Risk of developing active tuberculosis in rheumatoid arthritis patients on adalimumab in Japan.

SETTING: Nationwide study in Japan. OBJECTIVE: To identify the clinical characteristics of and risk factors for tuberculosis (TB) in rheumatoid arthritis (RA) patients receiving adalimumab. DESIGN: A post hoc case-control study involving 7755 RA patients evaluated in an all-case post-marketing surveillance of adalimumab from 18 June 2008 to 20 January 2011 and spontaneous report of TB during adalimumab treatment. RESULTS: The analysis included 22 TB cases and 7733 non-TB controls. Despite the high frequency of extra-pulmonary TB (17/22, 77.3%), all 22 TB cases had pulmonary signs or symptoms. Of patients enrolled in all-case post-marketing surveillance, there were relatively high percentages of patients who had latent tuberculous infection (LTBI) at baseline. The percentage of patients who received prophylaxis was about six times higher in patients with LTBI than those without. Of those patients who received prophylaxis, none developed TB after treatment with adalimumab. Multivariate (non-matched and age-matched) and propensity score analyses identified age ⩾65 years (OR 4.59, 95%CI 1.52-13.89, P = 0.0070), moderate to severe RA (OR 4.61, 95%CI 1.07-20.00, P = 0.0408], past or current renal dysfunction (OR 4.65, 95%CI 1.47-14.71, P = 0.0089) and diabetes mellitus (OR 3.30, 95%CI 1.31-8.26, P = 0.0110) as potential risk factors for TB. CONCLUSION: Screening, prophylaxis and monitoring for TB are essential to ensure the safety of adalimumab treatment.

Cathepsin B activity has a crucial role in the developmental competence of bovine cumulus-oocyte complexes exposed to heat shock during in vitro maturation.

Cathepsin B was found to be correlated inversely with the quality of bovine oocytes and embryos. The aims of this study were to evaluate i) the relationship between heat shock during in vitro maturation (IVM) of bovine cumulus-oocyte complexes (COCs) and cathepsin B activity in relation to apoptosis and ii) the effect of supplementation of cathepsin B inhibitor (E-64) during IVM of heat-shocked COCs on embryonic development. After IVM at 38.5 °C for 22 h (control group) or at 38.5 °C for 5 h followed by 41 °C for 17 h (heat shock group) either with or without 1 µM E-64, activities and protein expression of cathepsin B and caspase 3 were evaluated as well as TUNEL staining. After IVF, developmental rate, total cell number, and the percentage of apoptotic cells in blastocysts were evaluated on day 8 (day 0, IVF day). Heat-shocked IVM COCs showed significantly high activities and expressions of both cathepsin B, and caspase 3 accompanied by a significant increase in number of TUNEL-positive cells. Addition of E-64 significantly decreased the activities of cathepsin B and caspase 3, and TUNEL-positive cells in heat-shocked IVM COCs. Moreover, addition of 1 µM E-64 during IVM under heat shock conditions significantly improved both developmental competence and quality of the produced embryos. These results indicate that heat shock induction of cathepsin B is associated with apoptosis of COCs, and inhibition of cathepsin B activity can improve the developmental competence of heat-shocked COCs during IVM.

Efficacy and safety of voriconazole in the treatment of chronic pulmonary aspergillosis: experience in Japan.

