Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Congenital abnormalities of the diaphragm, specifically congenital diaphragmatic hernia (CDH), affect 1 in 3,000 live births and are associated with substantial morbidity and mortality. Evidence in humans and animal models support genetic causation. The etiology of most cases, however, remains unknown, though is likely polygenic in the majority. Another impediment to uncovering CDH etiology is that collection of human specimens at the onset of diaphragm development (4 weeks gestation) is not feasible. Identification of key transcriptional programs involved in normal diaphragm development is needed to gain a more comprehensive understanding of the genetic etiology of CDH. As an initial step, unique transcriptome-wide data sets are generated from laser-captured mouse embryonic diaphragms at three key time-points of diaphragm development. These data sets provide the first unbiased perspective on genes and signaling pathways active during early and late diaphragm morphogenesis. Moreover, using a curated list of known CDR-associated genes as "baits", the normal expression data sets are filtered for identification of biologically relevant CDH candidate genes. By this approach, 27 novel CDH candidate genes are described, among which, pre-B cell leukemia transcription factor 1 (Pbxl) is selected to validate the prioritization approach. Diaphragm defects resembling the human CDH phenotype, never previously appreciated, are observed among Pbxl mutant mice at E15.5. Secondly, a human family containing several affected individuals with CDH is used for gene discovery. A multiplatform analysis approach, coupled with external filtering with the normal diaphragm expression data, provide a mechanism for identification of candidate modifier loci. This integrative strategy, which identifies a FOG2 deletion and several potential modifiers of the CDH phenotype, is described. The design of a customized diagnostic/discovery capture array for next-generation sequencing of a large CDH patient cohort uses the set of CDR-candidate genes identified herein. / 2031-01-02

Traumatic diaphragmatic hernia (TDH) is a known complication in patients with abdominal injuries. Delayed TDH, which presents long after the traumatic event, is a rare subset and is often missed upon initial presentation. We discuss a case involving a 15-year-old female who presented with persistent nausea, vomiting, and epigastric pain and was subsequently diagnosed with TDH via chest x-ray, later confirmed by CT scan. Further investigation of the patient's history revealed a motor vehicle accident one year prior in which the patient sustained an injury to the left chest. A chest x-ray at that time did not show signs of a diaphragmatic hernia. Surgical evaluation of the diaphragmatic defect further supported previous trauma as the mechanism of injury. Our patient's presentation is particularly interesting considering the lack of TDH reported in the pediatric population, as well as the presenting complaints being primarily gastrointestinal rather than respiratory.

Thesis (doctoral)--Faculté de médecine de Paris, 1866. / At head of title: Faculté de médecine de Paris.

Bei kongenitalen Zwerchfelldefekten kommt es zu einer Herniation von abdominellen Organen in den Thorax. Es resultieren eine Lungenhypoplasie und eine pulmonale Hypertonie, die die hohe Mortalität und Morbidität bestimmen. In dieser Studie wurden prä-, peri- und postnatale Parameter von Patienten mit kongenitalen Zwerchfelldefekten retrospektiv betrachtet und auf eine mögliche Prädiktion für das Outcome sowie auf therapeutische Qualitätsänderungen überprüft. Im prospektiven Teil wurde die weitere Entwicklung der Kinder nach dem stationären Aufenthalt eruiert. Statistisch signifikante Unterschiede zeigten sich für einen höheren 1’ APGAR, eine seltenere Anwendung von NO und ein selteneres Vorkommen von assoziierten Anomalien bei den überlebenden verglichen mit den verstorbenen Patienten. Die Überlebenden hatten niedrigere Beatmungsfrequenzen, inspiratorische Spitzendrücke, Sauerstoffkonzentration sowie Mitteldrücke bei Beatmung und höhere arterieller Mitteldrücke. Als negativ für das Outcome erwiesen sich ein Polyhydramnion, eine Leberherniation oder die Notwendigkeit einer HFOV. Im zeitlichen Verlauf zeigten sich ein höherer 5’ APGAR, eine zeitigere Diagnosestellung in der Schwangerschaft, eine spätere Durchführung der Operationen und seltenere Rezidive. Die Kinder wurden mit niedrigeren Beatmungsdrücken und niedrigerem Sauerstoffgehalt beatmet, ohne dass sich das Outcome verschlechterte. Bezüglich der späteren Entwicklung gab es orthopädische und neurologische Folgen. Die Kinder hatten nur wenige Einschränkungen im Alltag. Dennoch zeigte sich das potentielle Auftreten einer Minderung der kognitiven Fähigkeiten.

