Histological variability and consequences in chronic bird-related hypersensitivity pneumonitis.

BACKGROUND AND OBJECTIVE: Lobar and temporal histological variability in chronic bird-related hypersensitivity pneumonitis (BRHP) has not been clearly elucidated. This study was designed to evaluate the spatio-temporal histopathological variability in chronic BRHP. METHODS: Fifty-two patients with chronic BRHP who underwent a surgical lung biopsy (SLB) between 1992 and 2008 were evaluated. The histopathological characteristics of the lung biopsy specimens were classified by the 2002 American Thoracic Society/European Respiratory Society (ATS/ERS) consensus classification of idiopathic interstitial pneumonias (IIPs). Autopsy specimens from seven patients were also evaluated to examine the serial changes from SLB to autopsy. RESULTS: In a study of lobar histological variability based on the findings of SLB, 7 patients were diagnosed with cellular nonspecific interstitial pneumonia (NSIP) pattern, 16 with fibrotic NSIP pattern, 20 with fibrotic NSIP pattern and usual interstitial pneumonia (UIP) (discordant UIP) pattern and 9 with UIP (concordant UIP) pattern. In a study of sequential changes, specimens of SLBs with fibrotic NSIP pattern changed to a bronchiolocentric interstitial pneumonia (BIP) pattern or UIP pattern. CONCLUSION: Interlobar and intralobar histological variability is present in chronic BRHP. In several patients with chronic BRHP, a fibrotic NSIP pattern may be an early lesion that progresses to a UIP pattern.

Serial high-resolution computed tomography findings of acute and chronic hypersensitivity pneumonitis induced by avian antigen.

PURPOSE: The purpose of this study was to evaluate serial changes and the prognostic value of high-resolution computed tomographic (HRCT) findings in hypersensitivity pneumonitis (HP). METHOD: The medical records of 112 patients with bird-related HP (17 acute, 33 recurrent, and 62 insidious) were retrospectively reviewed. High-resolution computed tomographic findings at the time of diagnosis and at follow-up were retrospectively interpreted. RESULTS: Ground-glass opacities and centrilobular nodules were predominant findings in acute and recurrent HP, whereas honeycombing was the outstanding feature in insidious HP. Areas of ground-glass opacities and centrilobular nodules decreased in all groups over a long-term follow-up. Areas of honeycombing, on the other hand, increased in chronic HP, especially in the insidious cases. Cox regression models revealed a higher mortality risk in cases with airspace consolidation and honeycombing on HRCT. CONCLUSION: Acute, recurrent, and insidious HP all have characteristic features on CT. Characteristic HRCT findings can predict the prognosis of chronic HP.

Churg-Strauss syndrome versus chronic eosinophilic pneumonia on high-resolution computed tomographic findings.

OBJECTIVES: The aim of this study was to compare the high-resolution computed tomographic findings between Churg-Strauss syndrome (CSS) and chronic eosinophilic pneumonia (CEP). METHODS: We retrospectively reviewed the clinical records of 16 patients with CSS and 34 patients with CEP. RESULTS: Twelve (35%) of the 34 patients with CEP had a history of asthma. Although the subpleural distribution of ground-glass opacities (GGOs) and consolidation was common both in CSS and CEP, the midzone distribution was more frequent in CSS (44%) than in CEP (12%). Centrilobular nodules within GGOs were significantly more frequent in CSS (56%) than in CEP (18%). In contrast, traction bronchiectasis associated with volume loss was demonstrated more frequently in CEP (74%) than in CSS (25%). CONCLUSIONS: On high-resolution computed tomography, the presence of the midzone distribution and nodules within GGOs without traction bronchiectasis suggests CSS rather than CEP.

[A case of sarcoidosis with pleural involvement but with no mediastinal or hilar lymph node enlargement].

