Search

Background Patients with Fontan circulation may develop heart failure resulting in atrial fibrillation during the late phase. Inotropic effects to ameliorate hemodynamics on the Fontan circulation are not well understood, especially when in atrial fibrillation. This study was performed to determine whether dobutamine therapy in patients with Fontan circulation has limited effects on improving hemodynamics. Methods Lumped computational models (sinus and atrial fibrillation) were employed including biventricular, atriopulmonary connection (APC), and extracardiac total cavopulmonary connection (TCPC) Fontan models. The condition of atrial fibrillation including lack of atrial beat, irregular ventricular contraction, and time-varying elastance for the ventricle was introduced. A different dose of dobutamine was given by varying the elastance of the ventricle, heart rate, and peripheral resistance. Results In all models, the cardiac output decreased by 22.5% to 25.8% in atrial fibrillation. At 10 μg/kg/min of dobutamine in sinus rhythm, the cardiac output increased by 32.3% in the biventricular model but by only 9.2% (p Conclusions In the Fontan circulation, atrial fibrillation itself reduced the cardiac output by approximately 25%, and dobutamine had a limited effect on increasing the cardiac output, especially when in atrial fibrillation. Maintaining sinus rhythm in patients with Fontan circulation is very important.

OBJECTIVE Tailored surgery to extensively resect epileptogenic lesions using intraoperative electrocorticography (ioECoG) may improve seizure outcomes. However, resection of large areas is associated with decreased memory function postoperatively. The authors assessed whether ioECoG could provide useful information on how to minimize the focus resection and obtain better seizure outcomes without memory deterioration. They examined the postoperative seizure-free period and memory alteration in a retrospective cohort of patients with mesial temporal lobe epilepsy (TLE) due to hippocampal sclerosis (HS) in whom the extent of removal was determined using ioECoG findings. METHODS The authors enrolled 82 patients with TLE associated with HS who were treated surgically. Transsylvian amygdalohippocampectomy was indicated as the first step. When visual inspection identified interictal epileptic discharges from the lateral temporal lobe on ioECoG, anterior temporal lobectomy (ATL) was eventually performed. The patients were divided into the selective amygdalohippocampectomy (SA, n = 40) and ATL (n = 42) groups. Postoperative seizure outcomes were assessed at 1, 2, 3, 5, and 7 years postoperatively using the International League Against Epilepsy classification. The Kaplan-Meier survival analysis was applied to evaluate the period of seizure recurrence between the SA and ATL groups. Factors attributed to seizure recurrence were analyzed using the Cox proportional hazards model, and they were as follows: epileptic focal laterality; age at seizure onset (< 10 or ≥ 10 years old); seizure frequency (more than weekly or less than weekly seizures); history of focal to bilateral tonic-clonic seizure; infectious etiology; and surgical procedure. The Wechsler Memory Scale–Revised was used to evaluate memory function pre- and postoperatively. RESULTS Seizure outcomes were significantly worse in the SA group than in the ATL group at 2 years postoperatively (p = 0.045). The International League Against Epilepsy class 1 outcomes at 7 years postoperatively in the SA and ATL groups were 63% and 81%, respectively. Kaplan-Meier analysis showed that seizure recurred significantly earlier in the SA group than in the ATL group (p = 0.031). The 2-way ANOVA analysis was used to compare the SA and ATL groups in each memory category, and revealed that there was no significant difference regardless of the side of surgery. CONCLUSIONS Visual assessment of ioECoG cannot be used as an indicator to minimize epileptic focus resection in patients with TLE associated with HS. ATL is more effective in obtaining seizure-free outcomes; however, both ATL and SA can preserve memory function.

Purpose The removal of the bottom of sulcus dysplasia (BOSD) often includes the gyral crown; however, this method has been controversial. We hypothesized that the epileptogenic zone of the BOSD does not include the gyral crown. To reveal the depth and extent of the epileptogenic zone of the BOSD, we applied the two electrophysiological modalities: (1) the occurrence rate (OR) of high-frequency oscillations (HFOs) and (2) modulation index (MI), reflecting the strength of phase-amplitude coupling between HFOs and slow oscillations. Methods We investigated the ripples [80-200 Hz] and fast ripples [200-300 Hz]) in HFOs and MI (HFOs [80-300 Hz] and slow oscillations [3-4 Hz]). We opened the sulcus at the BOSD and implanted the subdural electrodes directly over the MRI visible lesion. All patients (n = 3) underwent lesionectomy and the gyral crown was preserved. Results Pathological findings demonstrated focal cortical dysplasia type IIb and seizure freedom was achieved. The OR of the HFOs was not significantly different between the BOSD and the gyral crown. In contrast, the MI between HFOs and slow oscillations in the BOSD was significantly higher than that in the gyral crown. Conclusion High MI values distinguished the epileptogenic BOSD from the non-epileptogenic gyral crowns. MI could be a more informative biomarker of epileptogenicity than the OR of HFOs in a subset of patients with the BOSD.

Background Individuals with Sturge-Weber syndrome (SWS) often expereince intractable epilepsy and cognitive decline. We hypothesized that the extent of the leptomeningeal capillary malformation (LCM) may correlate with the severity of neurological impairment due to SWS. We tested the hypothesis in a cross-sectional study of seizure severity and electroencephalographic (EEG) findings and a retrospective cohort study for surgical indications related to the extent of the LCM. Methods We enrolled 112 patients and classified them according to LCM distribution: (1) bilateral, (2) hemispheric, (3) multilobar, and (4) single lobe. Age at seizure onset, seizure semiology and frequency, and EEG findings were compared. Surgical indications were evaluated for each group by Fisher exact test, and predictors for surgery were evaluated by univariate and multivariate analyses. Therapeutic efficacy was evaluated by the SWS-Neurological Score (SWS-NS). Results The bilateral and hemispheric groups had early seizure onset (4.0 months old and 3.0 months old), frequent seizures (88.9% and 80.6% had more than one per month), focal-to-bilateral tonic-clonic seizures (88.9% and 74.2%), and status epilepticus (100% and 87.1%). The groups’ EEG findings did not differ substantially. Surgical indications were present in 77.8% of the bilateral, 88.1% of the hemispheric, and 46.8% of the multilobar groups. Seizure more than once per month was a predictor of surgical treatment. Seizure subscore improved postoperatively in the hemispheric and multilobar groups. Even after surgical treatment, the bilateral and hemispheric groups exhibited higher SWS-NSs than members of the other groups. Conclusion Our study demonstrated a strong association between extensive LCM and epilepsy severity. Surgical intervention improved seizure outcome in patients with SWS with large LCMs.

