Yamaguchi University Hospital

The authors developed a simple method for determining the presampling modulation transfer function (MTF). which includes the unsharpness of the detector and the effect of the sampling aperture, in digital radiographic (DR) systems. With this method, the presampling MTF is determined by the Fourier transform of a ;finely sampled' line spread function (LSF) obtained with a slightly angulated slit in a single exposure. Since the effective sampling distance becomes much smaller than the original sampling distance of the DR system, the effect of aliasing on the MTF calculations can be eliminated. The authors applied this method to the measurement of the presampling MTF of a compound radiographic system and examined the directional dependence, the effect of exponential extrapolation, and the effect of different sampling distances. It is shown that the technique of multiple slit exposure and exponential extrapolation of the LSF tail, which has been commonly used in analog seven-film systems, can be employed in DR systems. The authors determined the glare fraction in order to estimate the component of low-frequency drop mainly due to ;glare'

We here report nine liver cirrhosis (LC) patients that underwent autologous bone marrow cell infusion (ABMI) from the peripheral vein. Subjects were patients with LC with total bilirubin of less than 3.0 mg/dl, platelet count of more than 5 (10(10)/l), and no viable hepatocellular carcinoma on diagnostic imaging. Autologous bone marrow (BM; 400 ml) was isolated from the ilium under general anesthesia. Mononuclear cells (MNCs) were separated by cell washing and were infused via the peripheral vein. MNC characteristics were confirmed by fluorescence-activated cell sorting analysis (CD34, CD45, and c-kit). After ABMI therapy, liver function was monitored by blood examination for 24 weeks. From 400 ml of BM, we obtained 7.81 +/- 0.98 x 10(9) MNCs. After washing, 5.20 +/- 0.63 x 10(9) MNCs were infused into patients with LC. Significant improvements in serum albumin levels and total protein were observed at 24 weeks after ABMI therapy (p < .05). Significantly improved Child-Pugh scores were seen at 4 and 24 weeks (p < .05). alpha-Fetoprotein and proliferating cell nuclear antigen (PCNA) expression in liver biopsy tissue was significantly elevated after ABMI therapy (p < .05). No major adverse effects were noted. In conclusion, ABMI therapy should be considered as a novel treatment for patients with decompensated LC.

The eradication of Helicobacter pylori often leads to platelet recovery in patients with chronic idiopathic thrombocytopenic purpura (cITP). Although this clinical observation suggests the involvement of H. pylori, little is known about the pathogenesis of cITP. We initially examined the effect of H. pylori eradication on platelet counts in 20 adult Japanese cITP patients. Then, using platelet eluates as the probe in immunoblot analyses, we examined the role of molecular mimicry in the pathogenesis of cITP. Helicobacter pylori infection was detected in 75% (15 of 20) of cITP patients. Eradication was achieved in 13 (87%) of the H. pylori-positive patients, seven (54%) of which showed increased platelet counts within the 4 months following treatment. Completely responsive patients also showed significant declines in platelet-associated immunoglobulin G (PAIgG) levels. Platelet eluates from 12 (nine H. pylori-positive and three H. pylori-negative) patients recognized H. pylori cytotoxin-associated gene A (CagA) protein, and in three completely responsive patients, levels of anti-CagA antibody in platelet eluates declined after eradication therapy. Cross-reactivity between PAIgG and H. pylori CagA protein suggests that molecular mimicry by CagA plays a key role in the pathogenesis of a subset of cITP patients.

INTRODUCTION: Fever is frequently observed in critically ill patients. An independent association of fever with increased mortality has been observed in non-neurological critically ill patients with mixed febrile etiology. The association of fever and antipyretics with mortality, however, may be different between infective and non-infective illness. METHODS: We designed a prospective observational study to investigate the independent association of fever and the use of antipyretic treatments with mortality in critically ill patients with and without sepsis. We included 1,425 consecutive adult critically ill patients (without neurological injury) requiring >48 hours intensive care admitted in 25 ICUs. We recorded four-hourly body temperature and all antipyretic treatments until ICU discharge or 28 days after ICU admission, whichever occurred first. For septic and non-septic patients, we separately assessed the association of maximum body temperature during ICU stay (MAXICU) and the use of antipyretic treatments with 28-day mortality. RESULTS: We recorded body temperature 63,441 times. Antipyretic treatment was given 4,863 times to 737 patients (51.7%). We found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen independently increased 28-day mortality for septic patients (adjusted odds ratio: NSAIDs: 2.61, P=0.028, acetaminophen: 2.05, P=0.01), but not for non-septic patients (adjusted odds ratio: NSAIDs: 0.22, P=0.15, acetaminophen: 0.58, P=0.63). Application of physical cooling did not associate with mortality in either group. Relative to the reference range (MAXICU ≥ 39.5°C increased risk of 28-day mortality in non-septic patients (adjusted odds ratio 8.14, P=0.01), but not in septic patients (adjusted odds ratio 0.47, P=0.11) [corrected]. CONCLUSIONS: In non-septic patients, high fever (≥39.5°C) independently associated with mortality, without association of administration of NSAIDs or acetaminophen with mortality. In contrast, in septic patients, administration of NSAIDs or acetaminophen independently associated with 28-day mortality, without association of fever with mortality. These findings suggest that fever and antipyretics may have different biological or clinical or both implications for patients with and without sepsis. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00940654.

Serum melatonin concentrations were studied in normal pregnant women and in women with several types of pathologic pregnancies, e.g., twins, preeclampsia or intrauterine growth retardation (IUGR). Blood samples were collected from the maternal antecubital vein at 14:00 hr (daytime) and 02:00 hr (nighttime) during pregnancy, and also from the umbilical vein and artery immediately after delivery. Serum melatonin concentrations were measured by radioimmunoassay. Daytime serum melatonin levels in normal (single fetus; singleton) pregnancies were low. While the levels showed an increasing tendency toward the end of pregnancy, no statistically significant changes occurred. On the other hand, the nighttime serum melatonin levels increased after 24 weeks of gestation, with significantly (P < 0.01) high levels after 32 weeks; these values decreased to non-pregnant levels on the 2nd day of puerperium. Nighttime serum melatonin levels were significantly (P < 0.05) higher in twin pregnancies after 28 weeks of gestation than in singleton pregnancies, whereas the patients with severe preeclampsia showed significantly (P < 0.05) lower serum melatonin levels than the mild preeclampsia or the normal pregnant women after 32 weeks of gestation. Melatonin concentrations in umbilical vessels showed a higher tendency in neonates who were born during at night compared with the other neonates; moreover, those in the umbilical artery were generally higher than those in the umbilical vein. The present results indicate that in humans, the maternal serum melatonin levels show a diurnal rhythm, which increases until the end of pregnancy, reflecting some pathologic states of the feto-placental unit. Fetuses may produce melatonin with a circadian rhythm.

