The diagnosis of primary pulmonary hypertension (PPH) and prediction of its course, whether treated or untreated, presents several problems. These are of particular relevance when selection of patients for, and timing of heart-lung transplantation is being considered. I performed a retrospective study on patients with PPH and chronic large vessel thromboembolic pulmonary hypertension (TPH) seen at Groote Schuur Hospital between 1957 and 1985 in an attempt to: 1. Establish the diagnostic and prognostic value of clinical features, lung function tests, cardiac catheterisation, isotope lung scans and, in the PPH group, response to therapy; 2. Review our experience of the effects of treatment with vasodilators and oral anticoagulants, and the results of heart and lung transplantation in the PPH group; 3. Attempt to identify features which could be used to predict prognosis in PPH; and thereby 4. Define criteria for selecting PPH patients whose prognosis could be improved by heart-lung transplantation.

acase@tulane.edu / Influenza is a highly contagious viral respiratory infection that occurs in annual outbreaks. Activity levels for the 2017-2018 influenza season reached heights not seen since the 2009 pandemic. This was partly due to the inefficiency of the vaccine (25% effective) against the predominant circulating strain, H3N2. To make matters worse, current antiviral therapies must be given within 48 hours of the onset of symptoms. This is often well outside the window of opportunity for hospitalized patients. Developing a therapy that promotes repair of the extensive damage that occurs in severely infected patients is vital for their recovery. Our lab focuses on the innate immune response, more specifically the IL-22 pathway, and the mechanisms involved in repair following pulmonary injury and infection. IL-22 is important in cell proliferation, wound healing, maintaining epithelial barriers and innate pathogen defense. In the lung, its receptor, IL-22Ra1, is only found on epithelial cells and is rapidly induced in response to damage of the lung epithelium. The central hypothesis of this dissertation is that IL-22Ra1 is induced during influenza infection on pulmonary epithelial and progenitor cells, allowing for enhanced sensitivity to IL-22. We have found this induction to be TLR3 and STAT1 dependent. In vivo, bronchial brushings from H1N1 infected mice (PR/8/34) mice demonstrate that Il-22ra1 is rapidly induced in the airways following infection. This occurs in a STAT1 dependent manner as upregulation does not occur in STAT1-/- mice in vivo or following STAT1 inhibition in vitro. This pathway is important as IL-22 treatment induces expression of tight junction transcripts both in vitro and in vivo. Moreover, we believe this induction of IL-22Ra1 is critical for the survival of lung progenitor cells as we have data showing that over 80% of basal cells express Il-22ra1 in the naïve lung. Furthermore, we have developed a lung organoid model and upon treatment with IL-22, organoid size was significantly increased after seven days as evidenced by measurement and BrdU incorporation. Overall, our data shows that IL-22Ra1 is highly induced after injury and subsequent treatment with IL-22 is essential for altering tight junctions and promoting lung repair. / 1 / Kelly Douglas Hebert II

Angioimmunoblastic T-cell lymphoma (AITL) is a rare type of lymphoid malignancy with most affected patients presenting in their late 60’s with nonspecific symptoms, laboratory signs and advanced stage disease. 78 year old female with history of hypertension presented to the hospital with complaints of dyspnea, dry cough and fatigue of one week duration. She denied having fever, chills, night sweats or recent weight loss. Labs on admission were significant for leukopenia with lymphocytopenia, thrombocytopenia, hyponatremia and hyperglobulinemia. Computer tomography chest and abdomen showed bilateral multifocal lung infiltrates, large left side pleural effusion, diffuse lymphadenopathy and splenomegaly. She was started on empiric antibiotics for community acquired pneumonia. Sputum culture did not identify any offending organism and although thoracentesis was consistent with exudative fluid, microbiology and pathologic studies also did not offer a diagnosis. Fine needle aspiration of a suspicious lymph node was also negative. She was discharged home to complete treatment for pneumonia but over the next two months, she presented on three different occasions with the same respiratory symptoms. Serial thoracentesis thereafter showed chylous fluid that was fast re-accumulating. A repeat flow cytometry of the pleural fluid was concerning for a lymphoproliferative process and subsequent excisional biopsy with molecular studies performed on rearrangement of T-cell receptors resulted in eventual diagnosis of Angioimmunoblastic T-cell lymphoma stage IV due to associated lung involvement. She declined aggressive management and opted for palliative care. Lymphoma presenting with chylothorax is not common due to early diagnosis of most lymphoma but it can be the initial presentation of AITL because most patients present with nonspecific symptoms and lab findings that make diagnosis difficult and delayed. In our patient, eventual diagnosis was three months from initial presentation. This is not ideal because most patients who succumb to the disease tend to do so from progressive worsening nutritional status and immunosuppression that ensues as the disease advances. The recurrent chylothorax seen in our patient is likely a result of tumor burden that obstructed chyle drainage through the thoracic duct and may have resolved with adequate treatment of the disease. Multiple laboratory abnormalities and B-type symptoms in a patient with unclear primary process should prompt workup for a possible neoplastic disease, particularly lymphoma. Clinicians who suspect a lymphoproliferative process in patients with diffuse lymphadenopathy and pulmonary symptoms of unclear etiology should consider getting an excisional tissue biopsy for further diagnostic studies. PCR based studies that assess for cell locality is also helpful in particularly difficult cases.

