Radiological evidence of involvement of dust exposure in pathogenesis of pulmonary alveolar proteinosis

A 52-year-old man was admitted because of increasing dyspnea on exersion and presence of pulmonary infiltrates. The patient had pulmonary tuberculosis at the age of 31, which resulted in volume loss and calcified foci in the upper lobe of his left lung. As a construction worker for more than 20 years, he had been exposed to inorganic dusts. Chest radiographs showed a symmetrical consolidation of infiltrates in both lungs with the exception of the left upper lobe, where no apparent infiltrates were shown. A computed tomographic scan of the chest revealed widely panlobular consolidation with the exception of the left upper lobe. A diagnosis of pulmonary alveolar proteinosis (PAP) was established by analysis of bronchoalveolar lavage fluid. Although the patient underwent segmental bronchoalveolar lavage four times under general anesthesia, he suffered frequent pulmonary infection and died two years after the onset his symptoms. Interestingly, the patient had a markedly narrowed orifice in the left upper lobe, as demonstrated by fiberoptic bronchoscopy. Chest radiographs of this lung field revealed no infiltrative shadows. These results suggest that some inhalative agent was involved in the pathogenesis of PAP in this case. In addition, significantly increased levels of KL-6 detected in both serum and bronchoalveolar lavage fluid were attributable to overproduction of KL-6 by Type II pneumocytes that had been stimulated or damaged by PAP.     

Epithelial and surfactant changes in influenzal pulmonary lesions

Pulmonary epithelial cell destruction in mice infected with PR8-A influenza virus has been studied with light and electron microscopy and enzyme histochemistry, and correlated with pulmonary surfactant activity. All epithelial cell types were infected by the virus, resulting in destruction, pneumonitis, and atelectasis by seven to ten days. Pulmonary surfactant activity decreased progressively following onset of infection, and was minimal by seven to ten days. Before types 1 and 2 alveolar pneumocytes regenerated, the regenerating bronchial cells grew peripherally into some of the denuded alveolar ducts and alveoli to form epithelial nodules. Eventually the types 1 and 2 pneumocytes regenerated to cover the alveolar surfaces that were not invaded by bronchial epithelium. This regeneration was associated with increased surfactant activity in the postinfluenzal lesions, suggesting that the type 2 pneumocytes are a source of surfactant.     

Translocation of Yersinia enterocolitica through an endothelial monolayer by polymorphonuclear leukocytes

An endothelial cell monolayer grown on a microporous membrane coated with basement membrane protein matrix was used to study translocation of yersinia-infected human polymorphonuclear leukocytes (PMNs). PMNs infected with one to eight bacteria were able to translocate living yersiniae from the upper chamber to the chemoattractant-containing lower chamber. This process may contribute to extravasation and dissemination of yersiniae in the infected host.     

Pneumocytes type II ultrastructural modifications after storage in preservation solutions for transplantation

Although lung transplantation represents a real therapeutic opportunity, the problem of preserving the organ for a prolonged period (> 10 h) still remains unsolved. Further studies are necessary to fully understand the behavior of different lung cell types during the ischemic period. As ultrastructural modifications of cells of lung samples stored in different means of preservation represent an index of the integrity and therefore of cellular viability, in the present work we have compared the time-related ultrastructural changes in human pneumocytes type II cells after hypothermic (10 degrees C) storage for 6 and 12 h in University of Wisconsin (UW) solution and in low potassium dextran (LPD) solution. An ultrastructural grading scale was used to quantify the damage and the results confirmed what was observed microscopically. Statistical analysis (t test) of the data showed that after 6 h in LPD solution, pneumocytes type II were less damaged than those stored in UW solution; these differences were statistically significant (p < 0.05). In our opinion, ultrastructural studies should be considered among the methods presently used to assess the effectiveness of different storage fluids.     