INTRODUCTION: Abnormal body temperatures (Tb) are frequently seen in patients with severe sepsis. However, the relationship between Tb abnormalities and the severity of disease is not clear. This study investigated the impact of Tb on disease severity and outcomes in patients with severe sepsis. METHODS: We enrolled 624 patients with severe sepsis and grouped them into 6 categories according to their Tb at the time of enrollment. The temperature categories (≤ 35.5 °C, 35.6-36.5 °C, 36.6-37.5 °C, 37.6-38.5 °C, 38.6-39.5 °C, ≥ 39.6 °C) were based on the temperature data of the Acute Physiology and Chronic Health Evaluation II (APACHE II) scoring. We compared patient characteristics, physiological data, and mortality between groups. RESULTS: Patients with Tb of ≤ 36.5 °C had significantly worse sequential organ failure assessment (SOFA) scores when compared with patients with Tb >37.5 °C on the day of enrollment. Scores for APACHE II were also higher in patients with Tb ≤ 35.5 °C when compared with patients with Tb >36.5 °C. The 28-day and hospital mortality was significantly higher in patients with Tb ≤ 36.5 °C. The difference in mortality rate was especially noticeable when patients with Tb ≤ 35.5 °C were compared with patients who had Tb of >36.5 °C. Although mortality did not relate to Tb ranges of ≥ 37.6 °C as compared to reference range of 36.6-37.5 °C, relative risk for 28-day mortality was significantly greater in patients with 35.6-36.5 °C and ≤ 35.5 °C (odds ratio; 2.032, 3.096, respectively). When patients were divided into groups based on the presence (≤ 36.5 °C, n = 160) or absence (>36.5 °C, n = 464) of hypothermia, disseminated intravascular coagulation (DIC) as well as SOFA and APACHE II scores were significantly higher in patients with hypothermia. Patients with hypothermia had significantly higher 28-day and hospital mortality rates than those without hypothermia (38.1% vs. 17.9% and 49.4% vs. 22.6%, respectively). The presence of hypothermia was an independent predictor of 28-day mortality, and the differences between patients with and without hypothermia were observed irrespective of the presence of septic shock. CONCLUSIONS: In patients with severe sepsis, hypothermia (Tb ≤ 36.5 °C) was associated with increased mortality and organ failure, irrespective of the presence of septic shock. TRIAL REGISTRATION: UMIN-CTR ID UMIN000008195.

PURPOSE: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy with poor prognosis. Patients with MPM who do not respond to standard first-line chemotherapy have limited treatment options. We evaluated the efficacy and safety of nivolumab, an immune checkpoint inhibitor, for the treatment of advanced or metastatic MPM. PATIENTS AND METHODS: Japanese patients with unresectable, advanced, or metastatic MPM resistant or intolerant to ≤2 regimens of chemotherapy and ≥1 measurable lesion(s) were enrolled. Patients received nivolumab 240 mg intravenously every 2 weeks until progressive disease or unacceptable toxicity. The primary endpoint was objective response rate by central assessment according to the Modified Response Evaluation Criteria in Solid Tumors. Adverse events (AEs) and treatment-related AEs (TRAEs) were evaluated. RESULTS: Thirty-four patients were enrolled between July 2016 and October 2016. Median follow-up was 16.8 (range: 1.8-20.2) months. Ten (29%, 95% confidence interval, 16.8-46.2) patients showed a centrally assessed objective response. The objective response rates were 26% (7/27), 67% (2/3), and 25% (1/4) patients for epithelioid, sarcomatoid, and biphasic histologic subtypes, respectively. Median duration of response was 11.1 months with a 68% disease control rate. Median overall survival and progression-free survival were 17.3 and 6.1 months, respectively. The objective response rate was 40% with programmed death-ligand 1 expression ≥1% and 8% with <1%. Thirty-two patients (94%) experienced AEs and 26 (76%) experienced TRAEs. CONCLUSIONS: .

BACKGROUND: Gemcitabine/cisplatin (GC) combination therapy has been the standard palliative chemotherapy for patients with advanced biliary tract cancer (BTC). No randomized clinical trials have been able to demonstrate the survival benefit over GC during the past decade. In our previous phase II trial, adding S-1 to GC (GCS) showed promising efficacy and we aimed to determine whether GCS could improve overall survival compared with GC for patients with advanced BTC. METHODS: of S-1 on days 1-7 every 2 weeks. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS), response rate (RR), and adverse events (AEs). This study is registered with Clinical trial identification: NCT02182778. RESULTS: Between July 2014 and February 2016, 246 patients were enrolled. The median OS and 1-year OS rate were 13.5 months and 59.4% in the GCS arm and 12.6 months and 53.7% in the GC arm, respectively (hazard ratio [HR] 0.79, 90% confidence interval [CI]: 0.628-0.996; P = .046 [stratified log-rank test]). Median PFS was 7.4 months in the GCS arm and 5.5 months in the GC arm (HR 0.75, 95% CI: 0.577-0.970; P = .015). RR was 41.5% in the GCS arm and 15.0% in the GC arm. Grade 3 or worse AEs did not show significant differences between the two arms. CONCLUSIONS: GCS is the first regimen which demonstrated survival benefits as well as higher RR over GC in a randomized phase III trial and could be the new first-line standard chemotherapy for advanced BTC. To exploit the advantage of its high RR, GCS is now tested in the neoadjuvant setting in a randomized phase III trial for potentially resectable BTC.

INTRODUCTION: To validate the Japanese Association for Acute Medicine (JAAM) disseminated intravascular coagulation (DIC) scoring system in patients with severe sepsis, we conducted a multicenter, prospective study at 15 critical care centers in tertiary care hospitals. METHODS: This study included 624 severe sepsis patients. JAAM DIC was scored on the day of diagnosis of severe sepsis (day 1) and day 4. Scores for disease severity and organ dysfunction were also evaluated. RESULTS: The prevalence of JAAM DIC was 46.8% (292/624), and 21% of the DIC patients were scored according to the reduction rate of platelets. The JAAM DIC patients were more seriously ill and exhibited more severe systemic inflammation, a higher prevalence of multiple organ dysfunction syndrome (MODS) and worse outcomes than the non-DIC patients. Disease severity, systemic inflammation, MODS and the mortality rate worsened in accordance with an increased JAAM DIC score on day 1. The Kaplan-Meier curves demonstrated lower 1-year survival in the JAAM DIC patients than in those without DIC (log-rank test P<0.001). The JAAM DIC score on day 1 (odds ratio=1.282, P<0.001) and the Delta JAAM DIC score (odds ratio=0.770, P<0.001) were independent predictors of 28-day death. Dynamic changes in the JAAM DIC score from days 1 to 4 also affected prognoses. The JAAM DIC scoring system included all patients who met the International Society on Thrombosis and Haemostasis overt DIC criteria on day 1. The International Society on Thrombosis and Haemostasis scoring system missed a large number of nonsurvivors recognized by the JAAM scoring system. CONCLUSIONS: The JAAM DIC scoring system exhibits good prognostic value in predicting MODS and poor prognosis in patients with severe sepsis and can detect more patients requiring treatment. Conducting repeated daily JAAM scoring increases the ability to predict the patient's prognosis.