Background: Previous reports have documented ground-glass opacities (GGOs), followed by appearance of the crazy pavement pattern and consolidation as the typical findings on chest computed tomography (CT) in patients with Coronavirus Disease-2019 (COVID-19) Case: A 69-year-old man with chronic renal failure and diabetes mellitus presented with a 2-day history of fever and fatigue, without cough or sputum production Chest auscultation revealed coarse crackles at the right base Laboratory findings included a normal leukocyte count, normal serum procalcitonin level, and a slightly elevated serum C-reactive protein level Chest CT performed on day 2 after symptom onset revealed consolidation in the right lower lobe with an air bronchogram The patient was tentatively diagnosed as having bacterial pneumonia, however, antibiotic treatment with ampicillin/sulbactam yielded no improvement of the symptoms, respiratory status, or laboratory findings A repeat chest CT revealed changes in the findings of the right lower lobe from areas of focal consolidation to GGOs GGOs and areas of consolidation were also detected in the other lung lobes A polymerase chain reaction test for Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) returned a positive result Discussion: Focal areas of lung consolidation is an atypical radiological presentation of coronavirus pneumonia It is possible that the initial findings of CT represented those of bacterial pneumonia which responded to the antibiotic therapy, and that the GGOs that developed subsequently reflected new-onset SARS-CoV-2 pneumonia However, the symptom of fatigue without cough or sputum, a normal leukocyte count, and a poor response to antibiotics are not typical findings of bacterial pneumonia Our experience suggests that it is important to consider other or concomitant diseases when the initial treatment is followed by a deteriorating clinical course in patients with pneumonia Moreover, it is essential to prevent the spread of hospital-acquired infection, especially if epidemic diseases need to be included in the initial differential diagnosis

Late relapse of herpes simplex encephalitis (HSE) is defined as the recurrence of HSE more than 3 months after the initial exposure. The postoperative diagnosis of HSE following neurosurgery is complicated because the clinical presentation can mimic other common complications of neurosurgery. Cerebrospinal fluid polymerase chain reactions (CSF-PCR) is the gold standard for the diagnosis of HSE. We describe a case of late HSE relapse after epilepsy surgery in a patient who required a brain biopsy due to repeated negative CSF-PCR results. A 38-year-old woman had a history of HSE from the age of 3 years. She had intractable epilepsy from the age of 20 years and underwent right posterior quadrant disconnection (PQD) at the age of 38 years. Postoperatively, she had a right hemispheric intracerebral hemorrhage (ICH) and her consciousness was gradually worsening. Her consciousness improved after removal of the ICH. However, her consciousness gradually deteriorated again. Fluid-attenuated inversion recovery (FLAIR) revealed bilateral hyperintensity in the frontal lobes, including the white matter. CSF-PCR for herpes simplex virus (HSV) was performed twice, but yielded negative results. We performed a brain biopsy to target FLAIR hyperintensity in the right frontal lobe. PCR of the brain specimen was positive for HSV. Her consciousness improved with acyclovir, methylprednisolone, and cyclophosphamide. To our knowledge, this is a case of HSE induced by epilepsy surgery which had the longest duration until relapse after the initial HSE episode. A brain biopsy can be used to confirm the diagnosis of suspected HSE when CSF-PCR results are negative.

Objectives: The usefulness of serial procalcitonin (PCT) measurements for predicting the prognosis and treatment efficacy for hospitalised community-acquired pneumonia (CAP) patients was investigated. Methods: This prospective, multicentre, cohort study enrolled consecutive CAP patients who were hospitalised at 10 hospitals in western Japan from September 2013 to September 2016. PCT and C-reactive protein (CRP) were measured on admission (PCT D1 and CRP D1), within 48–72 h after admission (PCT D3 and CRP D3), and within 144–192 h after admission. CURB-65 and the Pneumonia Severity Index (PSI) were assessed on admission. The primary outcome was 30-day mortality; secondary outcomes were early and late treatment failure rates. Results: A total of 710 patients were included. The 30-day mortality rate was 3.1%. On multivariate analysis, only PCT D3/D1 ratio >1 [odds ratio (95% confidence interval): 4.33 (1.46–12.82),P = 0.008] and PSI [odds ratio (95% confidence interval): 2.32 (1.07–5.03), P = 0.03] were significant prognostic factors. Regarding treatment efficacy, PCT D3/D1 >1 was a significant predictor of early treatment failure on multivariate analysis. PCT D3/D1 with the PSI significantly improved the prognostic accuracy over that of the PSI alone. Conclusions: PCT should be measured consecutively, not only on admission, to predict the prognosis and treatment efficacy in CAP. Keywords: Biomarker, C-reactive protein, Pneumonia, Procalcitonin, Prognosis

BACKGROUND AND DESIGN: The coronavirus disease (COVID-19) pandemic is having a devastating effect worldwide. Host genome differences between populations may influence the severity of COVID-19. The Japan COVID-19 Task Force is conducting host genome analysis of hospitalized patients with COVID-19 from more than 70 institutions nationwide in Japan. This report describes the clinical characteristics of patients enrolled to date. RESULTS: The median (interquartile range) age of the 1674 patients included in the analysis was 59 (45-71) years, and more than half of the patients (66.2%) were male. Less than half of the patients (41.2%) had severe disease. The case fatality rate was 3.2%. CONCLUSIONS: Since this is a hospital-based study, the number of severe cases was relatively high, but the case fatality rate was relatively low, when compared to that of other countries. In the future, we will continue to enroll patients and conduct genome analyses of patients with COVID-19.

The mechanism of epileptic spasms (ES) in Aicardi syndrome (AS) remains obscure. We compared intraoperative high-frequency oscillations (HFOs) and phase-amplitude coupling (PAC) before and after subtotal hemispherotomy in a 3-month-old girl with drug-resistant ES secondary to AS. Fetal ultrasonography showing corpus callosum agenesis, bilateral ventricular dilatation, and a large choroid plexus cyst confirmed AS diagnosis. Her ES started when she was 1 month old and had ten series of clustered ES per day despite phenobarbital and vitamin B6 treatment. After subtotal hemispherotomy, her ES dramatically improved. We analyzed two intraoperative electrocorticography modalities: (1), occurrence rate (OR) of HFOs; (2), PAC of HFOs and slow wave bands in the frontal, central, and parietal areas. We hypothesized that HFOs and PAC could be the biomarkers for efficacy of subtotal hemispherotomy in AS with ES. PAC in all three areas and OR of HFOs in the frontal and parietal areas significantly decreased, while OR of HFOs in the central area remained unchanged after subtotal hemispherotomy. We have demonstrated the usefulness of evaluating intraoperative HFOs and PAC to assess subtotal hemispherotomy effectiveness in AS patients with ES. Disconnecting the thalamocortical and subcortical pathways in the epileptic network plays a role in controlling ES generation.

Amyloid-β (Aβ) plays a central role in the pathogenesis of Alzheimer’s disease (AD). Because AD pathologies begin two decades before the onset of dementia, prevention of Aβ amyloidosis has been proposed as a mean to block the pathological cascade. Here, we generate a transgenic plant-based vaccine, a soybean storage protein containing Aβ4–10, named Aβ+, for oral Aβ immunization. One mg of Aβ+ or control protein (Aβ–) was administered to TgCRND8 mice once a week from 9 weeks up to 58 weeks. Aβ+ immunization raised both anti-Aβ antibodies and cellular immune responses. Spatial learning decline was prevented in the Aβ+ immunized group in an extended reference memory version of Morris water maze test from 21 to 57 weeks. In Tris-buffered saline (TBS), sodium dodecyl sulfate (SDS), and formic acid (FA) serial extractions, all sets of Aβ species from Aβ monomer, low to high molecular weight Aβ oligomers, and Aβ smears had different solubility in TgCRND8 brains. Aβ oligomers decreased in TBS fractions, corresponding to an increase in high molecular weight Aβ oligomers in SDS extracts and Aβ smears in FA fraction of the Aβ+ treated group. There was significant inhibition of histological Aβ burden, especially in diffuse plaques, and suppression of microglial inflammation. Processing of amyloid-β protein precursor was not different between Aβ+ and Aβ– groups. No evidence of amyloid-related inflammatory angiopathy was observed. Thus, Aβ+ oral immunization could be a promising, cheap, and long-term safe disease-modifying therapy to prevent the pathological process in AD.