The modulation by neurosteroids of the scopolamine-induced learning impairment in mice involves an interaction with sigma1 (sigma1) receptors

Pulmonary tuberculosis: primary tuberculosis, usually asymptomatic, represents the first infection and is shown by a parenchymal mostly mid-pulmonary focus and satellite lymphadenopathy. Postprimary pulmonary tuberculosis, mostly located in the upper fields may be caused by endogenous reinfection for reactivation of a hematogenous focus formed during primary infection or from exogenous reinfection. Extrapulmonary tuberculosis: it includes numerous forms mostly from hematogenous spread. Miliary tuberculosis may involve a number of organs and apparatus besides the lung. Tuberculous meningitis predominantly involves the base of the skull, the fluid is clear with hypoglycorrhachia and lymphocyte pleocytosis. Lymph node tuberculosis is generally unilateral and cervical. Tuberculous pleuritis is exudative or dry. Other forms of tuberculous serositis are pericarditis and peritonitis. Renal tuberculosis involves the medullaris and intestinal tuberculosis the ileocecum; tuberculous spondilitis (Pott's disease) involves the last dorsal vertebrae. Other forms are osteoarthritis, genital tract tuberculosis, pancreatitis, laryngitis, otitis.     

Disposition characteristics of glycosylated poly(amino acids) as liver cell-specific drug carrier

Alveolar type II pneumocytes (PII) were studied in 12 human donor lungs perfused with modified Euro-Collins solution during single-lung transplantation (SLTx). While one lung was transplanted, the contralateral donor lung (cDL) was fixed at the time of SLTx for examination by electron microscopy, stereology, and microanalysis. Three groups were then formed: group A (n = 7), cDL without contusions, uneventful early postoperative course; group B (n = 3), cDL with conclusions, uneventful early postoperative course; group C (n = 2), cDL without contusions, early postoperative respiratory dysfunction. The major findings were that the presence of contusions had no effect on PII ultrastructure and that intracellular surfactant-storing lamellar bodies of cDL in group C were characterized by a higher volume-to-surface ratio (VsR) and larger area per cell profile than group A. Correlation analysis based on pooled data (groups A and C) showed that ischaemic time had little effect on PII ultrastructure and bore no relationship to postoperative clinical variables. The duration of preoperative donor intubation had a pronounced influence on ultrastructure and postoperative clinical variables. The stereologically estimated amount of intracellular surfactant and mitochondrial VsR were the only ultrastructural parameters that were significantly associated with early postoperative oxygenation. Lamellar bodies were the only ultrastructural components found to have a significant relationship to postoperative intubation time. The ultrastructural integrity of type II pneumocytes of human donor lungs is an important determinant of early respiratory function following clinical lung transplantation.     

Smoke extract stimulates lung epithelial cells to release neutrophil and monocyte chemotactic activity

Inflammatory cells accumulate within the lungs of cigarette smokers. Current concepts suggest that these cells can induce protease-antiprotease and/or oxidant-antioxidant imbalance(s), which may damage the normal lung alveolar and interstitial structures. Because type II pneumocytes line the alveolar space, and because the inflammatory cells migrate and reside at the alveolus, we postulated that the type II pneumocytes might release chemotactic activity for neutrophils and monocytes in response to smoke extract. To test this hypothesis, A549 cells were cultured and the supernatant fluids were evaluated for the neutrophil and monocyte chemotactic activity (NCA and MCA) by a blind-well chamber technique. A549 cells released NCA and MCA in response to smoke extract in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis showed that the activity was chemotactic. Partial characterization of NCA and MCA revealed that the activity was partly heat labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of NCA and MCA. Molecular sieve column chromatography showed multiple peaks for both NCA and MCA. NCA was inhibited by anti-human-interleukin (IL)-8 antibody, granulocyte colony-stimulating factor (G-CSF) antibody, or leukotriene (LT)B4 receptor antagonist. Monocyte chemoattractant protein (MCP)-1 antibody or LTB4 receptor antagonist inhibited MCA. Immunoreactive IL-8, G-CSF, MCP-1, and LTB4 significantly increased in the supernatant fluids in response to smoke extract. These data suggest that the type II pneumocytes may release NCA and MCA and modulate the inflammatory cell recruitment into the lung.     

Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management

Tuberculosis is a serious opportunistic infection in transplant recipients. On the basis of the compilation of published reports in the literature, the incidence of Mycobacterium tuberculosis infection in organ transplant recipients worldwide ranged from 0.35% to 15%. Nonrenal transplantation (P = .004), rejection within 6 months before the onset of tuberculosis (P = .02) and type of primary immunosuppressive regimen (P = .007) were predictors of M. tuberculosis infection occurring within 12 months after transplantation. Thirty-three percent (155) of 476 transplant patients with tuberculosis had disseminated infection; receipt of OKT3 or anti-T cell antibodies (P = .005) was a significant predictor of disseminated tuberculosis. Overall, the mortality rate among 499 patients was 29%; disseminated infection (P = .0003), prior rejection (P = .006), and receipt of OKT3 or anti-T cell antibodies (P = .0013) were significant predictors of mortality in patients with tuberculosis. Clinically significant hepatotoxicity due to isoniazid occurred in 2.5%, 4.5%, and 41% of renal, heart and lung, and liver transplant recipients, respectively. The diagnosis and effective management of tuberculosis after transplantation warrant recognition of the unique epidemiological and clinical characteristics of tuberculosis in transplant recipients.     

Evaluation of a novel in vitro assay for assessing drug penetration into avascular regions of tumours

The poor blood supply to solid tumours introduces many factors that affect the outcome of chemotherapy, one of which is the problem of drug delivery to poorly vascularized regions of tumours. Whereas poor drug penetration has been recognized as a contributing factor to the poor response of many solid tumours, the question of drug penetration through multicell layers has not been thoroughly addressed, largely because of restrictions imposed upon these studies by the requirement for either radiolabelled or naturally fluorescent compounds. The aim of this study is to describe modifications made to a recently published assay that broadens the scope for assessing drug penetration during the early stages of drug development and to characterize the ability of various drugs to penetrate multicell layers. DLD-1 human colon carcinoma cells were cultured on Transwell-COL plastic inserts placed into 24-well culture plates so that a top and bottom chamber were established, the two chambers being separated by a microporous membrane. Drugs were added to the top chamber at doses equivalent to peak plasma concentrations in vivo and the rate of appearance of drugs in the bottom chamber determined by high-performance liquid chromatography (HPLC). Both 3-amino-1,2,4-benzotriazine 1,4-dioxide (tirapazamine) and 7-[4'-(2-nitroimidazol-1-yl)-butyl]-theophylline (NITP) rapidly penetrated DLD-1 multicell layers (50.9 +/- 12.1 microm thick) with t(1/2) values of 1.36 and 2.38 h respectively, whereas the rate of penetration of 5-aziridino-3-hydroxymethyl-1-methyl-2-[1H-indole-4,7-dione] prop-beta-en-alpha-ol (EO9) and doxorubicin through multicell layers was significantly slower (t(1/2) = 4.62 and 13.1 h respectively). Inclusion of dicoumarol increases the rate of EO9 penetration, whereas reducing the oxygen tension to 5% causes a reduction in tirapazamine penetration through multicell layers, suggesting that the extent of drug metabolism is one factor that determines the rate at which drugs penetrate multicell layers. The fact that EO9 does not readily penetrate a multicell layer, in conjunction with its rapid elimination in vivo (t(1/2) < 10 min), suggests that EO9 is unlikely to penetrate more than a few microm from a blood vessel within its pharmacokinetic lifespan. These results suggest that the failure of EO9 in the clinic is due to a combination of poor drug penetration and rapid elimination in vivo.     

1998 update on pregnancy in lupus patients. New horizons, new hopes

To clarify features of lung cancer in patients with tuberculosis sequelae, we analyzed data on 15 cases (5.1%) who were diagnosed with lung cancer before death among 294 deceased cases with tuberculosis sequelae at our hospital. There were 12 men and 3 women, with a mean age of 64 years. Most of the 15 patients had pulmonary dysfunction, and 4 had received home oxygen therapy. All 12 men had a history of smoking, and 10 of them had squamous cell carcinoma of the lung. There was no definite correlation between the locations of the tuberculosis lesion and those of lung cancer lesion on chest X-rays. Twelve patients had had thoracoplasty for tuberculosis, and in 6 of these patients the lung cancer occurred in the same lung. Lung cancer was apt to be diagnosed in an advanced stage. However, in patients who received home oxygen therapy, diagnosis had been made at an early stage because of the frequent chest X-ray follow-up. We conclude that lung cancer is an important complication in patients with tuberculosis sequelae, and early diagnosis of lung cancer by careful follow-up is essential in the care of cases with tuberculosis sequelae who have poor pulmonary function and/or systemic conditions.     