BACKGROUND: Serum glial fibrillary acidic protein (GFAP) is a specific predictor of brain damage and neurologic outcome in patients with traumatic brain injury (TBI). In this study, serum GFAP, S-100B, and neuron-specific enolase (NSE) were compared in the same samples from severe trauma patients to assess their ability to predict abnormalities detectable on head computed tomography (CT). METHODS: This study was a retrospective analysis at a single university emergency center. Thirty-four trauma patients were included. Serum samples were collected from the patients for 3 days. Serum GFAP, S-100B, and NSE concentrations were measured with enzyme-linked immunosorbent assays and compared in patients with and without TBI, as evaluated by head CT. RESULTS: Serum GFAP, S-100B, and NSE were significantly higher in the TBI patients than in the non-TBI patients (p < 0.05 for each protein). The receiver operating characteristic curves for TBI were compared for the three biomarkers for 3 days. Serum GFAP on day 1 had the largest area under the receiver operating characteristic curve (0.983), with 88.9% sensitivity and 100% specificity. CONCLUSIONS: Serum GFAP has remarkable diagnostic value for TBI, defined by abnormal head CT findings, in prehospital-triaged patients with severe trauma.

PURPOSE: To determine the maximum tolerable dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of lenvatinib in patients with advanced hepatocellular carcinoma (HCC). EXPERIMENTAL DESIGN: This multicenter, open-label, phase I, dose-escalation study included patients aged 20 to 80 years, refractory to standard therapy, and stratified by hepatic function measured using Child-Pugh (CP) scores: CP-A (score, 5-6) and CP-B (score, 7-8). Lenvatinib was administered continually once daily for 4-week cycles. MTD was defined as the maximum dose associated with ≤ 1 dose-limiting toxicity (DLT) occurring in cycle 1 among 6 patients. RESULTS: In total, 20 patients (9 in CP-A and 11 in CP-B) were enrolled. The MTD was 12 and 8 mg once daily in CP-A and CP-B, respectively; DLTs included proteinuria, hepatic encephalopathy, and hyperbilirubinemia. The most common grade 3 toxicities included hypertension in CP-A and hyperbilirubinemia in CP-B. Lenvatinib plasma concentration at 24 hours after administration (C24 h) for 12 mg once daily was higher in patients with HCC than in patients with other solid tumors shown in a previous phase I study, but C24 h for 25 mg once daily lenvatinib was comparable. After lenvatinib treatment, the number of circulating endothelial and c-Kit(+) cells decreased and the levels of interleukin (IL)-6, IL10, granulocyte-colony stimulating factor, and vascular endothelial growth factor increased (P < 0.05). Partial responses were observed in 3 patients and tumor shrinkage occurred in 14 patients. CONCLUSIONS: Lenvatinib (12 mg once daily) demonstrated preliminary efficacy with manageable toxicity and is the recommended dose for phase II studies in patients with HCC and CP-A.

Low back pain (LBP) is the most common cause of chronic pain. Numerous clinical scales are available for evaluating pain, but their objective criteria in the management of LBP patients remain unclear. This study aimed to determine an objective cutoff value for a change in the Pain Intensity Numerical Rating Scale (ΔPI-NRS) three months after LBP treatment. Its utility was compared with changes in six commonly used clinical scales in LBP patients: Pain Disability Assessment Scale (PDAS), Pain Self-Efficacy Questionnaire (PSEC), Pain Catastrophizing Scale (PCS), Athens Insomnia Scale (AIS), EuroQoL 5 Dimension (EQ5D), and Locomo 25. We included 161 LBP patients treated in two representative pain management centers. Patients were partitioned into two groups based on patient's global impression of change (PGIC) three months after treatment: satisfied (PGIC = 1, 2) and unsatisfied (3-7). Multivariate logistic regression analysis was performed to explore relevant scales in distinguishing the two groups. We found ΔPI-NRS to be most closely associated with PGIC status regardless of pre-treatment pain intensity, followed by ΔEQ5D, ΔPDAS, ΔPSEC, and ΔPCS. The ΔPI-NRS cutoff value for distinguishing the PGIC status was determined by ROC analysis to be 1.3-1.8 depending on pre-treatment PI-NRS, which was rounded up to ΔPI-NRS = 2 for general use. Spearman's correlation coefficient revealed close relationships between ΔPI-NRS and the six other clinical scales. Therefore, we determined cutoff values of these scales in distinguishing the status of ΔPI-NRS≥2 vs. ΔPI-NRS<2 to be as follows: ΔPDAS, 6.71; ΔPSEC, 6.48; ΔPCS, 6.48; ΔAIS, 1.91; ΔEQ5D, 0.08; and ΔLocomo 25, 9.31. These can be used as definitive indicator of therapeutic outcome in the management of chronic LBP patients.

BACKGROUND: Endothelial dysfunction is a key component of vascular vulnerability. Reactive hyperemia index (RHI), as assessed by the peripheral arterial tonometry, can noninvasively evaluate endothelial function. This study was designed to determine the additional prognostic value of endothelial function to the Synergy Between PCI With Taxus and Cardiac Surgery Score (SYNTAXsc) and the Framingham Risk Score (FRS) in predicting cardiovascular events in high-risk patients. METHODS AND RESULTS: We undertook a two-center prospective study in 528 stable patients at high-risk for cardiovascular events from the years 2006-2011. The RHI was measured before coronary angiography and coronary complexity was assessed by SYNTAXsc. After optimal therapies including coronary revascularization, there was follow-up with patients until August 2012. Cardiovascular events consist of cardiovascular death, myocardial infarction, unstable angina, ischemic stroke, coronary revascularization, heart failure-induced hospitalization, aortic disease, and peripheral arterial disease. During 1468 person-years of follow-up, 105 patients developed cardiovascular events. Multivariate Cox proportional hazards analysis identified B-type natriuretic peptide (BNP), SYNTAXsc, and RHI as independent cardiovascular event predictors (hazard ratio [95% confidence interval]: natural logarithm of BNP per 0.1: 1.019 [1.002 to 1.037]; P=0.023, SYNTAXsc per tertile: 2.426 [1.825 to 3.225]; P<0.0001, RHI per 0.1: 0.761 [0.673 to 0.859]; P<0.0001). When RHI was added to the FRS, BNP, and SYNTAXsc, net reclassification index was significantly improved (27.5%; P<0.0001), with a significant increase in the C-statistic (from 0.728 [0.679 to 0.778] to 0.766 [0.726 to 0.806]; P=0.031). CONCLUSIONS: Advanced endothelial dysfunction significantly correlated with near future cardiovascular events in high-risk patients. This physiological vascular measurement improved risk discrimination when added to the FRS, BNP, and SYNTAXsc. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov (http://www.clinicaltrials.gov). Unique identifier: NCT00737945.