Background Electroconvulsive therapy (ECT) is indicated for critical psychiatric conditions, which themselves constitute a risk for deep venous thrombosis (DVT) owing to prolonged immobility, dehydration, and venous stasis. Objective We describe challenging instances of ECT implementation while taking direct oral anticoagulants (DOACs). Method We report on 8 patients receiving DOACs for DVT who were successfully treated with ECT at the University of Yamanashi Hospital. We also provide a literature review on this topic. Results There were 6 female patients (the average age was 60.9+/-13.4 y.o.) and diagnoses included major depression, bipolar depression and schizophrenia. DOACs were edoxaban for 4 patients, rivaroxaban for 2, and apixaban for 2. A total of 92 ECT sessions were cautiously and safely completed in collaboration with multidisciplinary medical professionals without problematic adverse events, such as bleeding. A literature search found one case series of warfarin but currently available evidence is confined to sporadic case reports regarding ECT and DOACs for DVT. These reports were represented by successful implementation of ECT to patients receiving treatment with anticoagulants for DVT or thromboembolism. Ours is the first of a successful treatment with ECT while taking apixaban or edoxaban. Conclusion A clinical dilemma is that ECT is indicated for critical conditions that are likely to predispose patients to developing DVT. Paucity of data clearly highlights the need for more studies to support a contention that ECT, when carefully performed in consultation with other medical experts, is a viable treatment for those with DVT receiving oral anticoagulants.

To elucidate the host genetic loci affecting severity of SARS-CoV-2 infection, or Coronavirus disease 2019 (COVID-19), is an emerging issue in the face of the current devastating pandemic. Here, we report a genome-wide association study (GWAS) of COVID-19 in a Japanese population led by the Japan COVID-19 Task Force, as one of the initial discovery GWAS studies performed on a non-European population. Enrolling a total of 2,393 cases and 3,289 controls, we not only replicated previously reported COVID-19 risk variants (e.g., LZTFL1, FOXP4, ABO, and IFNAR2), but also found a variant on 5p35 (rs60200309-A at DOCK2) that was significantly associated with severe COVID-19 in younger (-8 (odds ratio = 2.01, 95% confidence interval = 1.58-2.55). This risk allele was prevalent in East Asians, including Japanese (minor allele frequency [MAF] = 0.097), but rarely found in Europeans. Cross-population Mendelian randomization analysis made a causal inference of a number of complex human traits on COVID-19. In particular, obesity had a significant impact on severe COVID-19. The presence of the population-specific risk allele underscores the need of non-European studies of COVID-19 host genetics.

Purpose/Method: No studies have reported on prognostic markers in patients with chronic kidney disease (CKD) according to the severity of the disease. Therefore, in this multicenter, prospective trial performed as part of the Gunma CKD SPECT Multicenter Study, we recruited 311 patients with CKD (eGFR < 60 min/mL/1.73 m(2)) including 50 patients on hemodialysis and followed them for 2 years. The study sample underwent stress (99m)Tc-tetrofosmin SPECT for suspected or possible ischemic heart disease. We evaluated the summed stress score (SSS), summed rest score (SRS), summed difference score (SDS) and cardiac function with electrocardiogram-gated SPECT. Then, we compared the differences in prognostic markers for major adverse cardiac, cerebrovascular, and renal events (MACCRE) between patients with mild CKD (30 min/mL/1.73 m(2) ≤ eGFR

The effectiveness of long-term administration of tolvaptan in heart failure (HF) patients with chronic kidney disease (CKD) has not been fully studied. Hence, in this study, we investigated the effects of chronic administration of tolvaptan on patients with HF and CKD. We consecutively enrolled 31 patients with acute HF syndrome (AHFS) who were administrated tolvaptan as a long-term medication (TLV group). All patients had a history of prior HF admission and CKD. We also consecutively enrolled 27 patients with AHFS, a prior history of HF and CKD (conventional group). We compared renal function and outcomes between the two groups at discharge for AHFS and after 6 months of follow-up. The estimate glomerular filtration rate (eGFR) was maintained at approximately the same level in the TLV group exhibited approximately the same eGFR (-1.1 ± 8.3 mL/min/1.73 m2) but decreased in the conventional group (-7.4 ± 10.4 mL/min/1.73 m2). There was a significant difference in the changes observed in eGFR between the conventional and TLV groups (p = 0.01). There were no significant differences in the frequencies of rehospitalization and death. Long-term administration of tolvaptan may prevent increased renal dysfunction in HF patients with CKD. This conclusion should be confirmed in a large-scale prospective study.

Background Inhalation studies suggested "protective" roles of exogenous prostaglandin E 2 , but the clinical relevance of endogenous prostanoids in asthma is poorly known. The objective of this study is to measure sputum levels of prostanoids in asthmatic patients to correlate with clinical indices. Methods Mild ( n = 41) or moderate-to-severe (19) asthmatics and 27 normal controls were examined for pulmonary function (FEV 1 and mid-forced expiratory flow), sputum cell differentials, and sputum levels of prostaglandins D 2 , E 2 , F 2α , and thromboxane B 2 measured by sandwich enzyme immunoassay. Results Each prostanoid level did not differ among the three groups. Sputum number of bronchial epithelial cells was greater in moderate-to-severe asthmatics than in the other two groups, suggesting epithelial desquamation. Levels of prostaglandin F 2α , D 2 , and thromboxane B 2 positively correlated with the severity of airflow obstruction in the 60 asthmatic patients, whereas prostaglandin E 2 levels were unrelated to pulmonary function. The ratio of combined "contractile" prostanoids (prostaglandin D 2 /prostaglandin F 2α /thromboxane B 2 ) to prostaglandin E 2 was 2.5-fold greater in moderate-to-severe asthmatics than in controls ( p = 0.001) or in mild asthmatics ( p = 0.0002) but did not differ between the latter two groups. In the two asthmatic groups combined, this ratio positively correlated with the sputum number of epithelial cells. The combined "contractile" prostanoids levels positively correlated with prostaglandin E 2 levels in controls and in mild asthmatics but not in moderate-to-severe asthmatics. Conclusions An imbalance in production, breakdown, or both between prostaglandin E 2 and other prostanoids possibly due to epithelial damage may be involved in the pathogenesis of moderate-to-severe asthma.

Cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and tau are biomarkers for Alzheimer's disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aβ40, Aβ42, total tau, phosphorylated-tau, and α-synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer's disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aβ40 and Aβ42 were approximately 25:1. Aβ40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α-synuclein ratio was 1:65. Significantly decreased Aβ42 levels and an increased Aβ40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α-synuclein levels were increased in ADD/MCI, there was no merit in measuring α-synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aβ40/42 ratio×p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aβ40, Aβ42, p181tau, and tau were identified as biomarkers for aggregated Aβ associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases.

