Giuseppe G. Pietra

Survival in Patients with Primary Pulmonary Hypertension: Results from a National Prospective Registry

OBJECTIVE To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. DESIGN Registry with prospective follow-up. SETTING Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. PATIENTS Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. MEASUREMENTS At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. MAIN RESULTS The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. CONCLUSIONS Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

Spontaneous regression of pulmonary leiomyomas during pregnancy.

Multiple pulmonary nodular densities simulating metastatic cancer were discovered in a routine chest roentgenogram of a 30‐year‐old pregnant woman. Lung biopsy revealed nodules composed of smooth muscle and collagenous tissue containing entrapped glandular elements. The lesions were initially interpreted as multiple pulmonary fibroleiomyomatous hamartomas (MPFLH). During pregnancy and the post‐partum period, the pulmonary nodules regressed spontaneously. Critical analysis of the published cases as well as our own case indicates that multiple pulmonary fibroleiomyomatous hamartomas (MPFLH) cannot be distinguished from benign metastasizing leiomyoma (BML) by either clinical, roentgenographic, or pathologic criteria and that all represent pulmonary metastases from a primary uterine neoplasm. The spontaneous regression of the pulmonary nodules in the present case as well as the increased risk for development of progressive pulmonary insufficiency in the pre‐menopausal patients indicates an apparent hormonal dependence. Total abdominal hysterectomy and bilateral salpingo‐oophorectomy appears to be the treatment of choice.

Histamine and interstitial Pulmonary Edema in the Dog

Histamine, administered to dogs by various routes, produced peribronchial interstitial edema. Using colloidal carbon as an electron-dense tracer, it was shown that bronchial venules had become leaky at the same time that the minute blood vessels of the pulmonary circulation remained unaffected by the histamine. The effect of histamine was rapid and brief in duration: wide interendothelial gaps appeared in the walls of bronchial venules through which blood and tracer escaped into the interstitium. This action of histamine seemed to be related to the presence in the bronchial venular endothelium of abundant cytoplasmic fibrils that presumably have contractile capacity. Water content of the lungs was consistent with morphologic evidence that histamine promoted the accumulation of fluid in the lungs. The same pattern of response was observed after bradykinin or compound 48/80, a mast cell degranulator. In contrast to these three agents, serotonin did not affect bronchial venular permeability to colloidal carbon. Consideration of these observations in the light of the large extent of the bronchial venular plexus, raises the possibility that the bronchial venular system may play an important reabsorptive role under normal circumstances and that it may also be involved in the genesis of certain types of interstitial pulmonary edema.

Handling of Bioactive Materials by the Lung

THE primitive lung was little more than an air sac containing minute vessels in its walls for gas exchange. It served as an accessory organ of breathing that allowed fishes seeking refuge from oxyg...

The expression of TIA-1+ cytolytic-type granules and other cytolytic lymphocyte-associated markers in CD30+ anaplastic large cell lymphomas (ALCL): correlation with morphology, immunophenotype, ultrastructure, and clinical features.