BACKGROUND: Sepsis is a leading cause of death and long-term disability in developed countries. A comprehensive report on the incidence, clinical characteristics, and evolving management of sepsis is important. Thus, this study aimed to evaluate the characteristics, management, and outcomes of patients with severe sepsis in Japan. METHODS: This is a cohort study of the Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis, and Trauma (FORECAST) study, which was a multicenter, prospective cohort study conducted at 59 intensive care units (ICUs) from January 2016 to March 2017. We included adult patients with severe sepsis based on the sepsis-2 criteria. RESULTS: In total, 1184 patients (median age 73 years, interquartile range (IQR) 64-81) with severe sepsis were admitted to the ICU during the study period. The most common comorbidity was diabetes mellitus (23%). Moreover, approximately 63% of patients had septic shock. The median Sepsis-related Organ Failure Assessment (SOFA) score was 9 (IQR 6-11). The most common site of infection was the lung (31%). Approximately 54% of the participants had positive blood cultures. The compliance rates for the entire 3-h bundle, measurement of central venous pressure, and assessment of central venous oxygen saturation were 64%, 26%, and 7%, respectively. A multilevel logistic regression model showed that closed ICUs and non-university hospitals were more compliant with the entire 3-h bundle. The in-hospital mortality rate of patients with severe sepsis was 23% (21-26%). Older age, multiple comorbidities, suspected site of infection, and increasing SOFA scores correlated with in-hospital mortality, based on the generalized estimating equation model. The length of hospital stay was 24 (12-46) days. Approximately 37% of the patients were discharged home after recovery. CONCLUSION: Our prospective study showed that sepsis management in Japan was characterized by a high compliance rate for the 3-h bundle and low compliance rate for central venous catheter measurements. The in-hospital mortality rate in Japan was comparable to that of other developed countries. Only one third of the patients were discharged home, considering the aging population with multiple comorbidities in the ICUs in Japan. TRIAL REGISTRATION: UMIN-CTR, UMIN000019742 . Registered on 16 November 2015.