In Western countries the incidence of amyotrophic lateral sclerosis (ALS) is 1.89 per 100,000 per year and the prevalence is 5.2 per 100,000. The incidence of ALS is lower among African, Asian, and Hispanic ethnicities when compared to Caucasians. The mean age of onset for sporadic ALS is about 60 years and there is a slight male predominance (male to female ratio of 1.5 to 1). Approximately two thirds of patients with ALS have the spinal form of the disease with symptoms presenting in the extremities. Patients typically have evidence of both lower motor neuron degeneration (atrophy, weakness, and fasciculations) and upper motor neuron degeneration (spasticity, weakness, and hyperreflexia). Patients with limb onset ALS typically complain of focal muscle weakness and wasting. The symptoms may start either distally or proximally in the upper and/or lower limbs. Gradually spasticity develops in the weakened atrophic limbs, affecting manual dexterity and gait. Patients with bulbar onset ALS typically present with dysarthria and dysphagia for solid or liquids. Limb symptoms can develop simultaneously with bulbar onset. In the vast majority of patients, limb weakness will occur within 1-2 years of bulbar onset ALS symptoms. A case of bulbar and sporadic limb ALS in a 70-year-old veteran, presenting with right diaphragmatic paralysis and respiratory failure, is presented.

The purpose of this study was to evaluate the effects of a computer program on the training and maintenance of diaphragmatic breathing. The biofeedback portion was visual computer training and the results were displayed concurrently with participants' breathing responses to monitor display. The verbal feedback portion was praise that was given and recorded when participants responded with predominantly diaphragmatic breathing at the scheduled moment and response instruction that was given when participants responded with predominantly thoracic breathing. The results of this study indicate the computer program's effectiveness needs to be increased by supplementation with verbal feedback.

Pulmonary vascular disease (PVD) and lung hypoplasia (LH) are the two main causes of mortality and morbidity in patients with congenital diaphragmatic hernia (CDH). Previous studies have shown that remodeling of the extracellular matrix (ECM) by elastase and matrix metalloproteinase (MMP) enzymes, concomitant with smooth muscle cell (SMC) proliferation and deposition of ECM proteins and growth factors, leads to primary pulmonary hypertension (PH) and that blockade of this pathway results in disease reversal. The aim of our study is to determine whether a similar pathway is induced in the PVD associated with CDH and to verify whether its inhibition will lead to reversal of PVD. Firstly, we confirmed various aspects of PVD in the nitrofen induced CDH rat model. These included: left lung hypoplasia, right ventricular hypertrophy, and increased arterial smooth muscle wall thickness alongside decreases in arterial lumen area and total number of distal pulmonary vessels. We also showed increases in elastase and matrix metalloproteinase (MMP) enzyme activities within distal pulmonary arteries (PAs), which, we were able to inhibit using serine elastase (sivelestat, elafin, and serpina1) and MMP (GM6001) inhibitors. Furthermore, we confirmed increased SMC proliferation and deposition of osteopontin (OPN) and epidermal growth factor (EGF) within the diseased vasculatures. We are now working on using sivelestat and GM6001 pharmaceuticals as well as endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs) modified to express elafin and serpina1 to determine their abilities to reverse the PVD associated with CDH. This project is part of our translational research program with the ultimate goal of developing a novel strategy of targeting PVD in infants with CDH to improve patient survival and long-term outcome.

No description available.

Persistent pain conditions are a major health problem throughout the world and are one of the primary reasons that people seek medical treatment (Gureje, Von Korff, Simon, & Gater, 1998; Verhaak, Kerssens, Dekker, Sorbi, & Bensing, 1998). These conditions are characterized by complex interactions between cognitive, emotional, and physiological disturbances and are often associated with comorbid psychological disorders (Gatchel, 2004). Though previous studies have examined the effect of interventions targeting persistent pain, such as physical self-regulation interventions, few studies have examined the complex interaction between such interventions and other variables such as psychological and physiological functioning and presence of social support. The current study was designed to evaluate the effect of a physical self-regulation intervention (i.e. diaphragmatic breathing entrainment) on response to a brief physical stressor (i.e., mild thermal stimulation) as well as to evaluate whether presence or absence of a supportive partner influenced this relationship. Participant response was measured via self-report of pain intensity and unpleasantness and via physiological measures of respiration rate, blood pressure, heart rate, and heart rate variability. The study consisted of 154 female participants who participated in pairs (i.e., 77 pairs). Each participant was randomly assigned to training in diaphragmatic breathing or a control condition as well as being randomly assigned to complete the study with or without their supportive partner present. Analyses revealed that breathing entrainment resulted in significantly slower breathing rate during the thermal stressor task (p < .01). Presence of a supportive partner interacted with breathing entrainment to influence heart rate during the thermal stressor task (p < .05) such that participants who completed the study with a support person present had a lower heart rate when trained in diaphragmatic breathing than when trained in a control protocol and participants who did not have a support person present showed the opposite effect. Presence of a supportive partner also interacted with breathing entrainment to influence ratings of task unpleasantness (p < .05) such that participants who were trained in diaphragmatic breathing rated the task similarly regardless of presence or absence of a supportive partner, whereas participants who were trained in a control protocol rated the task as more unpleasant when accompanied by a supportive partner. In conclusion, the present study demonstrates the impact of training in diaphragmatic breathing and presence of social support on response to thermal stimuli as measured by both self-report (i.e., ratings of task unpleasantness) and physiological (i.e., respiration rate and heart rate) measures. This study highlights the usefulness of implementing a self-regulatory training strategy for treatment of pain and in considering the efficacy of incorporating a supportive partner into such training.