The right temporal lobe variant of frontotemporal dementia (FTD) is an uncommon progressive neurodegenerative disorder. We present the case of a 77-year-old right-handed man who presented with altered behaviour and problems with interpersonal relationships. He had no decline in cognitive function but brain perfusion single-photon emission CT demonstrated distinct hypoperfusion in the right temporal pole. At 2-year follow-up, he could not recognise his wife's relatives; and at 3-year follow-up, he had semantic aphasia. Decreased brain perfusion extended from the right temporal lobe into the contralateral temporal and both frontal lobes. These findings suggest that the right temporal lobe variant of FTD should be considered in elderly patients with altered behaviour and problems with interpersonal relationships, even if dementia is not suspected. The right anterior temporal lobe may play a key role in the onset of the early symptoms of this disease.

Patients with chronic kidney disease (CKD) have an increased risk of adverse cardiovascular/cerebrovascular events. The aim of this study is to clarify whether stress myocardial perfusion single-photon emission computed tomography (SPECT) could predict cardiovascular/cerebrovascular events. In the Gunma-CKD SPECT Study, a multicenter prospective cohort trial, 311 patients with CKD (estimated glomerular filtration rate < 60 min/mL/1.73 m2) including 50 patients on hemodialysis underwent stress 99mTc-tetrofosmin SPECT for suspected ischemic heart disease and were followed for 2 years. The primary endpoint was the occurrence of cardiac death (CD), while the secondary endpoint was major adverse cardiovascular/cerebrovascular and renal events (MACCRE). MACCRE occurred in 91 out of 286 patients (CD in 13 and other MACCRE in 78 patients). According to a multivariate Cox analysis, hemoglobin (Hb) and end-systolic volume (ESV) were associated with CD (p < 0.05), while the summed difference score, diabetes mellitus (DM), and Hb were associated with MACCRE (p < 0.05). Kaplan-Meier analysis showed that the CD-free rate was higher in patients with ESV < 105 mL (log-rank, p = 0.0013), Hb > 12 g (log-rank, p = 0.0036), and a summed stress score < 6 (log-rank, p = 0.0058). The MACCRE-free rate was higher in patients with SDS = 0 (log-rank, p = 0.0097), without DM (log-rank, p = 0.0091), and with Hb > 12 g (log-rank, p = 0.0023). Myocardial perfusion SPECT parameters as well as renal anemia and DM can be reliable prognostic markers in patients with CKD including hemodialysis.

Study Design Single case report. Introduction A previous study clarified that spasticity and motor function were improved by combined treatment with botulinum toxin type A (BTX) injection and 1-Hz repetitive transcranial magnetic stimulation (rTMS) with intensive motor training at 4 weeks after injection. However, it is not clear whether 1-Hz rTMS with intensive motor training immediately after BTX injection also improves spasticity and motor function in stroke patients. Purpose of the Case Report The purpose of this case report is to test the short- and long-term effects of BTX injection and rTMS with intensive motor training on the spasticity, motor function, and usefulness of the paretic hand in a stroke patient. Methods A 64-year-old male, who suffered from a right cerebral hemorrhage 53 months previously, participated in the present study. BTX was injected into the spastic muscles of the affected upper limb. He then received the new protocol for a total of 24 sessions. The Modified Ashworth Scale (MAS), Fugl-Meyer Assessment (FMA), and Motor Activity Log, consisting of the amount of use and quality of movement scales, were assessed before and immediately after BTX injection, at discharge, and monthly for up to 5 months after discharge. Results For the short-term effects of the therapy, the MAS scores of the elbow and wrist, FMA score, and quality of movement score improved. For the long-term effects of the therapy, the MAS score of the fingers, FMA score, and amount of use score improved for up to 5 months after discharge. Conclusions The present case report showed the improvement of all assessments performed in the short and/or long term and suggest the possibility of shortening the intervention period of combined therapy of BTX and rTMS with intensive motor training.

Background: Cough variant asthma (CVA) is a phenotype of asthma presenting solely with coughing, characterized by airway hyperresponsiveness, eosinophilic inflammation and a cough response to bronchodilators. Leukotriene receptor antagonists (LTRAs) are antiasthma medications with anti-inflammatory and bronchodilatory properties. Although LTRAs exert antitussive effects in CVA, the mechanisms involved are unknown. Objectives: This study aimed to clarify the antitussive mechanisms of LTRAs in CVA patients. Methods: We prospectively observed the effect of montelukast (10 mg) daily for 4 weeks in 23 consecutive nonsmoking adults with anti-inflammatory treatment-naive CVA. We evaluated, before and after treatment, the cough visual analogue scale (VAS), pulmonary function (spirometry and impulse oscillation), methacholine airway responsiveness, cough receptor sensitivity, expressed by the concentration of capsaicin inducing 2 or more (C2) and 5 or more (C5) coughs, sputum eosinophil counts and levels of inflammatory mediators, including cysteinyl leukotrienes, leukotriene B4, prostaglandin (PG) D2, PGE2, PGF2α and thromboxane B2. We compared the baseline characteristics of the patients based on the symptomatic response to montelukast, defined as a decrease in the cough VAS of >25% (n = 15) or ≤25% (n = 8). Results: Montelukast significantly decreased the cough VAS (p = 0.0008), sputum eosinophil count (p = 0.013) and cough sensitivity (C2: p = 0.007; C5: p = 0.039), whereas pulmonary function, airway responsiveness and sputum mediator levels remained unchanged. Multivariate analysis showed that a better response to montelukast was associated solely with younger age (p = 0.032). Conclusion: The antitussive effect of montelukast in CVA may be attributed to the attenuation of eosinophilic inflammation rather than its bronchodilatory properties.

Masaya Takemura1, Katsumi Mitsui2, Ryo Itotani1, Manabu Ishitoko1, Shinko Suzuki1, Masataka Matsumoto1, Kensaku Aihara1, Tsuyoshi Oguma1, Tetsuya Ueda1, Hitoshi Kagioka1, Motonari Fukui11Division of Respiratory Medicine, 2Division of Pharmacy, Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka, JapanPurpose: Adherence to inhalation therapy is a critical determinant of the success of chronic obstructive pulmonary disease (COPD) management. However, in practice, nonadherence to inhalation therapy is very common in COPD patients. The effects of adherence to inhalation therapy in COPD have not been fully studied, and less is known about the relationship between medication adherence and quality of life in COPD. Our aim is to assess the factors that contribute to adherence to inhalation therapy and examine their correlation with quality of life.Patients and methods: A cross-sectional analysis of 88 COPD patients was performed using a self-reported adherence questionnaire with responses on a 5-point Likert scale.Results: Of the 88 patients who were potential participants, 55 (63%) responded with usable information. The only significant factor associated with the overall mean adherence score was receiving repeated instruction about inhalation techniques (P = 0.032). Of the 55 respondents, 22 (40.0%) were given repeated verbal instruction and/or demonstrations of inhalation technique by a respiratory physician. Significant correlations were found between the overall mean adherence score and the health-related quality of life score (St George’s Respiratory Questionnaire: total, r = −0.35, P = 0.023; symptoms, r = −0.43, P = 0.002; impacts, r = −0.35, P = 0.011). Furthermore, patients with repeated instruction showed better quality of life scores than those who did not receive instruction (total, P = 0.030; symptoms, P = 0.038; impacts, P = 0.019).Conclusions: Repeated instruction for inhalation techniques may contribute to adherence to therapeutic regimens, which relates to better health status in COPD.Keywords: COPD, adherence, quality of life, repeated instruction