BACKGROUND: Though various clinical conditions of aspergillosis can occur, depending essentially on the host's immunological status, the focus of research in North American and European countries has mainly been on invasive pulmonary aspergillosis in immunocompromised patients. There are, however, also many problems to overcome in chronic forms of aspergillosis. One of those problems is that there are no codified treatment guidelines for chronic pulmonary aspergillosis (CPA). Especially in Japan, this issue is more serious, because there are more cases with CPA due to the many aged people with past history of tuberculosis. Several clinical cases and case series have reported the usefulness of the various antifungal agents that are available. The new triazole, voriconazole, in particular, seems to be effective in the treatment of CPA. The aim of the present study is to evaluate the efficacy and safety of voriconazole in the treatment of CPA in non-immunocompromised patients. PATIENTS AND METHODS: We conducted a prospective, open-label, non-comparative, multicenter study over a 2-year period. For inclusion in the study, patients with confirmed or probable CPA were recruited in 11 hospitals of the National Hospital Organization in Japan. Clinical, radiological, serological, and mycological data were collected at baseline and 12 weeks after treatment or at the end of treatment. RESULTS: Among 77 patients enrolled in the study, 71 patients (mean age 65.9 years, 56 males and 15 females) were eligible for the study. All of the eligible patients presented with underlying lung diseases, including sequelae of tuberculosis (n = 35), non-tuberculous mycobacterial lung disease (n = 8), chronic obstructive pulmonary disease (COPD) (n = 8), interstitial pneumonia (n = 7), cystic lung disease (n = 4), pneumothorax (n = 3), bronchial cancer (n = 1), and others (n = 5). Voriconazole was indicated in 48 cases (68 %) as the first-line treatment for CPA and 23 patients previously received other antifungal therapies. Based on a composite of clinical, radiologic, serological, and mycologic criteria, good response was seen in 43 patients (60.6 %), no response was observed in 19 patients (26.8 %), and 4 cases (5.6 %) got worse. Five patients (7.0 %) were unassessable for efficacy. The common adverse events were visual disturbances (17 patients, 23.9 %), abnormal liver function test results (12 patients, 16.9 %), adverse psychological effects (3 patients, 4.2 %), and others (10 patients, 14.0 %). Treatment with voriconazole had to be stopped in 2 cases (2.8 %) because of serious adverse events (abnormal liver function test results). There was no association between adverse effects and trough voriconazole levels in serum. CONCLUSIONS: In Japan, voriconazole provides effective therapy of CPA in non-immunocompromised patients with an acceptable level of toxicity.

Importance of culture conditions during the morula-to-blastocyst period on capacity of inner cell-mass cells of bovine blastocysts for establishment of self-renewing pluripotent cells.

The hypothesis was tested that the pluripotency of the inner cell mass (ICM) of the bovine embryo is enhanced by the glycogen synthase kinase-3ß inhibitor CHIR99021 and the MAPK1 and MAPK3 inhibitor PD032591. Treatment with the two inhibitors from Days 6 to 8 after insemination increased blastocyst steady state concentrations of mRNA for NANOG (P < 0.05) and SOX2 (P = 0.055) and tended to decrease (P = 0.09) expression of GATA6. To evaluate pluripotency, the inner cell mass was isolated by immunosurgery at Day 8, seeded on a feeder layer of bovine embryonic fibroblasts, and cultured in the presence of the inhibitors. Ten of 52 (19%) ICM from control embryos had primary outgrowth formation vs. 23 of 50 (46%) of the ICM from embryos cultured with inhibitors (P < 0.01). For ICM outgrowths from embryos cultured without inhibitors, colonies either did not persist through Passage 2 or became differentiated. In contrast, for the inhibitor group, four colonies survived beyond Passage 2, and one line persisted for 19 passages. This cell line possessed alkaline phosphatase activity, expressed several genes characteristically expressed in pluripotent cells, and differentiated into embryoid bodies when cultured in the absence of the signal transduction inhibitors and the feeder layer. Propagation of the cells was difficult due to slow growth and inefficiency in survival through each passage. In conclusion, exposure to inhibitors during the morula-blastocyst transition facilitated formation of self-renewing pluripotent cell lines from bovine blastocysts.

Consequences of physiological heat shock beginning at the zygote stage on embryonic development and expression of stress response genes in cattle.

