Intractable diffuse pulmonary diseases: Manual for diagnosis and treatment

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014–FY2016 Health and Labor Sciences Research Grant on Intractable Diseases.This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities.The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.     

Glyburide prevents isoflurane’s reducing effects on hydroxyl radical formation in the postischemic reperfused rat heart

BACKGROUND:

The role of K_ATP channels in isoflurane’s reducing effects on oxygen free radical formation are not well known.

OBJECTIVES:

To investigate whether glyburide, an ATP-regulated potassium (K_ATP) channel blocker, abolishes isoflurane-induced cardioprotective effects and whether it affects hydroxyl radical formation in the postischemic reperfused heart.

ANIMALS AND METHODS:

Thirty-nine male Wistar rats were divided into four groups: group C (control, n=10), group I (isoflurane, n=9), group G (glyburide, n=10) and group GI (glyburide and isoflurane, n=10). The hearts were perfused as a Neely’s working heart model. Afterwards, global heart ischemia was induced for 15 min followed by reperfusion for 20 min. The formation of hydroxyl radicals in the coronary effluent and heart was measured with high performance liquid chromatography.

RESULTS:

Isoflurane alone and glyburide alone produced significant decreases in the duration of ventricular fibrillation during reperfusion (group C 452±345, group I 247±60, group G 261±135 s; P<0.05). In the presence of glyburide, isoflurane did not further decrease the duration of arrhythmia (group GI 230±48 s). Isoflurane reduced hydroxyl radical formation significantly in the coronary effluent during ischemia and reperfusion, but this was prevented by glyburide.

CONCLUSION:

The results suggest that isoflurane reduces hydroxyl radical formation, at least in part, through activation of K_ATP channels.     

Prophylactic hemodialysis does not prevent contrast-induced nephropathy after cardiac catheterization in patients with chronic renal insufficiency.

BACKGROUND: In Japan, prophylactic hemodialysis has been considered useful for preventing contrast-induced nephropathy (CIN). METHOD AND RESULTS: To assess whether hemodialysis prevented CIN, 391 patients (age: 69 +/- 8 years, 63 females) with chronic renal insufficiency (CRI, serum creatinine level (Scr) > or = 1.3 mg/dl) who underwent cardiac catheterization, were retrospectively analyzed. Patients were divided into 3 categories based on Scr: L (1.3 > or = Scr < 2.0 mg/dl, n = 332); M (2.0 > or = Scr < 3.0 mg/dl, n = 49); and H (Scr > or = 3.0 mg/dl, n = 10). To prevent CIN, 35 category M patients and all category L patients received hydration alone, whereas 14 category M patients and all category H patients received hemodialysis. CIN developed in 48 patients. The incidence of CIN in category H was significantly higher than that in category L or M (H, 40% vs L, 11% or M, 16% (p < 0.05)). In category M patients treated with hemodialysis, Scr increased from 2.4 +/- 0.3 to 3.0 +/- 0.5 mg/dl (p < 0.05) within 7 days, and 29% of patients developed CIN. However, in category M patients who did not receive hemodialysis, the Scr did not change (pre, 2.3 +/- 0.2 mg/dl to post, 2.2 +/- 0.4 mg/dl), and the incidence of CIN was 11%. CONCLUSION: Prophylactic hemodialysis for CRI patients undergoing cardiac catheterization does not prevent CIN.     