Background Sputum cell-subtype profiles in cough-variant asthma (CVA) are unknown. Methods Ninety-eight inhaled corticosteroid (ICS)-naive CVA patients were classified according to sputum eosinophil (eos)/neutrophil (neu) counts, as reported in subjects with asthma, as eosinophilic (E) (eos ≥ 1.0%, neu Results Subtype N patients, predominantly women, were marginally older than the other subtypes, but FEV 1 , airway responsiveness, and total and specific IgE results did not differ. ECP levels were higher in M and E than in N and P subtypes, being similar between M and E or N and P subtypes. Levels of IL-8 and NE were higher in M than in other subtypes, being similar among the latter. ICS doses were initially similar in all subtypes (800 μg equivalent of beclomethasone) but were higher in M than in N and P subtypes throughout follow-up, with E being intermediate between M and N or P subtypes. ICS doses decreased (halved or quartered) in E, N, and P patients followed for 24 months ( P Conclusions In addition to eosinophils, neutrophils, which are possibly activated in the presence of eosinophils, may participate in the pathophysiology of CVA.

Adherence to inhalation therapy is a critical determinant of the success of asthma management. Reasons for nonadherence have been well studied, but reasons for good adherence are poorly understood. Understanding the mechanisms of adherence to inhalation therapy is important in developing strategies to promote adherence. The objective of this study was to assess the factors and mechanisms that contribute to and the clinical outcomes relating to adherence to inhalation therapy.The factors and outcomes related to adherence to inhalation therapy were examined cross-sectionally in 176 adults with asthma using a self-reported adherence questionnaire that consisted of four items dealing with the use of inhaled controller medications. A 5-point Likert scale was used for the responses to each item. Adherence was assessed based on the overall mean adherence score.Of the 176 patients who were potential participants, 146 (83%) responded with usable information. Significant factors associated with the overall mean adherence score were older age (r = .18, p = .032) and receiving repeated instruction on inhalation techniques (p = .0016). Of the 146 respondents, 25 (17.1%) patients were given repeated verbal instruction or demonstrations of inhalation technique by a respiratory physician. On logistic regression analysis, good adherence to inhalation therapy was significantly related to the receiving of repeated instruction on inhalation technique, with an odds ratio of 2.90 (95% confidence interval 1.07-7.88; p = .037). Furthermore, less intentional nonadherent behavior was reported in patients with repeated instruction on inhalation technique compared to those without it. A significant correlation was found between the overall mean adherence score and the frequency of asthma exacerbations (r = -.19, p = .021), emergency room visits (r = -.19, p = .042), and the health-related quality of life score (St. George's Respiratory Questionnaire: Total, r = -.22, p = .024; Symptoms, r = -.21, p = .022; Impacts, r = -.20, p = .035).Repeated instruction on inhalation techniques may contribute to adherence to inhalation therapy through decreasing intentional nonadherence. Furthermore, good adherence to the therapeutic regimen may offer good asthma-related outcomes.

Sensitization to Trichophyton, a major dermatophyte, has been associated with asthma. Whether such sensitization is generally associated with the severity of asthma, like other molds such as Alternaria, is unknown.We compared 258 patients with asthma, which was classified by severity as mild (n = 123), moderate (101), or severe (34), and 114 healthy control subjects, with regard to specific IgE titers against Trichophyton rubrum and other common allergens such as mixed molds, house-dust mite, cat dander, dog dander, Japanese cedar pollen, mixed Graminea pollens and mixed weed pollens.Positive rate of Trichophyton-specific IgE was higher in the patients with moderate asthma (15.8%) than in the control subjects (7.0%, p = 0.04) and patients with mild asthma (4.9%, p0.006), and it was also higher in the patients with severe asthma (32.4%) than in control subjects (p = 0.0001), and patients with mild asthma (p0.0001) and moderate asthma (p = 0.04), but it did not differ between the control subjects and patients with mild asthma. The positive rates of mixed molds, cat dander, and dog dander were almost invariably higher in patients in all asthma subgroups than in the control subjects but did not differ among patients in the three asthma subgroups. The positive rates of other allergens were not different in all groups. Reanalysis of positive rate of Trichophyton-specific IgE after excluding 52 subjects with positive results for mixed molds showed a similar statistical trend to that of the original cohort. This may negate the potential effect of cross-reactivity to these molds. Multivariate analysis of asthma subgroups identified positive IgE results for Trichophyton as an independent determinant of asthma severity.Specific IgE response to Trichophyton may be associated with more severe asthma.

Background Cough variant asthma is a phenotype of asthma solely presenting with coughing. It involves airway inflammation and remodelling as does classic asthma with wheezing, and a subset of patients may progress to classic asthma. The atopic features of cough variant asthma remain unclear. Objective To compare atopic features between patients with cough variant asthma and those with classic asthma, and to examine the possible correlation of these features with the future development of wheezing in the former group. Methods Total and specific IgE levels of seven common aeroallergens [house dust mite (HDM), Gramineae/Japanese cedar/weed pollens, moulds, cat/dog dander] were examined in 74 cough variant asthma patients and in 115 classic asthma patients of varying severity. Forty of the former patients were prospectively observed for 2 years to determine whether cough variant asthma progressed to classic asthma despite inhaled corticosteroid treatment. Results Patients with classic asthma had higher total IgE (P

Peritoneal cytology is an important prognostic factor of gastric cancer. However, peritoneal cytology requires great skill, which may explain its low prevalence. A reverse transcriptase–polymerase chain reaction–based assay with multiple marker genes or immunocytochemistry was assessed as an alternative method of gathering the same kind of data as cytology. Peritoneal washings from 179 patients with gastric cancer were analyzed by multiplex reverse transcriptase–polymerase chain reaction with 10 marker genes and subsequent hybridization to a customized oligo-nucleotide array. Results with this assay were either validated as a prognostic factor or confirmed by demonstrating the presence of cancer cells by immunocytochemical cytology. Only 1 (2.2%) of 44 disease-free cases was shown to be positive by the microarray assay, whereas 13 (93%) of 14 conventional cytology–positive cases were found to be positive. This assay further detected approximately one-third of cytology-negative patients either with peritoneal recurrence (7 of 20, 35%) or with non-peritoneal recurrence (6 of 22, 27%). A high concordance between the microarray assay and immunocytochemical cytology with five antibodies against CK20, FABP1, MUC2, TFF1, and MASPIN was confirmed. The clinical outcome of the microarray assay–positive cases was poor, as was that of the cytology-positive cases. Our assay, though time-consuming and requiring special equipment, demonstrated a specificity and sensitivity equal to or better than cytology in our institutes. The minimal free peritoneal cancer cells detected by the microarray assay may provide the same clinical information as larger amounts of cancer cells for patients with gastric cancer. An anti-MASPIN antibody may be helpful in peritoneal cytology of gastric cancer.