No description available.

Rationale: Tissue Factor (TF) is a transmembrane glycoprotein that canonically functions as the initiator of the coagulation cascade. Increased levels of TF have been associated with inflammatory airway diseases. Since lipopolysaccharide (LPS) is known to elicit and inflammatory response in airway epithelium, we hypothesized that airway epithelial cells release TF when exposed to LPS. Since TF aids in local wound healing, we also hypothesized that inhibition of TF would decrease NHBE growth. The specific aim of this work was to evaluate the effects of LPS exposure on TF production and release from airway epithelia and determine the signaling pathways involved. A secondary aim was to evaluate the effects of TF inhibition on NHBE growth. Methods: Normal human bronchial epithelial cells were grown in submerged cell culture and exposed to LPS as well as several intracellular signaling pathway agonist and inhibitors. Measurements: Tissue Factor mRNA and protein were measured in culture media and cell lysate by reverse-transcriptase polymerize chain reaction and enzyme-linked immunosorbent assay, respectively. Signaling pathways were evaluated using selective agonists and inhibitors. Main results: TF protein levels increased nearly two-fold in cell media after exposure to LPS (p < 0.01). This did not occur in the presence of an MEK/ERK inhibitor (PD98059) or a SMAD inhibitor (SB431542). TF protein levels also increased nearly ten-fold in the presence of TGF-beta (p < 0.05). mRNA of TF and TGF-beta was not altered by LPS or TGF-beta exposure. NHBE grown in the presence of Tissue Factor Pathway Inhibitor grew significantly slower than those grown in standard media (P < 0.05). Conclusions: NHBE release TF when exposed to LPS. This phenomenon is post-translational and may be mediated by an autocrine mechanism involving MEK/ERK signaling that increases TGF-beta which then leads to the release of TF. Our data suggest that this airway epithelium release of TF serves as a local repair function.

A cross-sectional epidemiologic survey of the respiratory health status was conducted in the adult (15 years and older) Indian South African population resident in Lenasia, Johannesburg to study the distribution and determinants of respiratory symptoms, disease and lung function level. A slightly modified self-administered version of a standardised respiratory health questionnaire and a wedge spirometer was used. There were a high proportion of current smokers among men. Although women smoked less than men in other communities they nevertheless smoked on average more heavily than other Indian South African women. Indian men and women who smoked had a high prevalence of respiratory symptoms. The women also demonstrated an increased susceptibility to the effects of cigarette smoking when compared with women in other communities. Indians in this study had spirometric lung function levels that were lower than that recorded in recent studies in Blacks and Whites in South Africa. Respiratory symptoms, disease and lung function level were examined in a multiple logistic regression model which contained all the potential determinants recorded in the present study. Voluntary tobacco smoking, recent chest illnesses and any kind of heart trouble was associated with a significant risk for having most of the respiratory symptoms and diseases in men and women. In addition exposure to dust in the work environment, little or no exercise,>Std. 8 education a history of any kind of chest trouble and respiratory trouble before the age of 16 years was associated with an increased risk for having respiratory symptoms in men in this model. An increased risk for respiratory symptoms was demonstrated in women only with age. Age and standing height were the most important determinants of lung function level in men and women in the regression model. Dust exposure in the work environment was associated with a significantly lower lung function level in men. Alcohol consumption and a history of whooping cough was also independently associated with a lower lung function level in men but were of borderline significance. In women involuntary /passive tobacco smoke exposure and respiratory trouble before the age of 16 years were associated with a lower lung function level. Women who spent most of their lives in a rural area and those who had a university education had a higher lung function level. The deleterious effects of smoking on lung function were minimal in this study possibly because lung function was performed only in subjects in the 18-45 year age category. A "healthy smoker" effect was demonstrated in men. Men who ever smoked and were without cardiorespiratory symptoms had significantly higher lung function levels compared to men who never smoked and were without symptoms. / Thesis (M.D.)-University of Natal, Durban, 1992.