Background & Aims: Despite the evidence of hepatic iron overload in patients with chronic hepatitis C, it remains unknown if iron overload is related to hepatocarcinogenesis in this condition. The aim of this study was to determine whether iron overload contributes to development of hepatocellular carcinoma (HCC) in transgenic mice expressing the hepatitis C virus (HCV) polyprotein. Methods: Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or control diet. Mice in each group were assessed for altered liver morphology and function and the development of liver tumors. Results: Hepatic iron concentrations in mice fed the excess-iron diet were comparable to those of patients with chronic hepatitis C. There was no inflammation in transgenic and nontransgenic livers. Compared with mice in 3 other groups, transgenic mice fed the excess-iron diet showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, and greater hepatic content of lipid peroxidation products and 8-hydroxy-2′-deoxyguanosine at 12 months after initiation of feeding. The number of proliferating hepatocytes was significantly increased in mice fed the excess-iron diet but was not different between transgenic and nontransgenic mice. Hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet but not in mice in other groups at 12 months after initiation of feeding. Conclusions: Iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein. Background & Aims: Despite the evidence of hepatic iron overload in patients with chronic hepatitis C, it remains unknown if iron overload is related to hepatocarcinogenesis in this condition. The aim of this study was to determine whether iron overload contributes to development of hepatocellular carcinoma (HCC) in transgenic mice expressing the hepatitis C virus (HCV) polyprotein. Methods: Male C57BL/6 transgenic mice expressing the HCV polyprotein and nontransgenic littermates were fed an excess-iron diet or control diet. Mice in each group were assessed for altered liver morphology and function and the development of liver tumors. Results: Hepatic iron concentrations in mice fed the excess-iron diet were comparable to those of patients with chronic hepatitis C. There was no inflammation in transgenic and nontransgenic livers. Compared with mice in 3 other groups, transgenic mice fed the excess-iron diet showed marked hepatic steatosis including the centrilobular microvesicular type, ultrastructural alterations of the mitochondria and decreased degradation activity of fatty acid at 6 months, and greater hepatic content of lipid peroxidation products and 8-hydroxy-2′-deoxyguanosine at 12 months after initiation of feeding. The number of proliferating hepatocytes was significantly increased in mice fed the excess-iron diet but was not different between transgenic and nontransgenic mice. Hepatic tumors including HCC developed in 5 of 11 (45%) transgenic mice fed the excess-iron diet but not in mice in other groups at 12 months after initiation of feeding. Conclusions: Iron overload induces mitochondrial injury and increases the risk of HCC development in transgenic mice expressing the HCV polyprotein. Hepatocellular carcinoma (HCC) is a common malignancy and its incidence is increasing both in Japan and in the United States.1El-Serag H.B. Mason A.C. Rising incidence of hepatocellular carcinoma in the United States.N Engl J Med. 1999; 240: 745-750Crossref Scopus (2736) Google Scholar Persistent hepatitis C virus (HCV) infection is a major risk factor for the development of HCC. Approximately 80% of Japanese HCC patients are also diagnosed with HCV-associated cirrhosis or chronic hepatitis C.2Kiyosawa K. Tanaka E. Sodeyama T. Hepatitis C virus and hepatocellular carcinoma.in: Reesink H.W. Hepatitis C virus. Karger, Basel1998: 161-180Crossref Scopus (43) Google Scholar Nevertheless, the mechanisms underlying HCV-associated hepatocarcinogenesis are incompletely understood. Numerous studies have shown that oxidative stress is present in chronic hepatitis C to a greater degree than in other inflammatory liver diseases.3Barbaro G. Di Lorenzo G. Asti A. Ribersani M. Belloni G. Grisorio B. Filice G. Barbarini G. Hepatocellular mitochondrial alterations in patients with chronic hepatitis C ultrastructural and biochemical findings.Am J Gastroenterol. 1999; 94: 2198-2205Crossref PubMed Scopus (170) Google Scholar, 4Valgimigli M. Valgimigli L. Trere D. Gaiani S. Pedulli G.F. Gramantieri L. Bolondi L. Oxidative stress EPR measurement in human liver by radical-probe technique. Correlation with etiology, histology and cell proliferation.Free Radic Res. 2002; 36: 939-948Crossref PubMed Scopus (100) Google Scholar We also showed that HCV core protein produces reactive oxygen species (ROS) in human hepatoma Huh-7 cells and HeLa cells.5Okuda M. Li K. Beard M.R. Showalter L.A. Scholle F. Lemon S.M. Weinman S.A. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein.Gastroenterology. 2002; 122: 366-375Abstract Full Text Full Text PDF PubMed Scopus (830) Google Scholar Besides the directly induced generation of ROS by the HCV proteins, chronic inflammation with production of proinflammatory cytokines has the potential to deliver an additional burden of ROS. These multiple sources of ROS production create a procarcinogenic environment under which chromosomal damage is likely to occur.See editorial on page 2229. See editorial on page 2229. Hepatic iron accumulation has been shown to be present in patients with chronic hepatitis C,6Kageyama F. Kobayashi Y. Kawasaki T. Toyokuni S. Uchida K. Nakamura H. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C.Am J Gastroenterol. 2000; 95: 1041-1050Crossref PubMed Google Scholar, 7Farinati F. Cardin R. De Maria N. Della Libera G. Marafin C. Lecis E. Burra P. Floreani A. Cecchetto A. Naccarato R. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis.J Hepatol. 1995; 22: 449-456Abstract Full Text PDF PubMed Scopus (375) Google Scholar even though its levels are not extremely high.8Di Bisceglie A.M. Axiotis C.A. Hoofnagle J.H. Bacon B.R. Measurements of iron status in patients with chronic hepatitis.Gastroenterology. 1992; 102: 2108-2113Abstract PubMed Google Scholar, 9Haque S. Chandra B. Gerber M.A. Lok A.S. Iron overload in patients with chronic hepatitis C a clinicopathologic study.Hum Pathol. 1996; 27: 1277-1281Abstract Full Text PDF PubMed Scopus (115) Google Scholar This iron overload is potentially one of multiple sources of ROS production in chronic hepatitis C, in the of acid in of Google Scholar the of increased iron accumulation in the liver with hepatocarcinogenesis in has been and hepatocellular Full Text Full Text PDF PubMed Scopus Google Scholar it remains to be whether to increases in hepatic iron accumulation to the development of HCC in patients with HCV-associated chronic liver the other the of HCV transgenic mice have to the for T. of hepatitis hepatocellular Full Text Full Text PDF PubMed Scopus Google Scholar the this is likely to both and has been the of the HCV transgenic mice in this study that were to have hepatic steatosis and liver H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar but this has and even with the of The aim of this study was to the for this by the transgenic mice expressing the HCV polyprotein and to determine whether iron overload to that in chronic hepatitis C patients to the development of HCC in transgenic mice expressing the HCV polyprotein. the present have that even iron a major marked by oxidative stress, mitochondrial fatty acid and These the between HCV protein and iron in the development of The the to of of M.R. G. M. A. M. B. K. R. Lemon S.M. of a Japanese hepatitis C 1999; PubMed Scopus Google Scholar under the control of the was in by H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar the transgenic with evidence of of the the of in There was no inflammation in transgenic H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar were with C57BL/6 mice to These generation were by of the and the This of was to the of the HCV polyprotein. the to for the of for by for by for transgenic mice and C57BL/6 mice were and to the by the and a C57BL/6 mice were fed diet or an excess-iron diet or iron for 6 to The excess-iron diet the iron of the control diet Hepatic iron concentrations of mice at months after of were liver in mice fed the control in mice fed the diet and in mice fed the diet those of mice fed the diet at 6 The iron content of the of fed mice was to that in patients with to an with hepatic iron content comparable to that of patients with chronic hepatitis C and one that be for a to diet an excess-iron diet iron and control diet iron transgenic mice and C57BL/6 littermates were fed the excess-iron diet or control diet at the of nontransgenic mice were fed the control transgenic mice the control nontransgenic mice the excess-iron and transgenic mice the excess-iron diet. to 12 mice in each group were by of at and 12 months after the of and liver and were for of hepatic and iron lipid peroxidation oxidative hepatocellular and to the liver and the number and of liver tumors were at of liver was in for and of hepatic and iron The liver and liver tumors were in in and in for were with and for and for The and were by the Iron M.A. G. Iron accumulation in is a of A. 94: PubMed Scopus Google Scholar with The content was also with were by the with the The liver were with a of a or a of a at with were developed in The of cells for or were for 5 in each by a with hepatocytes were for 5 in each were the those for lipid for the of a cell and the of the for was by of cells in hepatic and a were in in in and and in in were with to steatosis by were with and and by a was in for at and in were in The iron was in an at by was for of hepatic iron concentrations by iron and and a Hepatic iron concentrations were of liver was the liver by the of and of lipid and J PubMed Scopus Google Scholar The levels were with a to the concentrations in liver were by the of measurement with the Full Text PDF PubMed Google Scholar by a protein of acid was B. G. C. P. E. D. D. of mitochondrial of fatty by in microvesicular steatosis to this Google Scholar a of acid was by in of by for The was for 6 in a by an of The was of 6 was and for activity with an was the liver a Hepatic content of 8-hydroxy-2′-deoxyguanosine was with an to the were in was the liver was with a by a to the The of and were the to The the the and inflammatory cytokines are in The were the which is by the of each gene by the of the and are for for for for and for for HCV for for for for in a are for for for for and for for HCV for for for for are groups multiple groups were by the of by at different in the group were by the The incidence of liver development was by the of than was to be We for mice for C57BL/6 littermates and transgenic mice by the and were 12 months after of iron and were not different between of the The iron was in Hepatic iron content was at and and 12 months after of iron shown in hepatic iron content of nontransgenic and transgenic mice fed the excess-iron diet significantly greater than that of nontransgenic and transgenic mice fed the control diet at 6 and 12 months after of iron be that the hepatic iron of transgenic mice fed the excess-iron diet for 6 months liver and 12 months were comparable to that of patients with chronic hepatitis C liver and comparable to the hepatic iron content of a number of patients with chronic hepatitis C in other H. C. M. P. F. P. Hepatic iron not to and therapy in patients with chronic hepatitis Hepatol. Full Text Full Text PDF PubMed Google Scholar, K. between hepatic iron content and in chronic hepatitis C patients with interferon and J Gastroenterol. PubMed Scopus Google hepatic iron content at 12 months after initiation of iron was greater than that at 6 months in transgenic mice the of the iron a at 6 months in nontransgenic mice fed the excess-iron diet. the mice fed the control hepatic iron content was significantly greater in transgenic mice than in nontransgenic mice at 6 and 12 months after of feeding. that the iron in the hepatocytes but no of hepatocytes in hepatic with hepatic in nontransgenic mice fed the control diet for 12 months increased iron were in transgenic mice at 12 months after initiation of iron Hepatic and were present in of hepatocytes and Hepatic were in mice fed the excess-iron diet but not in mice fed the control diet. The degree of hepatic to be in transgenic mice than in nontransgenic mice but not be between of the of in transgenic mice was to be present in an by but not in H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar determine whether the expression of was between transgenic mice fed the control diet and those fed the excess-iron the of core gene by at 6 months after initiation of feeding. The levels of were in both groups 5 for each We also assessed the hepatic expression of inflammatory cytokines that be in iron E. S. C. S. T. of inflammation by the of the iron PubMed Scopus Google Scholar, P. H. T. E. The and of in and A. PubMed Scopus Google Scholar and The expression of cytokines was