Patients with chronic kidney disease (CKD) have an increased risk of adverse cardio-cerebrovascular events. We examined whether stress myocardial perfusion single photon emission computed tomography (SPECT) provides reliable prognostic markers for these patients. In this multicenter, prospective cohort trial from the Gunma-CKD SPECT study protocol, patients with CKD [estimated glomerular filtration rate (eGFR) < 60 min/ml per 1.73 m2] undergoing stress 99mTc-tetrofosmin SPECT for suspected or possible ischemic heart disease were initially followed for 1 year, with the following study endpoints: primary, the occurrence of cardiac deaths (CDs), and secondary, major adverse cardiac, cerebrovascular, and renal events (MACCREs). The summed stress score (SSS), summed rest score, and summed difference score (SDS) were estimated with the standard 17-segment, 5-point scoring model. Left ventricular end-diastolic volume, end-systolic volume (ESV), and ejection fraction were measured using electrocardiogram-gated SPECT. During the first year of follow-up, 69 of 299 patients experienced MACCREs (CD, n = 7; non-fatal myocardial infarction, n = 3; hospitalization for heart failure, n = 13; cerebrovascular accident, n = 1; need for revascularization, n = 38; and renal failure, i.e., hemodialysis initiation, n = 7). ESV and SSS were associated with CDs (p

Small airways may have an important role in asthma but are more difficult to assess pathologically than central airways. Computed tomographic indices of lung density are assumed to reflect air trapping and may be a useful noninvasive measure of small airways disease, but their pathophysiological relevance remains undetermined.To evaluate lung density on high-resolution computed tomography and examine its correlations with clinical and physiologic variables in 29 patients with stable asthma.Both lungs were scanned at full-inspiratory and full-expiratory phases to quantify percentage of lung field occupied by low attenuation area (LAA%;-960 Hounsfield units) and mean lung density. Asthma severity, pulmonary function, methacholine airway sensitivity and reactivity, and sputum eosinophil counts were evaluated.The mean lung density increased and LAA% decreased in all patients at expiratory phase compared with inspiratory phase. The inspiratory density indices and expiratory mean lung density correlated only with FEV(1)/forced vital capacity (FVC). Expiratory LAA% correlated more strongly than other variables with FEV(1)/FVC and with indices of peripheral airflow obstruction. Expiratory/inspiratory ratios of LAA% and mean lung density correlated, the former more strongly, with disease severity, residual volume/total lung capacity, and airway sensitivity, as well as with indices of global (FEV(1) and FEV(1)/FVC) and peripheral airflow obstruction.Expiratory/inspiratory high-resolution computed tomography is useful for assessing small airways disease in asthma. Small airways involvement is associated with airflow obstruction, airway hypersensitivity, and more severe disease.Small airways are an important therapeutic target in asthma.

Background: The balance between matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of metalloproteinase-1 (TIMP-1) may be critical in extracellular matrix remodelling, a characteristic of asthmatic airways. An excess of TIMP-1 over MMP-9 has been associated with chronic airflow obstruction but the mechanisms underlying this association remain unknown. Recent computed tomographic (CT) studies indicate that airway wall thickening is associated with chronic airflow obstruction. Methods: Sputum levels of MMP-9, TIMP-1, and their molar ratio were examined in 26 patients with stable asthma and their relationship with pulmonary function and airway wall thickness, assessed by a validated CT technique which measured wall area corrected by body surface area (WA/BSA), the ratio of WA to outer wall area (WA%), and the absolute wall thickness corrected by √BSA of a segmental bronchus (T/√BSA), was examined. Results: Sputum MMP-9 levels were inversely correlated with WA% and TIMP-1 levels were positively correlated with WA/BSA and T/√BSA. The MMP-9/TIMP-1 molar ratio was inversely correlated with WA% and T/√BSA and positively correlated with post-bronchodilator values of mid-forced expiratory flow and maximum expiratory flow at the quartile of lung volume. Conclusion: Excess TIMP-1 may have a pathogenetic role in airway wall thickening in asthmatic patients which may result in chronic airflow obstruction.

BACKGROUND (18)F-fluorodeoxyglucose (FDG) positron-emission tomography (PET) is assumed to be the most useful method of evaluating the viability of the myocardium, but its use is limited by the need for a cyclotron. In the present study, the ability of a combination of (99m)Tc-tetrofosmin (TF) and (123)I-beta-methyliodophenyl pentadecanoic acid (BMIPP) single-photon emission computed tomography (SPECT), a combination of (18)F-FDG PET and (123)I-BMIPP SPECT, and a combination of (18)F-FDG PET and (99m)Tc-TF SPECT were compared to predict functional improvement of ischemic myocardium after a large acute myocardial infarction (AMI). METHODS AND RESULTS Ten patients with large AMI were studied by (99m)Tc-TF SPECT, (123)I-BMIPP SPECT and (18)F-FDG PET within 3 weeks. Six months later, (99m)Tc-TF imaging was performed. All patients underwent successful revascularization, and had no restenosis. Regional tracer uptake was scored using a 4-point scale in 20 segments of the SPECT and PET images. When the defect score of (123)I-BMIPP SPECT exceeded the defect score of (99m)Tc-TF SPECT or (18)F-FDG PET by 1 point or more, and when the defect score of (99m)Tc-TF SPECT exceeded the defect score of (18)F-FDG PET by 1 point or more, the segment was considered to show mismatching. When the defect score was the same in 2 tracers, the segment was considered to show matching. (99m)Tc-TF imaging at 3 weeks and 6 months used quantitative gated SPECT (QGS) to score wall motion using a 6-point scale (-1= dyskinesis, 0= akinesis, 1= severe hypokinesis, 2= moderate hypokinesis, 3= mild hypokinesis, and 4= normokinesis). The sensitivity of the combination of (123)I-BMIPP and (99m)Tc-TF imaging in predicting functional improvement was 61%, that of (18)F-FDG PET and (123)I-BMIPP SPECT was 94%, and that of (18)F-FDG PET and (99m)Tc-TF SPECT was 76%. The specificity of the combination of (123)I-BMIPP and (99m)Tc-TF imaging in predicting functional improvement was 83%, that of (18)F-FDG PET and (123)I-BMIPP SPECT was 40%, and that of (18)F-FDG PET and (99m)Tc-TF SPECT was 49%. The accuracy of the combination of (123)I-BMIPP and (99m)Tc-TF imaging in predicting functional improvement was 70%, that of (18)F-FDG PET and (123)I-BMIPP SPECT was 71%, and that of (18)F-FDG PET and (99m)Tc-TF SPECT was 63%. CONCLUSION The combination of (123)I-BMIPP and (99m)Tc-TF imaging is a practical modality for predicting the functional improvement of ischemic myocardium after a large AMI.