Background: Although glucocorticoids are the most effective treatment for asthma, some patients show a poor response. In such patients with steroid resistant asthma, this has been ascribed to altered glucocorticoid receptor (GR) ligand-binding affinity induced by IL-2 combined with IL-4 or IL-13 alone- all of which can also modulate glucocorticoid function in vitro. Objective: We sought to assess the ligand-binding affinity in a distinct group of oral steroid-dependent asthmatic subjects and examine the mechanisms by which IL-2 and IL-4 (or IL-13) modify the ligand-binding affinity of the GR. Methods: Using dexamethasone-binding assays, we examined PBMCs ex vivo from healthy subjects, subjects with controlled asthma, and oral steroiddependent subjects with severe asthma. In addition, IL-2 and IL-4 were used to alter GR affinity in vitro. We used mediators or inhibitors of signal transduction to investigate the mechanisms of resistance. We also determined cytokine production of PBMC's by means of ELISA. Results: GR ligand-binding affinity was significantly reduced in the nucleus but not in the cytoplasm of oral steroid-dependent asthmatic subjects compared with that seen in steroid-sensitive and healthy subjects (dissociation constant, 41.37 ± 17.83 vs. 25.36 ± 2.63 nmol/L vs. 9.40 ± 4.01 nmol/L, respectively [p<.05 for both in comparison to normals] ). This difference in ligand-binding affinity could be mimicked by IL-2 and IL-4 co-treatment and was blocked by the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580. PBMC's rendered resistant in vitro demonstrated lower IL-10 and increased GM-CSF production following LPS or PMA & PHA stimulation compared to cells with normal GR affinity. Resistant cells also showed reduced dexamethasone repression of LPSstimulated IL-10 release. These effects were also reversed by SB203580. Inhibition of the ERK MAPK pathway by PD098059 (10 mol/L), phosphoinositol 3 kinase by wortmannin (5 nmol/L) or treatment with IL-10 (10 ng/mL) failed to modulate the effect of IL-2 and IL-4 on receptor affinity. Ro318220 (10 nmol/L), a specific protein kinase C inhibitor and theophylline, similarly, had no effect on affinity. Conclusion: GR ligand binding affinity is tiered; compared to normal subjects; steroid responsive asthmatics have a mild reduction in ligand binding whereas oral steroid dependent asthmatics have greater reductions. When mononuclear cells are rendered resistant in vitro, cytokine production (low IL-10 and high GM-CSF) favours a pro-inflammatory state. Our data do not support the ERK MAPK, phosphoinositol 3 kinase, protein kinase C pathways in steroid resistance. Treatment with IL-10 and theophylline also failed to modulate the effect of IL-2 and IL-4 on receptor affinity. However, P38 MAPK inhibitors may have potential in reversing glucocorticoid insensitivity and re-establishing the beneficial effects of glucocorticoids in patients with severe asthma. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2007.

Tuberculosis (TB) is primarily a pulmonary disease caused by Mycobacterium tuberculosis (Mtb). Mtb is highly infectious, but studies have shown that only 5–15% of Mtb-infected individuals develop TB disease. The Bacille Calmette-Gu.rin (BCG) vaccine is the only commercially available Mtb vaccine, but its efficacy varies based on the strain used. The Mtb PhoPR-mutant variant, MTBVAC, has been tested as a possible attenuated live vaccine against Mtb. Although it has successfully conferred durable CD4+ T-cell responses in infants, it has also resulted in adverse effects. Our goal is to identify PhoPR-regulated gene(s) that mediate Mtb-induced burst size necrosis in infected cells. PhoPR is a two-component system in mycobacteria. PhoR responds to environmental cues, such as changes in pH, and phosphorylates the PhoP transcription factor, which then activates or suppresses the expression of approximately 40 Mtb genes. The Mtb PhoPR-mutant strain is able to replicate in infected macrophages, but it does not induce the horizontal spread of Mtb to other immune cells. Our lab has previously shown that virulent, cytopathic strains of Mtb, such as H37Rv, suppress early apoptosis, have faster replication rates in macrophages, and trigger cell death at a lethal load threshold of approximately 25 bacteria. Cell death of infected macrophages primarily occurs via necrosis, which involves nuclear pyknosis without DNA fragmentation and general disruption of lipid bilayer membranes. Viable bacilli are released to infect other macrophages and neutrophils recruited to the developing TB lesion. Here, we show that PhoP contributes to burst size necrosis in macrophages and that the PhoP-regulated genes, fadD21 and pks3, are potential drivers of this necrosis. FadD21 and pks3 are involved in the generation of diacyl trehalose/penta-acyl trehalose (DAT/PAT) for cell wall synthesis, suggesting that Mtb cell wall composition may determine virulence. Therefore, we have uncovered potential targets for early intervention or vaccinations to avoid granuloma formation or tissue damage in response to Mtb-induced macrophage necrosis.