Role of c-kit receptor tyrosine kinase-mediated signal transduction in proliferation of bile epithelial cells in young rats after ligation of bile duct: a study using Ws/Ws c-kit mutant rats

BACKGROUND/AIMS: Recently, it has been shown that the c-kit receptor tyrosine kinase (KIT) is expressed in the liver of young rats, and its expression is up-regulated in bile epithelial cells (BEC) after ligation of the common bile duct (BDL). To clarify a role of KIT in BEC, we examined whether BEC of Ws/Ws rats, whose KIT kinase activity was severely impaired, could proliferate in response to bile stasis after BDL. METHODS/RESULTS: When 2-week-old control normal (+/+) and Ws/Ws mutant rats underwent BDL, only a few BEC were found in the portal field of livers of Ws/Ws rats, whereas many BEC were found in that of +/+ rats. Furthermore, Ki-67 immunostaining showed that the proliferative activity of BEC in 2-week-old Ws/Ws rats was much lower than that in +/+ rats of the same age. In contrast, when 6-week-old +/+ and Ws/Ws rats underwent BDL, BEC similarly proliferated in the livers of +/+ and Ws/Ws rats, and the proliferative activity of BEC was comparable. CONCLUSIONS: The mechanism whereby BEC proliferate in response to bile stasis after BDL may be different between 2- and 6-week-old rats, and KIT mediated-signal transduction plays a crucial role in the proliferation of immature BEC in young rats.     

The impact of anti-inflammatory cytokines provoked by CD163 positive macrophages on ventricular functional recovery after myocardial infarction

Present study aimed to investigate the impact of anti-inflammatory cytokines provoked by the hemoglobin scavenger receptor, CD163, on left ventricular (LV) functional recovery after successful reperfusion in patients with acute myocardial infarction (AMI). Intraplaque hemorrhage accelerates plaque destabilization. Extracellular hemoglobin is cleared by CD163, a macrophage scavenger receptor. This process provokes secretion of anti-inflammatory atheroprotective cytokine, interleukin (IL)-10. In 40 patients with the first AMI, coronary atherothrombotic debris was retrieved during percutaneous coronary intervention (PCI), stained with antibodies to CD163 and IL-10. LV function was determined by echocardiography before PCI and 6 months after PCI. %CD163 was defined as ratio of CD163 (+)-cells to whole cells. %IL-10 was expressed as the ratio of positively stained areas per total tissue. Patients were divided into two groups depending on the amount of CD163 (+)-cells: CD163 > 10 % (CD_163high, n = 20) and CD163 ≤ 10 % (CD_163low, n = 20). CD_163high group had significantly higher %IL-10. Final thrombolysis in myocardial infarction (TIMI) flow grade was significantly lower in CD_163high group. In subgroups with the final TIMI-3 flow (CD_163high-Reflow, n = 15 and CD_163low-Reflow, n = 20), the time to reperfusion, infarct size, LV dimensions and fractional shortening (%FS) before PCI were similar. Significant correlation was observed between %IL10 and changes in LV dimensions (diastole, r = ?0.49, P = 0.01; systole, r = ?0.65, P < 0.01) or %FS (r = 0.51, P < 0.01) at 6 months after PCI. Plaque with CD163(+)-macrophages could impair distal flow after primary PCI. However, CD163(+)-macrophages enhance the anti-inflammatory cytokine expression that aids in ventricular functional recovery if distal flow can be achieved by successful reperfusion.     

Automatic fabrication of 3-dimensional tissues using cell sheet manipulator technique

Automated manufacturing is a key for tissue-engineered therapeutic products to become common-place and economical. Here, we developed an automatic cell sheet stacking apparatus to fabricate 3-dimensional tissue-engineered constructs exploiting our cell sheet manipulator technique, where cell sheets harvested from temperature-responsive culture dishes are stacked into a multilayered cell sheet. By optimizing the stacking conditions and cell seeding conditions, the apparatus was eventually capable of reproducibly making five-layer human skeletal muscle myoblast (HSMM) sheets with a thickness of approximately 70–80 μm within 100 min. Histological sections and confocal topographies of the five-layer HSMM sheets revealed a stratified structure with no delamination. In cell counts using trypsinization, the live cell numbers in one-, three- and five-layer HSMM sheets were equivalent to the seeded cell numbers at 1 h after the stacking processes; however, after subsequent 5-day static cultures, the live cell numbers of the five-layered HSMM sheets decreased slightly, while one- and three-layer HSMM sheets maintained their live cell numbers. This suggests that there are thickness limitations in maintaining tissues in a static culture. We concluded that by combining our cell sheet manipulator technique and industrial robot technology we can create a secure, cost-effective manufacturing system able to produce tissue-engineered products from cell sheets.     