Serum concentrations of lipopolysaccharide activity-modulating proteins during tuberculosis

Lipopolysaccharide (LPS) is the principal stimulator of host defense against gram-negative bacteria. LPS-binding protein (LBP), bactericidal/permeability-increasing protein (BPI), and soluble CD14 (sCD14) bind LPS and regulate its toxicity. Lipoarabinomannan, a cell wall component of Mycobacterium tuberculosis, resembles LPS with respect to induction of inflammatory responses through recognition by LBP and sCD14. LBP, BPI, and sCD14 were measured in serum of 124 patients with tuberculosis in various stages of disease, in persons who had been in close contact with patients with contagious pulmonary tuberculosis, and in healthy controls. Levels of these LPS toxicity-regulating proteins were elevated in patients with active tuberculosis compared with those in contacts and controls and declined during treatment. The levels of LBP and sCD14 were higher in patients with fever and anorexia. LPS-regulating proteins may play a role in host defense during tuberculosis, presumably through interaction with lipoarabinomannan.     

Induction of long-term potentiation at perforant path dentate synapses does not affect place learning or memory

B lymphocytes are crucial participants in pulmonary immune defense. However, excess local antibody production is associated with accelerated lung destruction in several types of lung disease. The purpose of the current study was to study the potential role of alveolar macrophages (AM) in the local regulation of immunoglobulin (Ig) production in the lung in response to a direct B cell mitogen, Staphylococcus aureus Cowan strain (SAC). AM, when added to peripheral blood mononuclear cells, caused a dose-dependent inhibition of IgG and IgM, while not affecting IgA production in response to SAC. The mechanism of the AM-induced inhibition included both membrane-bound and soluble signals. The inhibition was not abrogated by indocin and catalase, or reversed by blocking antibodies to transforming growth factor-beta or interferon-gamma. Mononuclear cells isolated from human lung parenchyma displayed a reduced response to SAC compared with blood cells. However, depletion of macrophages from the parenchymal cells was associated with a restoration of IgG production in response to SAC. The results demonstrate that AM inhibit B cell responses to direct B cell mitogen and suggest that the effect of AM is selective for IgM and IgG.     

Longitudinal studies of immune function in cattle experimentally infected with bovine immunodeficiency-like virus and/or bovine leukemia virus

The effects of single or dual infection with bovine immunodeficiency-like virus (BIV) and/or, bovine leukemia virus (BLV) on bovine immune function were examined over a 4 year period. Holstein calves were infected with BIV (four calves), BLV (five calves), BIV and BLV (five calves), or sham inoculated (three calves). Lymphocyte blastogenesis to mitogens, seven tests of neutrophil function, and mononuclear cell subset analysis by flow cytometry (BoCD4, BoCD8, BoCD2, BoWC1, sIgM+, and monocytes) were performed at regular intervals to 49 months post-infection. These data were analyzed for main effects of each virus and interaction as a 2 x 2 factorial. BIV infected cattle had lower neutrophil antibody-dependent cell-mediated cytotoxicity and iodination responses during 2 of the 4 years post-infection (P < 0.05). BIV infection was not associated with any long-term significant changes in lymphocyte blastogenesis to mitogens or changes in mononuclear cell subset numbers in blood. There was a tendency for animals infected with BIV alone to have decreased lymphocyte blastogenic responses to mitogens, but this was not statistically significant. BLV infection caused an increase in total mononuclear cells with no dramatic shift in the relative proportions of the various subsets. Co-infection with BIV and BLV did not consistently cause a different response than either virus did individually. One BIV infected animal died of non-BLV lymphosarcoma 7 months after infection. All other animals had no unusual clinical signs. In summary, infection with BIV caused a significant, temporary decrease in neutrophil function with no consistent statistically significant alteration in lymphocyte blastogenesis or mononuclear cell numbers during the first 4 years after infection. BLV infection caused an increase in lymphocyte numbers, and there appeared to be no synergism between the viruses.     