Anaplastic large cell lymphomas (ALCL) are a heterogeneous group of CD30+ large cell lymphomas; the most characteristic type have a T or null cell phenotype, often express epithelial membrane antigen (EMA) and cytolytic lymphocyte markers, and often possess a nonrandom t(2;5)(p23;q35) chromosomal translocation. We studied 22 (19 T, 1 null, 2 B cell) ALCL, including four primary cutaneous ALCL (PC-ALCL), for the expression of TIA-1, the cytotoxic T lymphocyte (CTL) or natural killer (NK) cell-associated antigens CD4, CD8, betaF1, TCRdelta1, CD56, and CD57, the ALCL-associated antigens p80 and EMA, and the Hodgkins disease-associated marker CD15 to better define the relationship of these markers to histological subtype, primary site, and patient clinical characteristics. TIA-1 expression was seen in 12 of 20 (60%) T or null cell ALCLs with a cytoplasmic, granular distribution. Ultrastructural studies showed cytotoxic-type granules (dense core, multivesicular, and intermediate types) with TIA-1 localized to granules on immunogold labeling. TIA-1 staining strongly correlated with young patient age (< or = 32 years, P < .05) and EMA expression (P < .05). Excluding the four PC-ALCL cases, TIA-1 staining also correlated with p80 expression (P < .05) in all of the T cell cases. Three CD15+ cases were TIA-1-. TIA-1 expression in T or null cell ALCL was seen in all morphological subtypes (2 of 2 small cell variant, 3 of 4 monomorphic variant, and 7 of 14 pleomorphic variant) and primary tumor sites (6 of 14 nodal, 2 of 4 primary cutaneous, 2 of 2 bone, and 2 of 2 soft tissue). TIA-1+ granules were seen in all subsets: 5 of 6 CD4+, 1 of 2 CD8+, 4 of 8 CD56+, and 1 of 2 CD57+ ALCL. Of note, 4 of 10 T or null cell ALCL expressed gammadelta T-cell receptors (TCR), whereas only 1 of 10 T or null cell ALCL was alphabeta TCR+; TCR were not detected in five cases. TIA-1 was expressed by 3 of 4 gammadelta TCR+ ALCL and 1 of 1 alphabeta TCR+ ALCL. These data support a cytotoxic lymphocyte phenotype in most T or null cell ALCL and suggest that some T cell ALCL are derived from cytolytic CD4+ T cells, gammadelta T cells, or NK-like (CD56+ or CD57+) T cells.

Analysis of Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after lung transplantation

BACKGROUND Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of lung transplantation. Besides immunosuppression the risk factors for PTLD development are largely unknown. METHODS The incidence of PTLD was ascertained in a lung transplant population consisting of 45 patients. Nine patients (20%) experienced PTLD. The clinical, histologic, and human leukocyte antigen (HLA) data were collected on all patients. The incidence of EBV infection in lymphoid tissue taken at the time of engraftment was studied by using EBV in situ hybridization. RESULTS All patients with PTLD had polymorphous lymphoproliferations, seven of which were polymorphous B-cell hyperplasias and two of which were polymorphous B-cell lymphomas. EBV was identified in all lesions. All patients with polymorphous B-cell hyperplasias had clinically unsuspected disease, five of which were identified at autopsy. The two polymorphous B-cell lymphoma lesions were monoclonal and regressed with immunosuppression reduction. EBV in situ hybridization on donor or recipient lymph nodes obtained at engraftment from the 45 transplant recipients showed no difference in the number of EBV positive cells in patients with and without PTLD. Cyclosporine and PTLD and azathioprine dosages and cyclosporine levels were similar between patients with and without PTLD. PTLD was seen in patients with high cumulative doses of antilymphocyte globulin. Analysis of HLA status showed a predominance of HLA A2 and DR7 in the donors of the patients with PTLD, whereas donor HLA B7 was more common in patients without PTLD> CONCLUSIONS Detailed studies are necessary to further elucidate the risk factors for PTLD development in the lung transplant population.

Glutamine enhancement of structure and function in transplanted small intestine in the rat

Total parenteral nutrition is required by all patients in need of small bowel transplantation. Untoward side effects of total parenteral nutrition include atrophy and hypofunction of the small intestine. Glutamine, the preferred fuel for the enterocyte, is presumably present in insufficient amounts in diets given to patients with intestinal dysfunction. In a rat model of total parenteral nutrition and small bowel transplantation, this study investigated the following: (1) whether glutamine improves graft structure and function, (2) the optimal route of glutamine delivery (intravenous vs direct infusion into the graft), and (3) the effect of glutamine on ultrastructure of the graft enterocyte. Lewis rats underwent small bowel transplantation as a Thiry-Vella graft and received total parenteral nutrition for 14 days while assigned to one of four infusion groups: 2% intravenous glutamine; 2% intravenous isonitrogenous mixture, nonessential amino acids (control); 2% glutamine into the graft; or 2% nonessential amino acids into the graft (control). Graft mucosal villous height, villous surface area, crypt depth, weight, protein, deoxyribonucleic acid content, glucose absorption, and enterocyte ultrastructure were then evaluated. Infusion of glutamine directly into the graft significantly increased mucosal villous height (p = .045), surface area (p = .029), and glucose absorption (p = .004) when compared with controls. Intravenous glutamine infusion significantly increased mucosal villous height (p = .002), surface area (p = .001), weight (p = .005), and glucose absorption (p = .04) when compared with controls. Most enterotrophic and functional benefits of glutamine were not significantly different between intravenous infusions and direct administration into the graft.(ABSTRACT TRUNCATED AT 250 WORDS)

