection to occur farther north, where the slant of the coastline relative to the north is steep. In the present paper, we propose that strong westerlies (0.4 Pa, implying a wind speed of ∼12 m s^–1 at zero degrees centigrade), which were supposedly common during glaciations, can also arrest the leakage. This arrest occurred because the …