The goal was to understand the role of heat shock at the zygote stage in causing infertility. Culture at 40°C reduced the percentage of inseminated oocytes that became a morula or blastocyst by d 6 or that were a blastocyst at d 8. An additional experiment was done to test whether effects of heat shock occur early in development or at the time of morula formation. Exposure to 40°C for 24 h decreased development to the blastocyst stage if exposure was at the zygote stage [8 to 32 h postinsemination (hpi)] but not if exposure occurred at the morula stage (116 to 140 hpi). To test effect of oxygen concentration, inseminated oocytes were cultured at 40°C for 12 or 24 h in either air (20.95% O2; high oxygen) or a 5% (vol/vol) O2 environment (low oxygen) that approximates the partial oxygen pressure of the reproductive tract. Blastocyst development was reduced by 40°C for 12 or 24 h under both atmospheres and was higher for embryos cultured in low oxygen than for embryos cultured in high oxygen. Examination of cell numbers at 72 hpi indicated that heat shock reduced developmental potential of embryos by reducing competence to complete cleavage divisions after first cleavage. Changes in expression of genes involved in heat shock and oxidative stress were measured to determine whether zygotes are more susceptible to heat shock because of reduced capacity for transcription. Heat shock was performed for 24 h at the 1-cell stage (expression examined in 2-cell embryos) or at d 5 (examined in morulae). Heat shock increased amounts of steady-state mRNA for HSPA1A but not for HSP90AA, SOD1, or CAT. We observed a tendency for a stage × temperature interaction for HSPA1A because the difference in expression between 38.5 and 40°C was greater for morulae than for 2-cell embryos. The amount of HSPA1A mRNA was less for morulae that were heat shocked than for 2-cell embryos cultured at 38.5°C. Heat shock at a temperature and oxygen tension similar to those seen in vivo can disrupt developmental competence of bovine zygotes. Increased susceptibility of the early embryo compared with the morula to heat shock was not due to reduced HSPA1A mRNA because amounts were higher for 2-cell embryos than for morulae.

Intracellular cathepsin B activity is inversely correlated with the quality and developmental competence of bovine preimplantation embryos.

Recently, the activity of cathepsins B was found to be correlated inversely with the developmental competence of bovine oocytes. In this study, we investigated (1) the role of intracellular cathepsin B expression and developmental competence as well as the quality of bovine preimplantation embryos, and (2) the effect of cathepsin B inhibitor (E-64) during in vitro culture (IVC) on the development and quality of bovine embryos. After in vitro fertilization (IVF) followed by IVC for 7 days, good and poor quality embryos classified by morphology and developmental rate on days 2, 4, and 7 were assessed for cathepsin B expression and activity. To investigate the effect of cathepsin B inhibition on embryonic development, putative zygotes were cultured with or without E-64, followed by evaluation of cleavage and blastocyst rates on days 2 and 7, respectively. Embryonic quality was evaluated by both TUNEL staining and total cell number in day-7 blastocysts. In each developmental stage, cathepsin B expression and activity were significantly higher in poor quality embryos than good quality ones. Moreover, addition of E-64 during IVC significantly increased both the blastocyst rate and the total cell number. TUNEL staining revealed that inhibition of cathepsin B significantly decreased the number of apoptotic nuclei in day-7 blastocysts. These results indicate that cathepsin B activity can be useful as a marker for inferior quality embryos. Moreover, inhibition of cathepsin B greatly improves the developmental competence of preimplantation embryos and increases the number of good quality embryos.

Cathepsin B activity is related to the quality of bovine cumulus oocyte complexes and its inhibition can improve their developmental competence.