A hérnia diafragmática congênita (CDH) tem incidência de aproximadamente 1:2500 nascidos vivos e mortalidade de aproximadamente 70%. A hipertensão arteiral pulmonar é umas das principais complicações neonatais e pode levar à sobrecarga cardíaca. A principal estratégia de tratamento para os casos de grave hipoplasia pulmonar no período pré-natal é a traqueo-oclusão fetal (TO), no entanto, as consequências geradas ao tecido cardíaco são incertas, tanto na CDH quanto no tratamento com TO. Troponininas (cTnI e cTnT) são proteínas intracelulares miocárdicas utilizadas como indicativo de lesão cardiomiocítica. Portanto, nosso objetivo foi avaliar as alterações anatômicas, funcionais e bioquímicas dos ventrículos esquerdo (VE) e direito (VD) na CDH e CDHTO por meio das análises de ecocardiografia (ECO), histologia e bioquímica no modelo experimental de CDH. Para isso, foram utilizados neonatos de coelhos (n=10) divididos em três grupos: controle (C), hérnia diafragmática congênita (CDH), e hérnia diafragmática congênita + traqueo-oclusão (CDHTO). A cirurgia de CDH foi realizada no dia 25 da gestação (DG) da coelha (termo = 31 dias), e a TO no 27DG. A coleta foi realizada em 30DG, a ECO neonatal foi realizada imediatamente após retirada do útero e após o sacrifício os pulmões e coração foram coletados. A mortalidade da CDH fi de 20% e de CDHTO de 30%. Os resultados da ECO e da histologia mostraram hipoplasia de VE nos grupos CDH e CDHTO (*p<0,05), sendo que no VD, o grupo CDH apresentou dilatação e o grupo CDHTO apresentou hipoplasia. Na imunofluorescência (IF), western blotting (WB) e RT-qPCR houve aumento de cTnI no VD dos grupos CDH e CDHTO em relação à C (*p<0,05), sem alteração de expressão de cTnI no VE (NS); cTnT não apresentou alteração em ambos ventrículos (NS). Concluímos que as alterações cardíacas em CDH e CDHTO podem ser verificadas logo após o nascimento e há associação das alterações ecocardiográficas, histométricas e bioquímicas, como a hipoplasia de VE e dilatação de VD associada ao aumento tecidual de cTnI no VD no grupo CDH, indicando sofrimento cardíaco ainda no período fetal. Além disso, a realização do tratamento fetal pela TO no grupo CDH (CDHTO) não apresentou melhora das alterações do comprometimento do miocárdio. / Congenital diaphragmatic hernia (CDH) has an incidence of approximately 1: 2500 live births and a mortality rate of approximately 70%. Pulmonary hypertension is one of the major neonatal complications and can lead to cardiac overload. The main treatment strategy for cases of severe prenatal pulmonary hypoplasia is fetal tracheal occlusion (TO), however, the consequences in the cardiac tissue are uncertain, in both the CDH and the TO treatment. cTnI and cTnT are myocardial intracellular proteins used as an indicative of cardiomyocyte injury that could be measured in neonates with CDH. Therefore, our aim was to evaluate the anatomical, functional and biochemical alterations in the left ventricle (LV) and in the right ventricle (RV) of neonates with CDH and CDHTO through echocardiography (ECO), histology and biochemistry analysis in the experimental rabbit CDH model. Neonates of rabbits (n = 10) were divided into three groups: C (control), CDH (congenital diaphragmatic hernia) and CDHTO (congenital diaphragmatic hernia + tracheal occlusion). CDH surgery was performed on day 25 of gestation (GD) of the rabbit (term = 31 days), and TO treatment on 27GD. The harvest was performed in 30GD, followed by neonatal ECO immediately after birth, then after sacrifice the lungs and heart were harvested. The mortality in the surgical groups was 20% CDH and 30% CDHTO. The ECO and histology results showed LV hypoplasia in the CDH and CDHTO (* p <0.05) groups. In the RV, the CDH group presented dilation and the CDHTO group presented hypoplasia. In the immunofluorescence (IF), western blotting (WB) and RTqPCR analysis there was an increase of cTnI in the RV of CDH and CDHTO groups in comparison with C group (* p<0.05), with no alteration of cTnI expression in the LV (NS). There was no difference of cTnT expression in both ventricles (NS). We conclude that cardiac alterations in CDH and CDHTO can be verified soon after birth, also there is an association of echocardiographic, histometric and biochemical alterations, such as LV hypoplasia and RV dilation with increased cTnI tissue expression in the RV of CDH group, indicating cardiac distress still in the fetal period. In addition, the performance of CDH fetal treatment by TO, (CDHTO) group, did not improve the myocardial detriment.