Fibrates, including bezafibrate (BF), upregulate the expression of ATP binding cassette protein B4 (ABCB4) through gene transcription in mice. To determine the effects of BF on the expression levels of ABCB4 and on the stimulation of biliary phosphatidylcholine (PC) transport in human HepG2 hepatoblastoma cells, mRNA and protein levels as well as subcellular localization were investigated in the cells treated with BF. The canalicular accumulation of a fluorescent PC was assessed by confocal laser scanning microscopy. Treatment with 300 micromol/l BF for 24 h increased levels of ABCB4 mRNA but not protein by up to 151%. BF caused redistribution of ABCB4 into pseudocanaliculi formed between cells. In association with this redistribution, BF accelerated the accumulation of fluorescent PC in bile canaliculi (up to 163% of that in nontreated cells). Suppression of peroxisome proliferator-activated receptor alpha (PPARalpha) expression by either a small interfering RNA duplex or morpholino antisense oligonucleotide attenuated the BF-induced redistribution of ABCB4. These findings suggest that BF may enhance the capacity of human hepatocytes to direct PC into bile canaliculi via PPARalpha-mediated redistribution of ABCB4 to the canalicular membrane. This provides a rationale for the use of BF to improve cholestasis and/or cholangitis that is attributable to hypofunction of ABCB4.

Background Investigations using high-resolution CT (HRCT) show that bronchial dilatation (BD) is found in many patients with asthma. However, the pathogenesis and pathophysiologic relevance of BD in asthma are poorly understood. A balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may control the remodeling of extracellular matrix, and excess MMPs have been associated with destruction or dilatation of airways in patients with bronchiectasis. Objectives To study the prevalence of BD as assessed by HRCT according to standard subjective criteria in 37 patients with stable asthma and 10 healthy control subjects, and to examine the relation of BD in asthmatic patients to clinical characteristics and sputum indices, including MMP-9 and TIMP-1 levels. Design A prospective cohort study. Results At least one dilated bronchus was present in 23 asthmatic subjects (62%) and 2 control subjects (20%) [p = 0.030]. The ratio of dilated bronchi to all eligible bronchi in each subject (individual BD%) was higher in the asthmatic patients than in the control subjects (11.4 ± 16.1% vs 1.3 ± 3.0%, p=0.011) [mean ± SD]. Asthmatic patients with (n = 23) and those without BD (n = 14) were similar with regard to age, duration and severity of asthma, atopy, pulmonary function, sputum eosinophil or neutrophil count, and sputum levels of MMP-9 or TIMP-1 and their molar ratio. Individual BD% of asthmatic patients was also unrelated to these clinical and sputum variables. When analysis was confined to the 23 patients with BD, however, individual BD% correlated with the severity score of asthma ( r = 0.49, p=0.023). The results of follow-up HRCT obtained from 19 patients suggested that BD was a fixed rather than transient phenomenon. Conclusion BD is more prevalent in asthmatic patients than in normal subjects and might be associated with the severity of asthma. Cellular inflammation or possible imbalance between MMP-9 and TIMP-1 was not demonstrated in this study to be related to BD in asthma.

Purpose and Experimental Design: Little is known about the molecular events leading to the development and progression of pathological tumor stage 2 (pT2) gallbladder carcinoma. An alteration in the site of O-glycosylation may be associated with malignant behavior of carcinoma cells by modulation of the biological properties of the target mucin. The UDP-N-acetyl-α-d-galactosamine-polypeptide N-acetylgalactosaminyltransferase isozyme 3 (GalNAc-T3) has the epithelial gland-specific expression and catalyzes mucin-type O-glycosylation. In this study, immunohistochemistry was performed to determine the expression level of GalNAc-T3 in 34 cases of pT2 gallbladder carcinoma to determine the correlation of the GalNAc-T3 expression level with mode of recurrence and postsurgical survival. Results: The expression levels of GalNAc-T3 protein and mRNA were increased in gallbladder carcinomas compared with the levels in adjacent noncancerous tissues and in intact gallbladders. Immunostaining of GalNAc-T3 was recognized in the cancerous epithelia, and the subcellular localization was classified into granular and diffuse types. In the 34 cases of pT2 carcinoma, the localization of GalNAc-T3 was granular type in 50% and diffuse type in 50% of the cases at the deepest invading sites in the subserosal layer. Postsurgical recurrence was significantly more frequent in cases showing diffuse-type localization of GalNAc-T3 at the deepest invading sites (65%) than in those showing granular-type localization (23%; P < 0.05). Postsurgical survival was significantly poorer in cases showing diffuse-type localization than in those showing granular-type localization (P = 0.033) Conclusions: In pT2 gallbladder carcinoma, the presence of diffuse-type localization of GalNAc-T3 in the subserosal layer is correlated with aggressiveness of the disease. This phenotype may serve as a unique biological feature associated with the malignant behavior.

Background & Aims: In hepatolithiasis, chronic proliferative cholangitis may influence the progression of the disease. Prostaglandin (PG) E 2 experimentally causes morphologic changes to intrahepatic bile ducts, analogous to the changes found in cholangitis. This study was designed to gain an understanding of the involvement of PGE 2 and PGE receptor (EP) subtypes in the development of cholangitis. Methods: The expression levels of secretory-type group IIA phospholipase A 2 (sPLA 2 -IIA) and cyclooxygenase (COX)-2 as well as EP subtypes were determined in the bile ducts with change of cholangitis. In in vitro experiments, growth promotion and mucin secretagogue properties of biliary epithelial cells in response to EP-selective agonists or antagonists were studied. Results: The messenger RNA (mRNA) level of sPLA 2 -IIA and the protein and mRNA levels of COX-2 were significantly increased in the bile ducts of patients with hepatolithiasis compared with the levels of the bile ducts of control subjects. These changes were associated with a concomitant increase in PGE 2 and total mucin concentrations in the bile. The mRNAs of EP subtypes EP 2 , EP 3 , and EP 4 but not EP 1 were amplified in the bile ducts. Treatment with an EP 4 -selective agonist (ONO-AE1-329) caused a dose-dependent increase in DNA synthesis, colony number, and mucin secretion in the cells. Conversely, treatment with an EP 4 -selective antagonist (ONO-AE3-208) abolished the biological effects of PGE 2 on the cells. Conclusions: In hepatolithiasis, an enhanced synthesis of sPLA 2 -/COX-2-derived PGE 2 and its actions mediated via the EP 4 receptor in the bile ducts may be of pathobiological significance for chronic proliferative cholangitis.

Postsurgical recurrence at distant sites frequently occurs in pathological tumor stage 2 (pT(2)) carcinoma of the gallbladder even though the carcinoma is limited to the gallbladder wall. Little is known, however, about the molecular events leading to its development and progression. A large body of evidence suggests that cyclooxygenase-2 (COX-2) is up-regulated in carcinoma tissues and plays roles in promoting cell-proliferation, growth and metastasis of carcinoma cells. In the present study, immunohistochemistry was performed to determine the expression levels of COX-2 in the subserosal layer of 33 cases of pT(2) gallbladder carcinoma in which curative resections had been performed and to determine the correlations of the expression levels of COX-2 with mode of recurrence and postsurgical survival. Immunostaining of COX-2 in the epithelia was recognized in more than 80% of normal epithelia, noncancerous pathological lesions of the gallbladder except for intestinal metaplasia and pT(1-4) carcinoma specimens. Intense staining was observed in large percentages of hyperplastic lesions (65%), pT(2) carcinoma specimens (76%) and pT(3) and pT(4) carcinoma specimens (64%) compared to the percentages of normal epithelia and other pathological lesions (0-25%). Intense staining was also observed in the adjacent stroma in pT(2) carcinoma specimens (33%) and in those in pT(3) and pT(4) carcinoma specimens (43%) but only in small percentages of the stroma adjacent to normal epithelia and pathological lesions (0-8%). In situ hybridization confirmed the existence of COX-2 mRNA in both the cancerous epithelia and adjacent stroma of pT(2)-pT(4) carcinomas. In 33 cases of pT(2) carcinoma, distant recurrence, i.e., liver metastasis, was seen in 3 of 9 cases of pT(2) carcinoma (33%, P0.05) with intense stromal staining in the subserosal layer and in 1 of 24 cases (4%) without intense staining, whereas no significant correlation was found between parameters of pathological malignancies (histological grade, lymphatic permeation, venous permeation and lymph node metastasis) and the intensity of stromal staining in the subserosal layer. The postsurgical survival outcome was significantly poorer in the former than in the latter (p = 0.010). In pT(2) gallbladder carcinoma, upregulation of COX-2 in the stroma adjacent to the cancerous epithelia in the subserosal layer correlates with the aggressiveness of the disease, such as the tendency to form distant recurrences. This phenotype may serve as a unique biological feature associated with the malignant behavior of pT(2) gallbladder carcinoma.