Recently, the quantity of cathepsin transcripts in cumulus cells was found to be associated with low-developmental competence of bovine oocytes. In the present study, we investigated (1) the relation between cathepsin B activity and the quality of in vitro-matured cumulus-oocyte complexes (IVM COCs) and denuded oocytes and (2) the effect of a cathepsin B inhibitor (E-64) on embryo development and quality. The activity of cathepsin B was evaluated in IVM COCs and denuded oocytes. After maturation of COCs with or without E-64, followed by in vitro fertilization, zygotes were cultured for 8 days. Cleavage and blastocyst rates were evaluated on days 2 and 8, respectively. Quality of embryos was evaluated by differential staining of day 8 blastocysts. TUNEL staining was conducted on IVM COCs and blastocysts. Cathepsin B activity was clearly detected in the low-quality oocytes, and in the cumulus cells of both high- and low-quality oocytes. This latter activity was diminished by addition of E-64. The presence of E-64 during IVM also significantly increased both the blastocyst rate and the total cell number, and improved blastocyst quality associated with a significant increase of trophoectoderm cells. TUNEL staining revealed that inhibition of cathepsin B significantly decreased the number of apoptotic nuclei in both the cumulus cell layer of matured oocytes and blastocysts. These results indicate that cathepsin B activity can be a useful marker of oocyte quality. Furthermore, inhibition of cathepsin B greatly improves the developmental competence of bovine oocytes and increases the number of high-quality embryos.

A Novel Therapeutic and Prophylactic Vaccine (HVJ-Envelope / Hsp65 DNA + IL-12 DNA) against Tuberculosis Using the Cynomolgus Monkey Model.

We have developed a novel tuberculosis (TB) vaccine; a combination of the DNA vaccines expressing mycobacterial heat shock protein 65 (HSP65) and interleukin 12 (IL-12) delivered by the hemagglutinating virus of Japan (HVJ)-envelope and -liposome (HSP65 + IL-12/HVJ). An IL-12 expression vector (IL-12DNA) encoding single-chain IL-12 proteins comprised of p40 and p35 subunits were constructed. This vaccine provided remarkable protective efficacy in mouse and guinea pig models compared to the BCG vaccine on the basis of C.F.U of number of TB, survival, an induction of the CD8 positive CTL activity and improvement of the histopathological tuberculosis lesions. This vaccine also provided therapeutic efficacy against multi-drug resistant TB (MDR-TB) and extremely drug resistant TB (XDR-TB) (prolongation of survival time and the decrease in the number of TB in the lung) in murine models. Furthermore, we extended our studies to a cynomolgus monkey model, which is currently the best animal model of human tuberculosis. This novel vaccine provided a higher level of the protective efficacy than BCG based upon the assessment of mortality, the ESR, body weight, chest X-ray findings and immune responses. All monkeys in the control group (saline) died within 8 months, while 50% of monkeys in the HSP65+hIL-12/HVJ group survived more than 14 months post-infection (the termination period of the experiment). Furthermore, the BCG priming and HSP65 + IL-12/HVJ vaccine (booster) by the priming-booster method showed a synergistic effect in the TB-infected cynomolgus monkey (100% survival). In contrast, 33% of monkeys from BCG Tokyo alone group were alive (33% survival). Furthermore, this vaccine exerted therapeutic efficacy (100% survival) and augmentation of immune responses in the TB-infected monkeys. These data indicate that our novel DNA vaccine might be useful against Mycobacterium tuberculosis including XDR-TB and MDR-TB for human therapeutic clinical trials.

Eosinophilia in bronchoalveolar lavage fluid and architectural destruction are features of desquamative interstitial pneumonia.

AIMS: Desquamative interstitial pneumonia (DIP) is a rare pattern of diffuse parenchymal lung disease known to overlap with respiratory bronchiolitis-interstitial lung disease (RB-ILD). The aim was to review biopsy-proven cases of DIP to investigate further the clinical, imaging and histological features of this disease. METHODS AND RESULTS: Twenty patients fulfilled the pathological criteria: 19 men and one woman with a mean age of 54 years. Clinical features, bronchoalveolar lavage (BAL) data, radiological findings, pathological findings other than criteria, effect of therapy and outcome were examined. The BAL data for 17 cases revealed marked eosinophilia (mean 18%) and moderate neutrophilia (mean 11%). Computed tomography in 17 patients showed peripheral involvement in all cases with a clear margin in 64% and thin-walled cysts in 35% of cases. Additional pathological features were a distinct lobular distribution (70%) and architectural destruction (70%) with cyst formation (55%). Eighteen of the 19 patients (95%) improved under steroid pulse and/or oral therapy. Sixteen subjects (80%) are alive, three died of other diseases and one died of DIP 74 months after the diagnosis. Percent vital capacity increased significantly and new thin-walled cysts appeared in one case. CONCLUSIONS: BAL eosinophilia, lobular distribution and architectural destruction with cyst formation are characteristic features of DIP.