A 66-year-old woman was referred to our hospital because of right chest pain on inspiration. Chest X-ray film revealed diffuse opacities, predominantly in the lower lung field, and right pleural thickening. Serum ACE and lysozyme levels were elevated. Chest CT revealed diffuse ground-glass opacity, centrilobular granular nodules, bronchovascular bundle irregular thickening and right pleural irregular thickening over the right inferior lobe, but bilateral hilar lymph node enlargement was not present. Bronchoalveolar lavage (BAL) fluid demonstrated increased numbers of total cells and CD4 T-helper lymphocytes. The transbronchial lung biopsy specimen revealed non-caseating epithelioid cell granulomas. From these findings, we established a diagnosis of type III sarcoidosis with pleural involvement. The patient has been observed without treatment, and 10 months later the lung involvement and pleural thickening have disappeared.

Contribution of down-regulation of intestinal and hepatic cytochrome P450 3A to increased absorption of cyclosporine A in a rat nephrosis model.

This study examined the contribution of changes in regulation of intestinal and hepatic cytochrome P450 3A (CYP3A) and multidrug resistance transporter 1 (Mdr1) to absorption of cyclosporine A (CsA) in a rat nephrosis model. Interleukin (IL)-6 was also measured. Puromycin aminonucleoside at a dose of 20 mg/100 g was administered intravenously. Tissue samples were dissected out from the upper and middle intestines and liver after development of nephrosis to measure the expression levels of mRNA and protein. CsA at a dose of 0.5 mg/100 g was administered into a closed loop of the upper and middle intestines. Blood from the inferior vena cava (IVC) and portal vein was taken until 30 min after administration. The expression levels of CYP3A decreased markedly, whereas those of Mdr1 showed large interindividual variations for all of the tissues in the nephrotic rats. Plasma concentrations of CsA reached higher levels in the nephrotic than in the control rats and were higher when administered from the upper than the middle intestine in both the portal vein and IVC. IL-6 increased in urine in the nephrotic rats. In summary, intestinal and hepatic CYP3A were down-regulated in the nephrosis model accompanying the increased levels of IL-6. Consistent results were not obtained for the regulation of Mdr1. In conclusion, these findings suggest that the down-regulation of CYP3A in the upper intestine and liver predominantly contributes to the increase in CsA absorption, and Mdr1 showed less contribution in this rat nephrosis model.

Pathology of hypersensitivity pneumonitis.

PURPOSE OF REVIEW: Hypersensitity pneumonitis, caused by inhalation of various antigens, is characterized by interstitial mononuclear cell infiltration, nonnecrotizing granulomas, cellular bronchiolitis, and fibrosis. The pathological picture of chronic hypersensitivity pneumonitis is, however, complicated; it is sometimes difficult to differentiate chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia, nonspecific interstitial pneumonia, and connective-tissue-related lung disease. The clinical, radiological, and pathological features of chronic hypersensitivity pneumonitis have recently been described. This study reviews the previously reported information and provides new insights into the pathological features of chronic hypersensitivity pneumonitis. RECENT FINDINGS: The pathological features of chronic hypersensitivity pneumonitis comprise overlapping usual interstitial pneumonia-like pattern with subpleural patchy fibrosis, alternating normal alveoli and fibroblastic foci, a nonspecific interstitial pneumonia-like pattern, and centrilobular fibrosis. In contrast to pathological features of acute and subacute hypersensitivity pneumonitis, epithelioid cell granulomas are sparse or absent, but giant cells are seen in the interstitium. Bridging fibrosis between peribronchiolar area and perilobular areas is an outstanding feature of chronic hypersensitivity pneumonitis. Autopsy cases of chronic hypersensitivity pneumonitis have demonstrated not only upper lobe contraction but also lower lobe contraction, mimicking usual interstitial pneumonia pattern and diffuse alveolar damage. SUMMARY: The present review focuses on the pathological features of chronic hypersensitivity pneumonitis and presents that centrilobular fibrosis and bridging fibrosis are the important hallmarks of chronic hypersensitivity pneumonitis, even with a usual interstitial pneumonia-like pattern.