not different between of the groups at 6 months after initiation of 6 for each to the degree of steatosis in transgenic mice fed the control transgenic mice fed the excess-iron diet developed steatosis including the centrilobular microvesicular at 6 months after the of and The of liver to was significantly greater in transgenic mice fed the excess-iron diet than in mice in the 3 other increased with in nontransgenic mice fed the excess-iron diet and transgenic shown by liver histology at 12 months after the of Hepatic content was to the degree of The content was significantly greater in transgenic mice fed the excess-iron diet than in mice in the other groups at 6 months and 12 months after the of or levels 3 months after initiation of in shown in transgenic mice fed the excess-iron diet showed significantly levels in than those in the 3 other groups at 6 months after initiation of feeding. levels were also in mice fed the excess-iron diet than in those fed the control diet but not between mice fed the excess-iron diet at 12 months after initiation of feeding. These mice showed no evidence of the in levels in nontransgenic and transgenic mice fed the excess-iron diet was to the degree of marked centrilobular microvesicular steatosis in transgenic mice fed the excess-iron of the mitochondria in mice of each group at 6 months after the of iron ultrastructural alterations of the mitochondria were in mice other than transgenic mice fed the excess-iron mitochondria were in transgenic mice fed the control diet. transgenic mice fed the excess-iron diet showed or the mitochondrial ultrastructural alterations of the mitochondria were shown in transgenic mice fed the excess-iron diet. transgenic mice fed the excess-iron diet steatosis centrilobular microvesicular steatosis and ultrastructural alterations of mitochondria mitochondrial in the transgenic mice fed in of acid acid is fatty the of the of and fatty are in the of fatty and PubMed Scopus (170) Google Scholar Compared with mice in the 3 other groups, transgenic mice fed iron showed significantly decreased in of acid These that iron and HCV mitochondrial Mitochondrial and ultrastructural alterations are likely to oxidative stress mitochondria are the of production of ROS. We the lipid peroxidation products and in the of mice in each 6 months after initiation of were no between the 12 months after initiation of the of the for or protein were significantly in transgenic mice fed iron than in mice in the 3 other groups mice fed the excess-iron diet also showed greater for than nontransgenic mice fed the control diet and were present in hepatocytes and the was in the of or There was no of and hepatic lipid peroxidation significantly with in transgenic mice fed the excess-iron diet with mice in the 3 other whether the oxidative stress induced in transgenic mice fed iron was to the hepatic content of 6 months after the initiation of the hepatic levels were between groups and not in group with the hepatic levels at 12 months after the initiation of were significantly than the or those at 6 months in the hepatic content of was significantly in transgenic mice fed the excess-iron diet than in mice in other groups the accumulation of in the the hepatic increased with and was in transgenic mice fed iron at 12 months after the initiation of feeding. in and studies that iron cell N. B. S. N. P. P. G. Iron both and in hepatocytes by Hepatol. Full Text PDF PubMed Scopus Google Scholar, H.W. of iron and on cell and in in human hepatoma cell PubMed Scopus Google Scholar, Y. B. Iron and hepatocellular Hepatol. PubMed Scopus Google Scholar in transgenic and nontransgenic mice fed the excess-iron diet or control diet for 12 months by the of for shown in the of in mice fed the excess-iron diet were significantly than those in mice fed the control was no in the of between transgenic mice and nontransgenic both of which were fed tumors were present in mice in group at months after the of feeding. tumors a to in were present in 5 (45%) of the 11 transgenic mice fed the excess-iron diet at 12 months after the initiation of iron transgenic multiple of which were HCC and was transgenic a with HCC in a in and in HCC developed in 3 transgenic mice fed The morphology of the showed of the increased is that developed in transgenic mice fed the excess-iron diet by 12 months after iron the generation of mice developed liver at greater than H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar of mice have no developed tumors. The for this are but to the the mice were to the this no liver developed in transgenic mice fed the control diet at than liver tumors including were present in 6 of the 12 transgenic mice fed the excess-iron diet at the of in the Iron of nontransgenic mice fed control transgenic mice fed control nontransgenic mice fed excess-iron transgenic mice fed excess-iron diet. in a nontransgenic mice fed control transgenic mice fed control nontransgenic mice fed excess-iron transgenic mice fed excess-iron diet. is a of chronic hepatitis of hepatitis C virus 1995; PubMed Scopus Google Scholar was no in in the of liver tumors. liver in in the of liver tumors not Hepatic iron has been shown to be one of the in patients with chronic liver and to be significantly in patients than in hepatitis F. Kobayashi Y. Kawasaki T. Toyokuni S. Uchida K. Nakamura H. Successful interferon therapy reverses enhanced hepatic iron accumulation and lipid peroxidation in chronic hepatitis C.Am J Gastroenterol. 2000; 95: 1041-1050Crossref PubMed Google Scholar, 7Farinati F. Cardin R. De Maria N. Della Libera G. Marafin C. Lecis E. Burra P. Floreani A. Cecchetto A. Naccarato R. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis.J Hepatol. 1995; 22: 449-456Abstract Full Text PDF PubMed Scopus (375) Google Scholar hepatic iron overload is Bisceglie A.M. Axiotis C.A. Hoofnagle J.H. Bacon B.R. Measurements of iron status in patients with chronic hepatitis.Gastroenterology. 1992; 102: 2108-2113Abstract PubMed Google Scholar the present mice in which hepatic iron content was to that of patients with chronic hepatitis C. The iron in this study was than those for mice or C. B. P. Y. P. induces in Hepatol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar or or Bacon B.R. A.S. of iron overload in Google Scholar in was in hepatocytes of the mice in to of shown induced iron overload in C. B. P. Y. P. induces in Hepatol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar and Bacon B.R. A.S. of iron overload in Google Scholar the in the hepatic iron a at 6 months after the initiation of iron in nontransgenic mice. hepatic iron content increased with the of iron in transgenic mice. The hepatic iron content was also greater in transgenic mice than in nontransgenic mice iron at 6 and 12 months after feeding. These that the of iron not be in transgenic mice. We that of a in iron A. S. A. P. K. a human 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, E. A. T. iron by to and its PubMed Scopus Google Scholar was decreased in transgenic mice and was not increased iron S. K. T. Y. M. M. Lemon S.M. K. Iron overload in the of hepatic inflammation in transgenic mice expressing the hepatitis C virus Scholar also is to iron by of E. A. T. iron by to and its PubMed Scopus Google Scholar an iron decreased levels are to the iron which in accumulation of iron in The by which was is unknown but to inflammatory cytokines factor and were the development of or HCC has not been even in mice with greater iron C. B. P. Y. P. induces in Hepatol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, P. B. of hepatic in the after the of PubMed Scopus Google Scholar, P. for both the and of iron Google Scholar it to be that not or HCC in nontransgenic mice fed the iron overload in the present study was not to HCC by This was to the of iron in hepatocarcinogenesis under the expression of levels of the HCV polyprotein. We that iron overload not the expression levels of in transgenic mice. also be that transgenic mice with iron overload developed other in to HCC. of the other groups developed tumors. The that or developed in the HCV transgenic mice the of this for the study of in hepatitis C. a to degree of steatosis was in transgenic mice fed the control diet H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar the development of steatosis in transgenic mice fed iron was one of the in the present This steatosis was not by the in and not between of hepatic content that the degree of steatosis was significantly in transgenic mice with iron overload than in mice in the 3 other groups at 6 and 12 months after the initiation of feeding. The degree of steatosis also to with of iron or the of HCV microvesicular which is in G. The hepatic in Google Scholar or fatty liver of fatty liver of in 12 J Med. Google Scholar was present in transgenic mice fed the excess-iron the of mitochondrial injury and increased lipid Mitochondrial oxygen and oxidative stress to PubMed Scopus Google Scholar ultrastructural alterations of mitochondria were in transgenic mice fed G. Di Lorenzo G. Asti A. Ribersani M. Belloni G. Grisorio B. Filice G. Barbarini G. Hepatocellular mitochondrial alterations in patients with chronic hepatitis C ultrastructural and biochemical findings.Am J Gastroenterol. 1999; 94: 2198-2205Crossref PubMed Scopus (170) Google Scholar showed the of the mitochondria one of ultrastructural in patients with chronic not the mitochondrial ultrastructural alterations in mice but was to the in transgenic mice fed the control diet than those in transgenic mice fed the excess-iron diet. The the of mitochondria in transgenic mice with iron overload was to the mitochondrial ultrastructural alterations in the transgenic mice expressing levels of the factor in which mitochondrial injury was of ROS S. Y. A.M. levels of the factor steatosis and mitochondrial PubMed Scopus Google Scholar of in of acid is not to of fatty in mitochondria fatty to be by the mitochondrial that the marked steatosis in transgenic mice fed iron activity of mitochondrial of fatty remains whether the activity of mitochondrial of fatty is in chronic HCV showed that steatosis in transgenic mice fed the excess-iron diet was with decreased degradation activity of fatty acid in mitochondria and that iron and HCV mitochondrial function the mitochondrial study by G. A. P. G. A. Y. K. D. G. C. Hepatitis C virus core protein protein activity and a of 2002; PubMed Scopus Google Scholar showed that HCV core protein protein activity and a for steatosis but not of fatty The of the other HCV and iron the different expression levels of core protein in the present study for this alterations or function of mitochondria were at 6 months after the initiation of iron in but the evidence for oxidative stress or oxidative damage was not at the Hepatic lipid peroxidation and oxidative damage assessed by the hepatic levels significantly at 12 months after the initiation of iron in transgenic mice. These the of for oxidative stress or oxidative damage in the of inflammation or the this has been shown to be with increased of the to which is by iron S. S. F. the of the in PubMed Scopus Google Scholar K. H. Y. H. T. K. Y. S. T. K. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic Med. PubMed Scopus Google Scholar also showed that HCC developed in HCV core transgenic mice after the of months and showed hepatic lipid peroxidation levels in core transgenic but not in transgenic than in K. K. T. Y. H. H. T. T. K. T. K. T. S. K. Oxidative stress in the of inflammation in a for hepatitis C Res. Google Scholar Compared with hepatic lipid peroxidation and oxidative damage at an This showed the of iron overload to oxidative stress and oxidative damage in HCV transgenic mice. We also of cell in mice fed the excess-iron but was no in cell between transgenic and nontransgenic This that the of hepatic cell is but not to the development of HCC in no liver tumors developed in nontransgenic mice fed iron by 12 months after the initiation of iron this the of oxidative stress and mitochondrial injury induced by iron and HCV in the development of HCC. M. Nakamura T. G. K. R. Y. K. M. T. T. Y. of hepatic 8-hydroxy-2′-deoxyguanosine levels in chronic hepatitis C patients by and iron Res. Google Scholar that the in hepatic content by the risk of to which showed the of in the development of HCC in patients with chronic hepatitis C. the present study was but to the has been the of the transgenic mice that were to have steatosis and liver H. M. Beard M.R. K. Y. M. R. Weinman S.A. Lemon S.M. and liver in transgenic mice expressing the and of hepatitis C 2002; 122: Full Text Full Text PDF PubMed Scopus Google Scholar but this has and even with the of We have that even iron a major of transgenic mice marked by oxidative stress, mitochondrial fatty acid and This the between HCV and iron in the development of and the carcinoma (HCC) is the common hepatic and the and common malignancy in and Hepatitis and C, to and cirrhosis have been major risk of HCC remains of but in have to the and in Japan and HCV has the major of PDF