Glutamine and hypotaurine improves intracellular oxidative status and in vitro development of porcine preimplantation embryos.

We previously developed an in vitro-production system for porcine embryos and reported that the addition of glutamine (Gln) and hypotaurine (HT) during in vitro culture improved embryo development. This study examined the effects of Gln and HT on in vitro development, intracellular oxidative status and DNA damage of porcine preimplantation embryos. Porcine zygotes produced by in vitro maturation (IVM) and in vitro fertilization (IVF) were cultured until day 2 (day 0 = day of IVF) in porcine zygote medium (PZM) including 2 mM Gln and 5 mM HT, namely PZM-5. On day 2, the cleaved embryos were selected and cultured for 24 h in PZM-5 to which one of the following substances was added: (1) none (control); (2) Gln; (3) HT; or (4) Gln + HT. After 24 h of culture in each medium, the embryos were then returned to PZM-5 and cultured until day 5. Day-5 blastocyst yield was significantly higher in the Gln and Gln + HT groups (p < 0.05) than in the control and HT groups. In addition, Gln + HT significantly increased the total number of cells in blastocysts (p < 0.05) compared with the control. Although the number of cells and the intracellular GSH levels in day-3 cleaved embryos did not differ among treatments, addition of Gln, HT or Gln + HT significantly (p < 0.05) reduced the intracellular H2O2 content and the extent of DNA damage compared with the control. These results indicate that the presence of Gln and HT in PZM-5 from day 2 to day 3 promotes the development of porcine embryos by improvement of intracellular oxidative status.

Pulmonary Mycobacterium avium complex infection associated with the IVS8-T5 allele of the CFTR gene.

BACKGROUND: The T5 allele in intron 8 (IVS8) on specific haplotype backgrounds (e.g., long TG repeats) causes abnormal splicing in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, and is also known to be associated with chronic airway diseases. OBJECTIVE: To investigate the role of CFTR variations for susceptibility to pulmonary Mycobacterium avium complex (MAC) infection. PARTICIPANTS: Three hundred patients with pulmonary MAC infection (72 males, 228 females; mean age at onset 61.6 + or - 12.4 years) took part in this study. Diagnosis of MAC infection was based on American Thoracic Society criteria. Clinical profiles were collected and blood samples were genotyped for TG repeats, poly-T and M470V polymorphisms. RESULTS: We found significantly higher T5 frequency in MAC patients than in healthy controls from our own study (0.035 and 0.005, respectively, P = 0.023) and other reports. Homozygote for the T5 allele was found in two MAC patients. All T5 alleles were associated with longer TG repeats, the TG12 or TG13 allele. Seventeen of the 21 T5 alleles appeared to be associated with the V470 allele. Other polymorphisms did not show any significant differences in frequency. CONCLUSIONS: These findings suggest that the IVS8 5T allele might be involved in susceptibility to pulmonary MAC infection.

[Tuberculosis of the elderly (above the age of 75) in national hospitals].