Estimation of the timing of human visual perception from magnetoencephalography.

To explore the timing and the underlying neural dynamics of visual perception, we analyzed the relationship between the manual reaction time (RT) to the onset of a visual stimulus and the time course of the evoked neural response simultaneously measured by magnetoencephalography (MEG). The visual stimuli were a transition from incoherent to coherent motion of random dots and an onset of a chromatic grating from a uniform field, which evoke neural responses in different cortical sites. For both stimuli, changes in median RT with changing stimulus strength (motion coherence or chromatic contrast) were accurately predicted, with a stimulus-independent postdetection delay, from the time that the temporally integrated MEG response crossed a threshold (integrator model). In comparison, the prediction of RT was less accurate from the peak MEG latency, or from the time that the nonintegrated MEG response crossed a threshold (level detector model). The integrator model could also account for, at least partially, intertrial changes in RT or in perception (hit/miss) to identical stimuli. Although we examined MEG-RT relationships mainly for data averaged over trials, the integrator model could show some correlations even for single-trial data. The model predictions deteriorated when only early visual responses presumably originating from the striate cortex were used as the input to the integrator model. Our results suggest that the perceptions for visual stimulus appearances are established in extrastriate areas [around MT (middle temporal visual area) for motion and around V4 (fourth visual area) for color] approximately 150-200 ms before subjects manually react to the stimulus.

Chronic summer-type hypersensitivity pneumonitis: clinical similarities to idiopathic pulmonary fibrosis.

BACKGROUND: Chronic hypersensitivity pneumonitis (HP) eventually ensues to extensive lung fibrosis when exposure to the causative antigen continues. Differential diagnosis from idiopathic interstitial pneumonias is sometimes difficult especially in the advanced stage. AIM OF THE WORK: To describe the clinical course of chronic summer-type HP, which is the most prevalent type of HP in Japan, in terms of early diagnosis and similarity to idiopathic pulmonary fibrosis (IPF). METHODS: 14 patients with chronic summer-type HP diagnosed between 2000 and 2005 were reviewed retrospectively. RESULTS: KL-6, a mucin-like glycoprotein, and surfactant protein-D (SP-D) were elevated in most cases. Specific antibodies against Trichosporon asahii (T. asahii) and T. mucoides in sera and BAL fluids were positive in 12 of 14 cases. A lymphocyte proliferation test induced by Trichosporon related antigen was positive in all examined cases (n=5). On high-resolution CT, traction bronchiectasis and honeycombing were observed in more than 70% of cases. By video-assisted thoracoscopic surgery (VATS) and autopsy specimens, honeycombing, fibroblastic foci, centrilobular fibrosis, and bridging fibrosis between bronchiolar and subpleural areas were observed. Antigen avoidance by improving domestic environments kept patients stable without decline in vital capacity (VC). However, 3 of the 4 patients who did not remedy their houses died of respiratory failure after progression of this disease. CONCLUSION: Correct diagnosis in the early stage is crucial, since chronic summer-type HP can result in a fatal outcome after continuous exposure to the causative antigen.

Effect of cigarette smoking on the development of murine chronic pigeon breeder's lung. The difference between a short-term and a long-term exposure.

Previous reports suggested that cigarette smoke had a protective effect of on the development of hypersensitivity pneumonitis (HP). However, smoking rate in chronic pigeon breeder's lung (PBL) seemed to be high in our clinical experiences. We developed a murine model of PBL by intranasal instillation with pigeon dropping extracts (PDE) for 4 weeks (short-term exposure) and 17 weeks (long-term exposure) to investigate the effect of cigarette smoke on disease processes. In this model, lung inflammation associated with the production of anti-PDE antibodies and antigen dependent lymphocyte proliferation was induced. Long-term exposure to PDE without cigarette smoking resulted in an increase in lung weight/body weight ratio, total cell number in bronchoalveolar lavage (BAL) fluid, and content of hydroxyproline in the lung compared to shortterm exposure. After a short-term exposure, cigarette smoke lessened the lymphocytosis in BAL fluid, and lymphocyte proliferation. On the other hand, after a long-term exposure cigarette smoke increased lung hydroxyproline. These results suggest that a short-term cigarette smoking attenuates lung inflammation, but a long-term cigarette smoking enhances lung inflammation with fibrosis.