Localized Leukemic Pulmonary Infiltrates: Diagnosis by Bronchoscopy and Resolution with Therapy

Although commonly found at autopsy, leukemic infiltration of the lung is rarely recognized as a cause of respiratory symptoms or roentgenographic densities. Previously reported cases of patients who had symptomatic or roentgenographic acute leukemic lung diseases invariably presented with diffuse pulmonary infiltrates. We describe three patients with leukemic involvement of the lung who presented with cough, fever, and localized roentgenographic infiltrates suggestive of bacterial pneumonia. In each case, the diagnosis was made by transbronchial biopsy specimen and confirmed by complete response to chemotherapy. In common with the other reported cases, all of our patients had peripheral blast counts above 40 percent (greater than 6,000 blasts per ml3) at the time the pulmonary diagnosis was made. Leukemic invasion of the lung should be considered in patients with acute leukemia who develop lung infiltrates--whether diffuse or focal--in association with a high peripheral blast count.

Vascular Immunotargeting of Glucose Oxidase to the Endothelial Antigens Induces Distinct Forms of Oxidant Acute Lung Injury: Targeting to Thrombomodulin, But Not to PECAM-1, Causes Pulmonary Thrombosis and Neutrophil Transmigration

Oxidative endothelial stress, leukocyte transmigration, and pulmonary thrombosis are important pathological factors in acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Vascular immunotargeting of the H(2)O(2)-generating enzyme glucose oxidase (GOX) to the pulmonary endothelium causes an acute oxidative lung injury in mice.(1) In the present study we compared the pulmonary thrombosis and leukocyte transmigration caused by GOX targeting to the endothelial antigens platelet-endothelial cell adhesion molecule (PECAM) and thrombomodulin (TM). Both anti-PECAM and anti-TM delivered similar amounts of (125)I-GOX to the lungs and caused a dose-dependent, tissue-selective lung injury manifested within 2 to 4 hours by high lethality, vascular congestion, polymorphonuclear neutrophil (PMN) sequestration in the pulmonary vasculature, severe pulmonary edema, and tissue oxidation, yet at an equal dose, anti-TM/GOX inflicted more severe lung injury than anti-PECAM/GOX. Moreover, anti-TM/GOX-induced injury was accompanied by PMN transmigration in the alveolar space, whereas anti-PECAM/GOX-induced injury was accompanied by PMN degranulation within vascular lumen without PMN transmigration, likely because of PECAM blockage. Anti-TM/GOX caused markedly more severe pulmonary thrombosis than anti-PECAM/GOX, likely because of TM inhibition. These results indicate that blocking of specific endothelial antigens by GOX immunotargeting modulates important pathological features of the lung injury initiated by local generation of H(2)O(2) and that this approach provides specific and robust models of diverse variants of human ALI/ARDS in mice. In particular, anti-TM/GOX causes lung injury combining oxidative, prothrombotic, and inflammatory components characteristic of the complex pathological picture seen in human ALI/ARDS.

Desmin myopathy involving cardiac, skeletal, and vascular smooth muscle : Report of a case with immunoelectron microscopy

Desmin myopathy is a rare idiopathic disorder characterized by abnormal aggregates of desmin-type intermediate filaments, which affects cardiac and skeletal muscle, and rarely the intestinal smooth muscle. We report a 42-year-old woman with atrial fibrillation and progressive restrictive cardiomyopathy. Left ventricular biopsy, cardiac explant, and subsequent autopsy study of skeletal muscle revealed cytoplasmic granulo-filamentous inclusions that were continuous with Z-lines and were immunoreactive for desmin filaments both at the light immunohistochemical and electron microscopic level. In addition, we report the presence of characteristic inclusions within the smooth muscle of intramural coronary blood vessels. This is the first description of desmin inclusions within vascular smooth muscle, and underscores the systemic nature of this rare myopathy.