Heat shock proteins (HSP) for immunotherapy of rheumatoid arthritis (RA).

Rheumatoid arthritis (RA) is an inflammatory disease that primarily involves the joints and has a worldwide prevalence of about one percent, with a female to male ratio of 3:1. This chapter summarizes some of the recent progress in molecular immunology, and discusses the application of this new knowledge for therapeutic purposes. We focus on our recent experiences and that of others in modulation of antigen specific responses as a tool for manipulating autoimmune inflammation. Particular emphasis is given to the concept of exploiting for therapeutic purposes a natural mechanism of immune regulation. This mechanism is based on sequential cross recognition of bacterial and human derived heat shock protein peptides.

Predicting survival of lung transplantation candidates with idiopathic interstitial pneumonia: does PaO(2) predict survival?

OBJECTIVE: To find a parameter that would discriminate between the patients with idiopathic interstitial pneumonia who survived to undergo transplantation and those who died while waiting to undergo transplantation. METHODS: A retrospective review was performed of all lung transplant referrals for idiopathic interstitial pneumonia that were listed with United Network for Organ Sharing at the University of California San Diego from January 1990 to February 1999. Of the 331 patients who were listed, 48 met the eligibility criteria. Patient demographics, radiographic studies, pathology reports, and the results of resting and exercise cardiopulmonary function tests were recorded from each patient's chart. Patients were divided into the following two groups: those patients who survived until transplantation and those still waiting were classified as "alive"; and those patients who died before undergoing transplantation were classified as "deceased." RESULTS: Forty-three of 48 patients had a pathologic diagnosis. The cohort included 25 patients with usual interstitial pneumonitis, 3 patients with nonspecific interstitial pneumonitis, 1 patient with desquamative interstitial pneumonitis, and 14 patients with interstitial lung disease of unknown etiology. The only significant difference between the two groups was resting PaO(2) (p = 0.035). A stepwise multivariate analysis demonstrated that PaO(2) and FEV(1)/FVC ratio were significantly associated with survival (hazards ratio, 1.06; confidence interval, 0.99 to 1.13; p = 0.019). CONCLUSIONS: A survival analysis using PaO(2) and FEV(1)/FVC ratio values proved to be statistically significant, but a prospective trial is needed to determine the clinical relevance of these parameters for predicting survival in patients with idiopathic interstitial pneumonia.

Outpatient inhaled nitric oxide in a patient with idiopathic pulmonary fibrosis: a bridge to lung transplantation.

Inhaled nitric oxide (INO) has been shown to improve oxygenation and decrease intrapulmonary shunt and pulmonary hypertension in various lung diseases. In this study we report a patient with end-stage idiopathic pulmonary fibrosis and pulmonary hypertension who received INO after coronary artery bypass surgery, with significant improvement in arterial oxygenation and pulmonary arterial pressure. Using a pulsing delivery system, the patient continued to receive outpatient INO for 30 months while waiting for lung transplantation. Exercise study and two-dimensional echocardiogram, after 3 months of inhaled NO, demonstrated continued benefits of INO for improvement of arterial oxygenation, pulmonary arterial pressure and exercise tolerance.

Severe alveolar proteinosis following chemotherapy for acute myeloid leukemia in a lung allograft recipient.

A 64-year-old man was diagnosed with acute myeloid leukemia (AML) 5 years following single lung transplantation performed for severe pulmonary hypertension from scleroderma. Chemotherapy for treatment of AML with fludarabine, cytosine arabinoside, G-CSF (FLAG) regimen was initiated. Despite intensive antibiotic treatment for a presumptive diagnosis of bacterial pneumonia, the patient developed acute respiratory failure and died before a complete cycle of chemotherapy could be administered. At autopsy, both native and allograft lungs showed widespread alveolar proteinosis that was determined as the main cause of acute respiratory failure. Alveolar proteinosis, a potentially treatable disease, should be considered in the radiologic differential diagnosis of diffuse lung disease in this clinical setting.

Approach to pulmonary hypertension.

Until recently, many physicians considered pulmonary hypertension a rare and esoteric condition that is difficult to diagnose and nearly impossible to treat. However, pulmonary hypertension can complicate a variety of relatively common diseases and, with the development of new and effective therapies, there is a need for greater awareness of this condition. Pulmonary hypertension should be considered when patients present with unexplained shortness of breath, chest pain, or syncope. The usual delay of 1 to 2 years between onset of symptoms and diagnosis underscores the importance of considering pulmonary hypertension in the differential diagnosis of patients who present with atypical cardiorespiratory symptoms.

"High probability" perfusion lung scans in pulmonary venoocclusive disease.

"High-probability" ventilation/perfusion (V/Q) lung scans generally indicate proximal pulmonary arterial occlusion by thromboemboli or, rarely, other processes such as tumors, fibrosing mediastinitis, or vasculitis. In this report we describe three patients with high probability V/Q scans in whom pulmonary angiography failed to demonstrate arterial occlusion. All three patients were determined to have pulmonary venoocclusive disease (PVOD). In two patients, a tissue diagnosis of PVOD was made, in one case with explanted tissue taken after a successful heart-lung transplant and in the other case with tissue taken at autopsy. PVOD in the third patient was diagnosed with pulmonary venography. A potential explanation for the discrepancy between perfusion lung scan and pulmonary angiographic findings in PVOD is discussed.