Background. Premature infants are at risk for many complications. Among these, growth failure and intermittent hypoxia (IH) can independently impact the outcomes of other comorbidities. Recent data suggest that IH may directly affect postnatal growth. Our study aims to evaluate the impact of IH on growth velocity in preterm infants. Methods. This prospective cohort study utilized inpatient oximetry, nutrition, and growth data to evaluate the relationship between IH and growth velocity. Enrolled infants were dichotomized by high- versus low-exposure to IH. This relationship was explored in both unadjusted analyses and generalized linear models with repeated measures. Results. The study population included 19 preterm infants, with average birth gestational age of 29 weeks, each contributing one or more measures of weekly data. Infants in the high-exposure cohort had lower birth weight, higher rates of bronchopulmonary dysplasia, and longer duration of respiratory support and caffeine treatment. The unadjusted analysis revealed a marginally significant trend towards higher IH rates during weeks of slower growth. The logistic regression with repeated measures analysis also supported increased odds of slower growth associated with higher IH rates, but this relationship was also only marginally significant. Conclusion. Our study suggests a relationship between exposure to IH and slower growth velocity in preterm infants. The prospectively collected data allowed for accurate measures of IH, growth, and nutrition, but the small sample size likely contributed to the lack of significance of our results.

L’essor de la statistique en médecine est l’ultime étape de la quête d’une médecine scientifique poursuivie tout au long de l’histoire de la discipline. Cette méthodologie de production des preuves médicales est reconnue par tous comme un gage de qualité justifiant les prises de décisions médicales au niveau individuel et collectif.Initialement, le concept est une démarche pédagogique prônant l’autonomie de chaque praticien dans la recherche, l’analyse critique et l’application personnalisée des preuves disponibles. La démarche rejette le dogmatisme médical. Ce concept a été et demeure largement controversé. Pour autant, il a rapidement traversé les frontières pour devenir une exigence déontologique et juridique au risque d’une dérive normative.La priorité laissée à la qualité méthodologique des preuves médicales au détriment de leur applicabilité en vraie-vie pose question.L’hypothèse de ce travail est qu’il existe, aux différentes étapes du circuit de la preuve médicale, des biais cognitifs et/ou méthodologiques qui peuvent impacter l’exercice pertinent de la médecine malgré son alibi scientifique.Au travers de l’exemple des maladies respiratoires chroniques, ce travail épistémologique se propose de caractériser la preuve médicale. Il décompose le circuit de la preuve médicale pour analyser sa méthodologie de production, ses sources, vecteurs et cibles de diffusion, les conséquences de l’implication des agences réglementaires et de l’Etat dans son applicabilité mais aussi les biais cognitifs auxquels sont soumis médecins et patients. Il vise à déterminer avec transparence sur quelles preuves la médecine se fonde pour en permettre une utilisation pertinente. / The use of statistics in medicine is the final step for the development of scientific medicine pursued throughout the history of the discipline. This method of production of medical evidence is recognized by healthcare professionals, drug manufacturers and political institutions as a pledge of quality that justifies medical decision-making at the individual and collective levels. Initially, the concept is an educational approach advocating the autonomy of each practitioner in bibliographic research and critical appraisal of available evidence for their use in the context of personalized medicine. The approach rejects medical dogmatism. This concept has been and remains largely controversial. However, it has quickly become a deontological and legal requirement that could drift back to dogmatism. The priority given to the methodological quality of medical evidence while poor attention is paid to its real-life applicability raises concerns. In this work we hypothesize that, from the production to the use of medical evidence there are cognitive and/or methodological biases that may alter the relevance of medicine practice despite its scientific alibi. Through the example of chronic respiratory diseases, this epistemological work aims at characterizing the medical evidence. To do so, we analyzed its production methodology, the sources, vectors and targets for dissemination, the consequences of the involvement of regulatory agencies and governments in its applicability and the cognitive biases that may apply to physicians and patients. It aims at determining transparently on what type of evidence medicine is based to enable its relevant practice.