Elemental analysis of inorganic dusts in lung tissues of interstitial pneumonias.

People have the opportunity to inhale inorganic dusts under various environments. Inorganic dust exposures as a result of occupational exposure may induce or modulate pulmonary fibrosis. We analyzed the deposition of elements in lung tissues of patients with idiopathic pulmonary fibrosis (IPF) and compared element deposition with chronic hypersensitivity pneumonitis (chronic HP) and collagen vascular diseases (CVD). Thirty-five patients (18 men and 17 women with the mean age of 64.3) were studied, including 15 IPF, 8 chronic HP, 6 CVD, and 6 control patients. Four IPF patients have occupational dust exposures. Inorganic particles were counted by polarizing light microscopy and scanning electron microscopy. Energy dispersive X-ray spectroscopy was performed to analyze an elemental deposition. The number of birefringent particles was greater in IPF, even in IPF without occupational exposure, than in controls. The silicon (Si)/sulfur (S) ratio and aluminium (AI)/S ratio were increased in IPF independent of occupational exposure. A point elemental analysis showed that the major compound of the particles was aluminium-silicate in IPF. These results suggest that unrecognized dust exposures are relatively common in some IPF patients and aluminium-silicate could be associated with the disease process of IPF.

[A case of hypersensitivity pneumonitis caused by smut spores of Ustilago esculenta].

A 49-year-old woman was admitted with cough, general fatigue, and dyspnea on effort. Her hobby was the Japanese traditional handicraft of lacquer-carving. She sometimes used smut spores of Ustilago esculenta, pronounced as "Makomozumi"on lacquer ware. The chest radiographs showed diffuse ground-glass opacities and small centrilobular nodules. Bronchoalveolar lavage yielded a marked number of lymphocytes as well as total cell counts and a low CD4 +/CD8 + ratio. The transbronchial lung biopsy specimen revealed lymphocytic alveolitis and non-necrotizing epithelioid cell granulomas. The results of provocation test by Makomozumi were positive. Serum tests of the specific antibody against extracted soluble antigens of smut spores were positive. The peripheral lymphocyte proliferation test, performed with Mokomozumi antigens was also positive. The final diagnosis was hypersensitivity pneumonitis induced by smut spores of fungus Ustilago esculenta.

Modes of Effective Connectivity within Cortical Pathways Are Distinguished for Different Categories of Visual Context: An fMRI Study.

Context contributes to accurate and efficient information processing. To reveal the dynamics of the neural mechanisms that underlie the processing of visual contexts during the recognition of color, shape, and 3D structure of objects, we carried out functional magnetic resonance imaging (fMRI) of subjects while judging the contextual validity of the three visual contexts. Our results demonstrated that the modes of effective connectivity in the cortical pathways, as well as the patterns of activation in these pathways, were dynamical depending on the nature of the visual contexts. While the fusiform gyrus, superior parietal lobe, and inferior prefrontal gyrus were activated by the three visual contexts, the temporal and parahippocampal gyrus/Amygdala (PHG/Amg) cortices were activated only by the color context. We further carried out dynamic causal modeling (DCM) analysis and revealed the nature of the effective connectivity involved in the three contextual information processing. DCM showed that there were dynamic connections and collaborations among the brain regions belonging to the previously identified ventral and dorsal visual pathways.

Comparison of maximum drug concentration and area under the time-concentration curve between humans and animals for oral and intravenous investigational drugs.