B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure.

OBJECTIVES: We explored the stimulus for B-type natriuretic peptide (BNP) secretion in the clinical setting of heart failure (HF). BACKGROUND: Increasingly, plasma BNP levels are being incorporated into the clinical assessment and management of systolic heart failure (SHF) as well as diastolic heart failure (DHF). However, heterogeneity in BNP levels among individuals with HF can cause some confusion in interpreting results. METHODS: In 160 consecutive patients presenting with HF, we measured plasma BNP levels and performed echocardiography and cardiac catheterization. Systolic and diastolic meridional wall stress was calculated from echocardiographic and hemodynamic data. RESULTS: Although plasma BNP had a significant correlation (r2 = 0.296 [p < 0.001]) with left ventricular end-diastolic pressure (EDP) as previously reported, the correlation between plasma BNP and end-diastolic wall stress (EDWS) (r2 = 0.887 [p < 0.001]) was more robust. In a subanalysis of 62 patients with DHF, a similar result was obtained (r2 = 0.143 for EDP and r2 = 0.704 for EDWS). In a comparison between SHF and DHF, the BNP level was significantly higher in SHF (p < 0.001). Although EDP did not show any difference, EDWS was significantly higher in SHF than in DHF (p < 0.001). CONCLUSIONS: The present study shows that plasma BNP levels reflect left ventricular EDWS more than any other parameter previously reported, not only in patients with SHF, but also in patients with DHF. The relationship of left ventricular EDWS to plasma BNP may provide a better fundamental understanding of the interindividual heterogeneity in BNP levels and their clinical utility in the diagnosis and management of HF.     

Difference in elevation of N-terminal pro-BNP and conventional cardiac markers between patients with ST elevation vs non-ST elevation acute coronary syndrome.

BACKGROUND: N-terminal pro-B-type natriuretic peptide (NT-proBNP) is elevated in patients with acute coronary syndrome (ACS), and is a powerful predictor of long-term mortality. Differences in the clinical utility and pathophysiological implication of NT-proBNP and conventional cardiac markers in patients with ST elevation (STE) vs non-STE (NSTE) ACS were investigated in the present study. METHODS AND RESULTS: Ninety consecutive patients admitted with acute chest pain and a diagnosis of unstable angina or acute myocardial infarction were analyzed. Patients with >or=Killip class II were excluded to focus on the effect of myocardial ischemia on the release of cardiac markers. The markers were measured on admission and analyzed according to the time from onset. Conventional cytosolic marker (creatine kinase-MB) and myofibril marker (troponin T: TnT) were both significantly higher in STE-ACS patients compared with NSTE-ACS patients. Conversely, NT-proBNP was significantly higher in NSTE-ACS patients than STE-ACS especially within 3 h of onset, suggesting a larger ischemic insult despite the smaller extent of myocardial necrosis compared with STE-ACS patients. There was no significant correlation between NT-proBNP level and left ventricular ejection fraction (LVEF) obtained at acute-phase echocardiography in either NSTE-ACS patients (LVEF 57.7+/-11.2%) or STE-ACS patients (LVEF 55.1+/-12.7%). Comparison between NT-proBNP and TnT levels revealed a marked difference of elevations, with significantly augmented elevation of NT-proBNP (p<0.001) in NSTE-ACS patients as compared with prominent elevation of TnT in STE-ACS patients. CONCLUSIONS: NT-proBNP is an early sensitive marker of myocardial ischemia that rises much higher in the earlier phase as compared with conventional markers of myocardial damage, especially in NSTE-ACS patients.