Varicocele is the most common and treatable cause of male infertility. Studies of a rat experimental left varicocele model and human testicular biopsy samples have shown the involvement of various factors in its pathophysiology. Among them, oxidative stress plays a major role in impairing spermatogenesis and sperm function. Therefore, in addition to palpation, scrotal ultrasonography and color Doppler ultrasound, evaluation of testicular oxidative stress (e.g. scrotal temperature is a surrogate parameter) is recommended to enable diagnosis and suitable treatment of varicocele. Varicocelectomy increases the fertilization, pregnancy and live birth rates, indicating improved sperm function; it is therefore important even in couples undergoing intracytoplasmic sperm injection. Routine sperm-function tests are warranted to monitor the sperm quality after varicocelectomy and consequent improvement in the outcomes of assisted reproductive technology. Furthermore, the indications of varicocelectomy in assisted reproductive technology should be widened.

BACKGROUND: The aim of this study was to elucidate the correlation between angiographic coronary vasomotor responses to intracoronary acetylcholine (ACh) injection, clinical features, and long-term prognosis in patients with vasospastic angina (VSA). METHODS AND RESULTS: This is a retrospective, observational, single-center study of 1877 consecutive patients who underwent ACh-provocation test between January 1991 and December 2010. ACh-provoked coronary spasm was observed in 873 of 1637 patients included in the present analysis. ACh-positive patients were more likely to be older male smokers with dyslipidemia, to have a family history of ischemic heart disease, and to have a comorbidity of coronary epicardial stenosis than were ACh-negative patients. ACh-positive patients were divided into 2 groups: those with focal (total or subtotal obstruction, n=511) and those with diffuse (severe diffuse vasoconstriction, n=362) spasm patterns. Multivariable logistic regression analysis identified female sex and low comorbidity of coronary epicardial stenosis to correlate with the ACh-provoked diffuse spasm pattern in patients with VSA. Kaplan-Meier survival curve indicated better 5-year survival rates free from major adverse cardiovascular events in patients with diffuse spasm pattern compared with those with focal spasm pattern (P=0.019). Multivariable Cox hazard regression analysis identified diffuse spasm pattern as a negative predictor of major adverse cardiovascular events in patients with VSA. CONCLUSIONS: ACh-induced diffuse coronary spasm was frequently observed in female VSA patients free of severe coronary epicardial stenosis and was associated with better prognosis than focal spasm. These results suggest the need to identify the ACh-provoked coronary spasm subtypes in patients with VSA.