The study compared maximum drug concentration (C(max)) and area under the time-concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for C(max) and AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal-human ratios of C(max) were different among animals in both normalizations. Surface area-normalized AUC ratios were not different, whereas weight-normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose-normalized C(max) and AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human C(max) and AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability.

Proinflammatory and anti-inflammatory cytokine gene polymorphisms in hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immunologically-mediated lung disease caused by repeated inhalation of dispersed antigen. Various cytokines have been reported to be involved in the immunopathogenesis of HP Recently, some reports suggested an association between the genetic control of cytokine production and disease susceptibility. To evaluate whether cytokine gene polymorphisms are associated with HP, we performed a case-control association study involving 61 patients with HP, consisting of summer-type HP (SHP) and bird fancier's lung (BFL, also named bird fancier's disease), as well as 101 healthy controls. Polymorphisms of the genes for tumor necrosis factor (TNF)-alpha (-308G/A, -857C/T, -863C/A, -1031T/C), interleukin (IL)-10 (-592C/A, -819C/T, -1082G/A), transforming growth factor (TGF)-beta1 (-509C/T, +869T/C), and IL-6 (-634C/G) were examined by restriction fragment length polymorphism analysis. There were no significant differences in allele frequency and genotype distribution among control, SHP, and BFL group. When HP group was divided into acute or chronic, no significant differences were detected between any groups. LPS-stimulated IL-6 secretion by whole blood cells was similar between subjects with GG genotype and non-GG genotype in IL-6 -634C/G polymorphism. In conclusion, the association between HP susceptibility and cytokine polymorphisms studied was not demonstrated.

[Clinical evaluation of bird related hypersensitivity pneumonitis].

We retrospectively evaluated 8 cases of bird related hypersensitivity pneumonitis in Tenri hospital, all of whom underwent surgical lung biopsy. They had a history of contacting with birds and had serological studies using lymphocyte stimulation test to pigeon serum or antibody in serum and bronchoalveolar lavage fluid to pigeon dropping extracts yielded positive results. Computed tomography revealed a radiographic pattern unlike typical UIP. The result of pathological diagnosis of surgical lung biopsy was 'others' or NSIP pattern. Only one case had pathological findings of granuloma. Four cases had an improved or stable course only offer segregation from bird antigens. The other four cases needed corticosteroids and immunosuppressants, and two of the four cases had a progressive course and died of respiratory failure.

Concentrations of Immunoglobulin G Antibodies Against Pertussis Toxin Does Not Decrease Over a Long Period of Time in Japan.

Objective Adult patients with pertussis rarely show typical symptoms, such as paroxysmal coughing, inspiratory "whoop", or post-tussive vomiting. While a culture is regarded as the gold standard for diagnosis, the sensitivity is very low. Therefore, the diagnosis of pertussis in adults in clinical practice is mostly based on single-sample serology using an enzyme-linked immunosorbent assay (ELISA) with the pertussis toxin antigen. Various cut-off values for the anti-pertussis toxin IgG (PT-IgG) have been proposed. It has been reported that concentrations of PT-IgG fall below the defined cut-off about 4.5 months after infection on average, and within 1 year in most patients. We investigated the distribution and time course of the PT-IgG levels. Methods The data were collected from the medical records. Patients The study retrospectively identified subjects who had visited Ikebukuro Otani Clinic, which is a specialized clinic for patients with cough. We retrospectively reviewed 406 patients with PT-IgG measurements to investigate the age distribution of PT-IgG levels. The changes in PT-IgG levels over time were assessed in the 205 patients who had more than one PT-IgG measurement. Results PT-IgG levels were ≥100 EU/mL in more than 15% of subjects. The PT-IgG levels of a few subjects had diminished over a long period of time. Conclusion A PT-IgG level greater than the defined cut-off value simply indicates past infection or immunization in most subjects. As such, a single measurement of PT-IgG using the cut-off values might lead to overdiagnosis of pertussis. Further data collection and analysis are required.

Temporal summation of magnetic response to chromatic stimulus in the human visual cortex.