In Japan tuberculosis is becoming rapidly the disease of the elderly. We studied the background, the type and level of hospital cares needed, and the outcome of patients with pulmonary tuberculosis (sputum smear and/or culture positive) above the age of 75 who were admitted to 8 national hospitals during the period from January 1 to December 31, 1997. The study included 150 patients (male: 109, female: 41, mean age: 81.6), of whom 25% needed care in a single-bed room, 84.3% had underlying diseases (cardiovascular diseases: 43.3%, malignant diseases: 20.9%, neuro-psychiatric diseases: 13.4%), and 47.6% needed cares mainly in feeding and excretions. 92 patients (62.6%) improved and 45 patients (30.6%) died, of whom the cause of death was directly related to tuberculosis in 42. The mean hospital stay was 4.7 months. However, in 42 patients whose cause of death was related to tuberculosis, 66% died within 3 months, while in 102 patients who were discharged 71% stayed more than 3 months. The same comparison was done in 508 patients with bacteriologically proven tuberculosis above the age of 75 admitted to National Tokyo Hospital during the period from 1990 to 1999. The result was almost the same, among 133 patients died in the hospital 60% died within 3 months, while in 375 patients who were discharged hospital stay was more than 3 months in 70%. In the near future, the elderly will occupy more than 25% of the beds of the tuberculosis ward in Japan and most of them have underlying diseases other than tuberculosis. Because tuberculosis, once the disease of the young, is becoming rapidly the disease of the elderly, it is imperative for us to make necessary adjustments to meet this inevitable trend.

[Clinical study on the cases in which INH or RFP was discontinued during treatment for pulmonary tuberculosis].

Short course regimens; 2HRZ (E)(S)/4HR (E), 6HRS (E)/3-6HR and 6-9HR have been accepted as a standard chemotherapy (SC) for initial treatment of pulmonary tuberculosis in Japan. We studied the frequency of the treatment completion, the causes of the treatment failure and the outcome of the patients in whom INH or RFP was discontinued within 6 months after starting SC. The subjects included 597 newly diagnosed culture positive pulmonary tuberculosis patients admitted to 16 national hospital in 1996. Results were as follows. 1. In 47 (7.9%) of the 597 patients, either INH (19; 3.2%) or RFP (33; 5.5%) was discontinued. These 47 cases were defined as a SC incompleted group and the other 550 as a SC completed group. 2. The patients in the SC incompleted group were seen more frequently in the ages of 20s (11.9%), 50s (10.9%), 60s (11.7%) or 70s (11.4%). 21 (13.6%) of 154 female patients and 26 (5.9%) of 443 male patients were in the SC incompleted group. 3. The causes of cessation of INH or RFP were drug side effects (33; 5.5%), drug resistance (10; 1.7%) and complications or underlying diseases (8; 1.3%). 4. Fever or eruption (19; 3.2%) and drug induced hepatitis (12; 2.0%) were frequently seen as drug related side effects causing the cessation of INH or RFP. 5. The rate of culture negative conversion of TB bacilli at 6 months after the start of the treatment was 98.9% in the SC completed and 88.9% in the SC incompleted group respectively. In the SC incompleted group, there were three cases continuously positive and two other patients who relapsed and became culture positive again. In these five patients, INH or RFP was discontinued because of drug resistance.

Clinical and high-resolution computed tomographic findings in five patients with pulmonary tuberculosis who developed respiratory failure following chemotherapy.

AIM: The purpose of this study was to describe the clinical and high-resolution computed tomographic (HRCT) findings in patients with pulmonary tuberculosis who developed respiratory failure after starting chemotherapy. MATERIALS AND METHODS: The clinical records, chest radiographs, and HRCT findings in five patients with non-miliary pulmonary tuberculosis who developed respiratory failure after starting chemotherapy were reviewed. RESULTS: Chest radiographs taken early in the course of acute respiratory failure showed progression of the original lesions with (n = 4) or without (n = 1) new areas of opacity away from the site of the original lesions. HRCT demonstrated widespread ground-glass attenuation with a reticular pattern as well as segmental or lobar consolidation with cavitation and nodules, consistent with active tuberculous foci in all five cases. Prominent interlobular septal thickening was seen in two cases. Four of the five patients had received corticosteroids. Of these five, two died and three recovered with continued corticosteroid therapy. Transbronchial biopsy in three cases showed evidence of acute alveolar damage. CONCLUSION: In selected patients with tuberculosis who develop respiratory failure following the initiation of antituberculous therapy, HRCT may be a helpful adjunct to clinical evaluation in differentiating hypersensitivity reactions (presumed to be due to the release of mycobacterial antigens) from other pulmonary complications.

Asbestos-related lung cancer and mesothelioma in Japan.