Pulmonary vascular remodeling distal to pulmonary artery ligation is accompanied by upregulation of endothelin receptors and nitric oxide synthase.

There is increasing evidence that the pathogenesis and progression of many forms of pulmonary vasculopathy are related to abnormalities in endothelial mediators, including endothelin-1 (ET-1) and nitric oxide (NO). Using a rat model of chronic unilateral pulmonary artery ligation, we investigated the role of ET-1 and NO in postobstructive pulmonary vasculopathy (POPV). Eight months after a left thoracotomy with either left main pulmonary artery ligation (ligated group) or no ligation (sham group), rat lungs, including those contralateral to the ligation (hyperperfused group), were fixed and mounted for histologic sectioning. Morphometric measurements were carried out by computer-assisted image analysis and immunohistochemical staining was performed using specific antibodies against ET-1, ETA, and EBB receptors, and endothelial NO synthase (eNOS). Compared to sham lungs, the ligated lungs showed (1) an increase in muscular, adventitial, and intimal thickness of pulmonary artery; (2) increase in external diameter of the bronchial artery (39.8 +/- 2.2 microns vs. 16.8 +/- 0.9 microns in sham group; P < .005) and number of bronchial arteries per bronchiole (3.21 +/- mu 0.26 vs. 1.86 +/- mu 0.21 in sham group; P < .001); and (3) increase in the intensity of eNOS and ETA, B receptor immunoreactivity. No morphometric or immunohistochemical differences were observed between the hyperperfused and sham lungs. These findings suggest that increased synthesis of endothelial NO may serve as a compensatory mediator in ET-1-mediated vascular remodeling.

Endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

It is well known that endothelin (ET)-1 mediates vascular remodelling in various kinds of clinical and experimental pulmonary hypertension. The aim of this study was to investigate whether ET-1 is associated with the development of pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension. Pulmonary hypertension was induced in 10 mongrel dogs by repeated embolization with ceramic beads. In five of the dogs, bosentan, a nonselective ET receptor antagonist, was administered throughout the study. Haemodynamic measurements and plasma ET-1 assays were performed every 2 months. Eight months after initial embolization, computer-assisted morphometry and immunohistochemistry were performed on the lung tissue including that from three control dogs. Pulmonary arterial pressure and pulmonary vascular resistance were increased in all embolized dogs, compared to baseline. In nontreated embolized dogs, plasma ET-1 concentration and pulmonary arterial wall thickness were increased compared to control animals, and ET-1 immunoreactivity was detected in thickened pulmonary arteries. In bosentan treated dogs, pulmonary arterial walls were not significantly thickened. Pulmonary vascular remodelling, associated with elevated plasma endothelin-1 levels and positive endothelin-1 immunoreactivity in lung tissue is attenuated by the endothelin receptor antagonist, bosentan. These findings suggest that endothelin mediates pulmonary vascular remodelling in a canine model of chronic embolic pulmonary hypertension.

Successful pulmonary thromboendarterectomy in two patients with sickle cell disease.

Patients with sickle cell disease have been reported to have an increased risk of thromboembolism and pulmonary hypertension. Some of these patients may benefit from pulmonary thromboendarterectomy (PTE), a procedure that requires profound hypothermia, cardiopulmonary bypass, and periods of circulatory arrest, factors that may potentially increase the risk of sickling. Two patients with sickle cell disease (sickle-thalassemia [Hb S/beta+] and Hb SS) presented to the Pulmonary Vascular Center of UCSD Medical Center with significant shortness of breath and limitation of daily activities. Both of these patients were found to have surgically accessible chronic thromboembolic disease with pulmonary hypertension. PTE was performed in both patients using exchange transfusion, with avoidance of anemia, hypoxia, and acidosis. A successful outcome with resolution of pulmonary hypertension was achieved in both cases. To our knowledge this is the first report of patients with sickle cell disease who successfully underwent PTE for chronic thromboembolic pulmonary hypertension.

Discrepancy between laboratory determination and visual estimation of blood loss during normal delivery.

Blood loss during normal delivery was measured in 37 primiparas and 25 multiparas who had no obstetric or medical complications and who underwent normal delivery in a teaching hospital following spontaneous onset of labour at term. Measured blood loss was significantly greater than the estimated volume of blood loss. In primigravidas, the mean ( +/- SE, standard error of the mean) estimated blood loss was 260 +/- 12 ml and the mean measured blood loss was 401 +/- 29 ml. In multiparas the mean estimated blood loss was 220 +/- 10 ml and the mean measured blood loss was 319 +/- 41 ml. The mean estimated blood loss was significantly lower (P less than 0.05) than the mean measured blood loss in both groups. The size of the discrepancy between measured and estimated blood loss was proportional to the measured blood loss. These findings show that visual estimation of blood loss was grossly inaccurate.

Routine serological screening for syphilis during pregnancy--disposable anachronism or fundamental necessity?

Between 1984 and 1988 inclusive 34 patients with syphilis during pregnancy were identified in this unit by routine serological screening. There were 2 stillbirths in this group of patients giving a perinatal mortality rate of 59 per 1,000 total births. Analysis of the patients' history and physical examination findings did not reveal any predictive factors for sexually transmitted diseases in most cases. Despite the dramatic fall in the prevalence of syphilis both during pregnancy and the general population in Hong Kong, routine serological screening for syphilis during pregnancy must continue.