The temporal-summation characteristics of the human visual cortex were investigated by recording the magnetic responses to isoluminant red-green gratings. In one condition, exposure duration (ED) of a single-pulse stimulus was varied between 16.7 ms and 200 ms, and in the other, stimulus-onset-asynchrony (SOA) of a double-pulse (presented for 16.7 ms each) stimulus was varied between 16.7 ms and 200 ms. The magnetic responses showed an initial peak at a latency of around 100 ms, the origin of which was estimated to be in the vicinity of the striate cortex. The peak amplitude increased with increasing ED and decreased with increasing SOA, showing a clear sign of temporal summation. The critical ED and SOA estimated from the peak amplitude vs. ED/SOA functions were about 50 ms. These values indicate the upper limit of temporal summation for chromatic stimuli in the human early visual cortex.

Magnetic responses of human visual cortex to illusory contours.

To examine the neural mechanism underlying illusory-contour perception, we measured the magnetic responses of the human visual cortex to an abutting-line grating inducing illusory contours (test stimulus) and a non-abutting-line grating (control stimulus) using the technique of magnetoencephalography (MEG). In the initial latency period of 60-80 ms, the MEG response to the test stimulus was nearly identical with that to the control stimulus, but in the subsequent period of 80-150 ms, the former was larger than the latter. The origin of the peak MEG response to the test stimulus was estimated to be in the vicinity of striate cortex/extrastriate visual cortex for two of the four subjects. These results suggest that, in accord with those of the previous electrophysiological and functional magnetic resonance imaging studies, illusory-contour signals are generated in the very early stage(s) of processing in the primate visual cortex.

Usefulness of cyclosporine A on rapidly progressive interstitial pneumonia in dermatomyositis.

BACKGROUND: Interstitial pneumonia in polymyositis and dermatomyositis (PM/DM) is recognized to be a major complication of PM/DM. Rapidly progressive interstitial pneumonia (RPIP) in DM is frequently refractory to steroids and is the prognosis-determining factor in DM. Recently cyclosporine A (CyA) has emerged as an available treatment for interstitial pneumonia in PM/DM, but its efficacy on RPIP is unclear. AIM OF THE WORK: To evaluate the usefulness of CyA in the treatment of RPIP in DM. METHODS: We reviewed the medical charts of 10 cases with RPIP in DM to whom CyA was administered. RESULTS AND CONCLUSIONS: Combined administration of oral CyA and steroids with/without immuno-suppressants was likely to be beneficial in 4 of 10 cases that were refractory to the conventional preceding therapy. The values of PaO2/FIO2 when CyA were initiated were suggested to be a prognosis-determining factor for the outcome of the disease, showing that initiation of CyA should be considered in the early stage of RPIP in DM. The dosage of steroids was tapered in 3 out of 4 CyA-responsive cases without re-exacerbation. Therefore administration of CyA might be useful in lowering the dosage of steroids.

Surround suppression in the human visual cortex: an analysis using magnetoencephalography.

The responses of neurons in the primate and cat primary visual cortices (V1s) to the stimuli within their classical receptive fields (CRFs) are markedly suppressed by the surrounding stimuli outside CRFs. In the present study, we show that a similar suppressive effect occurs for visually evoked magnetic responses in the human visual cortex. The initial peak amplitude of the magnetic response (at a latency of around 90 ms) to a test grating accompanied by high-contrast surround gratings was smaller than that for the test without the surround. Current source localization with a single dipole model indicated that the initial response originated from cortical activity near the occipital pole in the contralateral hemisphere to the visual stimulation. The peak amplitude for the test decreased with increasing surround contrast, and increased with increasing test contrast. The contrast dependence and the early development of the surround suppression were in agreement with the results of the V1 single-cell studies of monkeys and cats. We suggest that the surround suppression of the initial peak amplitude of the magnetic response may be ascribed to the inhibition of the neural activity at the early processing stage(s), presumably at V1, in the human visual cortex.