INTRODUCTION: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is characterized by features other than increased pulmonary vascular permeability. Pulmonary vascular permeability combined with increased extravascular lung water content has been considered a quantitative diagnostic criterion of ALI/ARDS. This prospective, multi-institutional, observational study aimed to clarify the clinical pathophysiological features of ALI/ARDS and establish its quantitative diagnostic criteria. METHODS: The extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI) were measured using the transpulmonary thermodilution method in 266 patients with PaO2/FiO2 ratio ≤ 300 mmHg and bilateral infiltration on chest radiography, in 23 ICUs of academic tertiary referral hospitals. Pulmonary edema was defined as EVLWI ≥ 10 ml/kg. Three experts retrospectively determined the pathophysiological features of respiratory insufficiency by considering the patients' history, clinical presentation, chest computed tomography and radiography, echocardiography, EVLWI and brain natriuretic peptide level, and the time course of all preceding findings under systemic and respiratory therapy. RESULTS: Patients were divided into the following three categories on the basis of the pathophysiological diagnostic differentiation of respiratory insufficiency: ALI/ARDS, cardiogenic edema, and pleural effusion with atelectasis, which were noted in 207 patients, 26 patients, and 33 patients, respectively. EVLWI was greater in ALI/ARDS and cardiogenic edema patients than in patients with pleural effusion with atelectasis (18.5 ± 6.8, 14.4 ± 4.0, and 8.3 ± 2.1, respectively; P < 0.01). PVPI was higher in ALI/ARDS patients than in cardiogenic edema or pleural effusion with atelectasis patients (3.2 ± 1.4, 2.0 ± 0.8, and 1.6 ± 0.5; P < 0.01). In ALI/ARDS patients, EVLWI increased with increasing pulmonary vascular permeability (r = 0.729, P < 0.01) and was weakly correlated with intrathoracic blood volume (r = 0.236, P < 0.01). EVLWI was weakly correlated with the PaO2/FiO2 ratio in the ALI/ARDS and cardiogenic edema patients. A PVPI value of 2.6 to 2.85 provided a definitive diagnosis of ALI/ARDS (specificity, 0.90 to 0.95), and a value < 1.7 ruled out an ALI/ARDS diagnosis (specificity, 0.95). CONCLUSION: PVPI may be a useful quantitative diagnostic tool for ARDS in patients with hypoxemic respiratory failure and radiographic infiltrates. TRIAL REGISTRATION: UMIN-CTR ID UMIN000003627.

To investigate the possible role of the superoxide radical and its scavenging system in the human endometrium, the immunohistochemical distribution of superoxide dismutase (SOD), activities of SOD and lipid peroxide concentrations were studied in the human endometrium throughout the menstrual cycle and in early pregnancy. The endometrial epithelium showed a positive immunostaining for Cu, Zn-SOD and Mn-SOD throughout the entire menstrual cycle and in early pregnancy. In the stroma, weak immunostaining for Cu,Zn-SOD and moderate immunostaining for Mn-SOD were observed in the predecidual cells in the late secretory phase. Decidual cells in early pregnancy showed strong immunostaining for Cu,Zn-SOD and Mn-SOD. Total SOD activity in the endometrium increased from early proliferative phase to mid-late proliferative phase and further increased in the mid-secretory phase, and decreased in the late secretory phase. The total SOD activity in the endometrium of of early pregnancy was the same level as that in the mid-secretory phase. Cu,Zn-SOD and Mn-SOD activities changed in a similar manner to total SOD activity throughout the menstrual cycle and in early pregnancy. Lipid peroxide concentration in the endometrium increased from early proliferative phase to mid-late proliferative phase and further increased in the late secretory phase. However, lipid peroxide concentration in the endometrium of early pregnancy was the same as that in the mid-secretory phase. These results suggested that the superoxide radical and its scavenging system may play an important role in the regulation of human endometrial function.

Although mild therapeutic hypothermia is an effective neuroprotective strategy for cardiac arrest/resuscitated patients, and asphyxic newborns, recent randomized controlled trials (RCTs) have equally shown good neurological outcome between targeted temperature management at 33 °C versus 36 °C, and have not shown consistent benefits in patients with traumatic brain injury (TBI). We aimed to determine the effect of therapeutic hypothermia, while avoiding some limitations of earlier studies, which included patient selection based on Glasgow coma scale (GCS), delayed initiation of cooling, short duration of cooling, inter-center variation in patient care, and relatively rapid rewarming. We conducted a multicenter RCT in patients with severe TBI (GCS 4-8). Patients were randomly assigned (2:1 allocation ratio) to either therapeutic hypothermia (32-34 °C, n = 98) or fever control (35.5-37 °C, n = 50). Patients with therapeutic hypothermia were cooled as soon as possible for ≥ 72 h and rewarmed at a rate of <1 °C/day. All patients received tight hemodynamic monitoring under intensive neurological care. The Glasgow Outcome Scale was assessed at 6 months by physicians who were blinded to the treatment allocation. The overall rates of poor neurological outcomes were 53% and 48% in the therapeutic hypothermia and fever control groups, respectively. There were no significant differences in the likelihood of poor neurological outcome (relative risk [RR] 1.24, 95% confidence interval [CI] 0.62-2.48, p = 0.597) or mortality (RR 1.82, 95% CI 0.82-4.03, p = 0.180) between the two groups. We concluded that tight hemodynamic management and slow rewarming, together with prolonged therapeutic hypothermia (32-34 °C) for severe TBI, did not improve the neurological outcomes or risk of mortality compared with strict temperature control (35.5-37 °C).