Regulation of nuclear factor-kappa B and its inhibitor I kappa B-alpha/MAD-3 in monocytes by Mycobacterium tuberculosis and during human tuberculosis

Blood monocytes from patients with active tuberculosis are activated in vivo, as evidenced by an increase in the stimulated release of proinflammatory cytokines, such as TNF-alpha, and the spontaneous expression of IL-2R. Further, monocytes from patients demonstrate an augmented susceptibility to a productive infection with HIV-1 in vitro. Mycobacterium tuberculosis and its components are strong signals to activate monocytes to production of cytokines. In this study we examined the basis of activation of monocytes during active tuberculosis and by M. tuberculosis. We found a constitutive degradation of I kappa B-alpha, the major cytoplasmic inhibitor of nuclear factor kappa B (NF-kappa B), in freshly isolated PBMC and monocytes from patients with tuberculosis. In contrast, I kappa B-alpha levels in PBMC and monocytes from healthy subjects or from patients with nontuberculous pulmonary conditions were intact. Further, by electrophoretic mobility shift assay, NF-kappa B was activated in monocytes from tuberculous patients. The expression of I kappa B-alpha gene, which is responsive to activation by NF-kappa B, was up-regulated in PBMC and monocytes from patients, but not in mononuclear cells from healthy subjects or those with nontuberculous lung diseases. By contrast, the expression of other adherence-associated early genes, such as IL-8 and IL-1 beta, was not up-regulated in PBMC of tuberculous patients. Further, M. tuberculosis and its tuberculin, purified protein derivative, induced the degradation of I kappa B-alpha and the expression of I kappa B-alpha mRNA, and purified protein derivative induced the activation of NF-kappa B in monocytes.     

Prevalence of tuberculosis in Kishtwar Tehsil of Jammu region in Jammu and Kashmir State

A study of prevalence of tuberculosis in Kishtwar tehsil of Jammu region was conducted from June 1991 to May 1992. A total of one thousand two hundred ninety-eight rural as well as urban population suffering from various types of lung diseases was studied for prevalence of tuberculosis and a sizeable number (98) of patients were found to be positive of various types of tuberculosis, viz, pulmonary tuberculosis, tuberculous pleural effusion and miliary tuberculosis. Of the population studied 7.55% were found to be positive for tuberculosis and among them 88.76% patients were anaemic and the commonest type of anaemia was normocytic normochromic and normocytic hypochromic. The ESR was raised in almost of all the patients. Of the population, 80.61% were seen to be positive on skiagram chest and 58.16% were found to be positive on other diagnostic tests like Mantoux's tests, sputum for acid-fast bacilli, etc. Mantoux's test was positive in 27.55% cases and sputum was positive in 30.61% cases. All the cases studied were subjected to special investigations. The changes in parameters are consistent with the diagnosis of tuberculosis. Large family size, poverty, excessive smoking, illiteracy, etc, are the major contributing factors.     

Acute exacerbation following bronchoalveolar lavage in idiopathic interstitial pneumonia

We report two cases of idiopathic interstitial pneumonia (IIP) with acute deterioration after bronchoalveolar lavage (BAL). Case 1 was a 54-year-old woman, and case 2 was a 75-year-old man. Both were diagnosed as having IIP, and hospitalized with complaints of high fever and dyspnea. After BAL, the degree of dyspnea increased. White blood cell count and lactate dehydrogenase were elevated, and PaO2 was decreased. Chest X-ray revealed consolidation of the upper lung fields and reticulo-granular shadows spreading through both lungs. BAL fluid examination showed an elevated neutrophil fraction (case 1: 6.5%, case 2: 35.2%), suggesting respiratory tract infection although bacteria could not be detected. Case 1 died of respiratory failure despite corticosteroid therapy. Autopsy revealed diffuse alveolar damage with focal pneumonia in the right S6 corresponding to the upper lobe consolidation. Case 2 improved after antibiotic therapy. These findings suggest that aspiration of infected fluid during BAL can cause acute exacerbation of IIP. It is important to recognize that the BAL procedure can induce an acute exacerbation of IIP.