In Japan, crocidolite had been used for asbestos cement pipe and spraying, and amosite had been used for building board and spraying. These two types of asbestos had stopped to use in Japan in the late 1970s. An extreme increase in imported asbestos (all 3 commercial types) was observed between 1960 and 1974. In 1960, 77,000 tons of asbestos were imported, and reached the peak as 352,316 tons in 1974. This extreme rise of asbestos imports corresponds with the recent rapid increase in mortality of malignant pleural mesothelioma. Between 1995 and 1999, an estimated mean annual death from pleural mesothelioma was about 500. The annual number of compensated occupational respiratory cancers due to asbestos exposure has also been increasing. Up to the end of March 2000, 162 cases with malignant mesothelioma and 197 cases with lung cancer were compensated. As for lung cancer, epidemiological studies are scanty in Japan. Limited environmental data of the working places in asbestos textile factories suggests that heavy asbestos exposure in the past made deaths from respiratory diseases. Less asbestos exposure will enable exposed workers to survive enough to reach cancer age. Even now smoking rate among males in Japan are over 50%. So lung cancer deaths caused by the interaction between smoking and asbestos exposure will be continuing.

Microsatellite instability in transforming growth factor-beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis.

It has been reported that transforming growth factor (TGF)-beta, which plays an integral role in the pathogenesis of idiopathic pulmonary fibrosis (IPF), suppresses proliferation of alveolar epithelial cells in vitro. Although hyperplastic lesions of alveolar lining epithelial cells (ALECs) are characteristic pathologic features of IPF, the mechanism of their involvement in the pathogenesis has not yet been extensively studied. On the assumption that the hyperplastic ALECs have escaped from the growth-inhibitory effects of TGF-beta, we searched for mutations in the microsatellite of the TGF-beta receptor type II (T beta RII) gene. To detect a deletion in the polyadenine tract in exon 3 of the T beta RII gene, cells were isolated by microdissection from lung sections of IPF patients, and DNA was extracted from these cells and amplified by high-fidelity polymerase chain reaction. A total of 121 sites of hyperplastic ALECs from 11 IPF patients were analyzed, and a one-base-pair deletion was detected in nine sites from five patients. The mutation was also detected in smooth muscle-like cells of the thickened pulmonary artery. In some tissue areas where the deletion was detected, low T beta RII expression was confirmed by immunohistochemical staining. These data suggest that microsatellite instability in the T beta RII gene occurred in some lesions of hyperplastic ALECs in IPF, although at a low incidence, and that this genetic disorder might play a partial role in the pathologic changes of IPF.

Non-specific interstitial pneumonia: findings on sequential CT scans of nine patients.

BACKGROUND: The purpose of this study was to describe findings on sequential high resolution computed tomographic (CT) scans of nine patients with non-specific interstitial pneumonia. METHODS: Thin section CT scans of nine patients with pathologically proven non-specific interstitial pneumonia were evaluated retrospectively. All patients underwent sequential CT scanning (mean follow up 3.1 years (range 1-8)). RESULTS: The predominant finding on the initial CT scans in seven patients was patchy areas of ground glass opacity in both the central and peripheral lung, with (n = 5) or without (n = 2) irregular areas of consolidation. In another two patients areas of consolidation in both the central and peripheral lung were seen as the predominant abnormality. The initial parenchymal abnormalities had resolved completely in four patients with predominant ground glass opacity without bronchiolectasis. Some of the bronchiectasis and bronchiolectasis resolved. In two patients bronchiectasis and bronchiolectasis occurred at one year and two years of follow up, respectively. In two patients with predominant consolidation the consolidation decreased but persisted, and in one patient the consolidation evolved into honeycombing. In the other patient bronchiectasis progressed over the course of seven years, forming varicoid bronchiectasis. CONCLUSION: Patients with non-specific interstitial pneumonia may recover completely after treatment with corticosteroids, but as many as half of these patients will have persistent pulmonary abnormalities on CT scans including bronchiectasis and honeycomb lung.