The molecular mechanism of gallbladder carcinogenesis and cancer growth remains unknown. BK5.erbB2 transgenic mice in which erbB2 is overexpressed and activated in the biliary epithelia develop adenocarcinoma of the gallbladder at a high incidence. Although it has been reported that erbB2 plays an important role in tumorigenesis, little is known about the involvement of its ligand(s). The expression level of Muc4, a potential functional ligand for erbB2, and its interaction with erbB2 in the gallbladder of BK5.erbB2 mice were determined. By immunohistochemistry and in situ hybridization, both Muc4 mRNA and protein levels were strongly expressed in the cancerous epithelia of gallbladder from BK5.erbB2 mice. Also, in the hyperplastic (precancerous) epithelia, the protein levels were modestly expressed. Immunostaining with Muc4 (ASGP2) Ab overlapped with that with erbB2 Ab in the apical membranous components of the cancerous epithelia, indicating the co-localization of Muc4 and erbB2. Immunoprecipitation experiments revealed an interaction between Muc4 and erbB2 in the gallbladders. The interaction was associated with the hyperphosphorylation of erbB2, MAPK and Akt, and also with the overexpression of cyclooxygenase-2. However, in other organs that overexpressed erbB2 (trachea, esophagus and forestomach), Muc4 was expressed in only trace or modest amounts, and erbB2 was not hyperphosphorylated. Collectively, Muc4 is upregulated and interacts with erbB2 in gallbladders from BK5.erbB2 mice. It is likely that Muc4 plays an important role during gallbladder carcinogenesis and/or cancer growth by potentiating erbB2 signaling.

Background Dyspnea on exertion (DOE) is a major symptom of chronic obstructive pulmonary disease (COPD) and is difficult to control. This study was performed to determine whether acupuncture is superior to placebo needling in improving DOE in patients with COPD who are receiving standard medication. Methods Sixty-eight of 111 patients from the Kansai region of Japan who were diagnosed as having COPD and were receiving standard medication participated in a randomized, parallel-group, placebo-controlled trial (July 1, 2006, through March 31, 2009) in which the patients, evaluators, and statistician were unaware of the random allocation. Participants were randomly assigned to traditional acupuncture (real acupuncture group, n = 34) or placebo needling (placebo acupuncture group, n = 34). Both groups received real or placebo needling at the same acupoints once a week for 12 weeks. The primary end point was the modified Borg scale score evaluated immediately after the 6-minute walk test. Measurements were obtained at baseline and after 12 weeks of treatment. Result After 12 weeks, the Borg scale score after the 6-minute walk test was significantly better in the real acupuncture group compared with the placebo acupuncture group (mean [SD] difference from baseline by analysis of covariance, −3.6 [1.9] vs 0.4 [1.2]; mean difference between groups by analysis of covariance, −3.58; 95% CI, −4.27 to −2.90). Patients with COPD who received real acupuncture also experienced improvement in the 6-minute walk distance during exercise, indicating better exercise tolerance and reduced DOE. Conclusion This study clearly demonstrates that acupuncture is a useful adjunctive therapy in reducing DOE in patients with COPD. Trial Registration umin.ac.jp/ctr Identifier: UMIN000001277

Mucus hypersecretion is an important pathophysiologic index of airway disease. Measurement of secreted mucin in sputum has been reported in asthma, but not in chronic cough with or without increased sputum production.We studied 49 patients with classic asthma (CA), 39 with cough-variant asthma (CVA), nine and five with chronic cough associated with sinobronchial syndrome (SBS) and gastroesophageal reflux disease (GERD), respectively, and 11 healthy controls. Seventeen patients with CA, but none from the other groups, were taking antiinflammatory medications. Mucin levels in induced sputum supernatants were measured by enzyme-linked immunosorbent assay, which detects airway mucin, probably including MUC5AC and MUC5B.Mucin levels were higher in patients with CA (674.2 +/- 548.8 microg/mL) and SBS (638.4 +/- 650.7 microg/mL) than in controls (212.0 +/- 167.1 microg/mL) (P = .0037 and .044). They were also higher in patients with CA than in those with CVA (350.4 +/- 374.0 microg/mL) and GERD (134.3 +/- 93.1 microg/mL) (P = .0016 and 0.015), but results did not differ between the latter groups and controls. When the four disease groups were combined, patients with frequent sputum production had greater mucin levels than those with occasional (P = .0023) or no sputum production (P.0001). Patients with CA showed negative correlations of mucin levels with respiratory resistance indices on impulse oscillation and with airway sensitivity to methacholine.Sputum mucin levels differ in various respiratory conditions when compared with controls, primarily reflecting the degree of sputum production. Airway mucin might possibly exert protective effects in asthma, at least between exacerbations, but this issue needs to be further clarified by future studies.

Summary Background Analyses of microRNA expression profiles have shown that many microRNAs are expressed aberrantly and correlate with tumorigenesis, progression, and prognosis of various haematological and solid tumours. We aimed to assess the relation between microRNA expression and progression and prognosis of gastric cancer. Methods 353 gastric samples from two independent subsets of patients from Japan were analysed by microRNA microarray. MicroRNA expression patterns were compared between non-tumour mucosa and cancer samples, graded by diffuse and intestinal histological types and by progression-related factors (eg, depth of invasion, metastasis, and stage). Disease outcome was calculated by multivariable regression analysis to establish whether microRNAs are independent prognostic factors. Findings In 160 paired samples of non-tumour mucosa and cancer, 22 microRNAs were upregulated and 13 were downregulated in gastric cancer; 292 (83%) samples were distinguished correctly by this signature. The two histological subtypes of gastric cancer showed different microRNA signatures: eight microRNAs were upregulated in diffuse-type and four in intestinal-type cancer. In the progression-related signature, miR-125b, miR-199a, and miR-100 were the most important microRNAs involved. Low expression of let-7g (hazard ratio 2·6 [95% CI 1·3–4·9]) and miR-433 (2·1 [1·1–3·9]) and high expression of miR-214 (2·4 [1·2–4·5]) were associated with unfavourable outcome in overall survival independent of clinical covariates, including depth of invasion, lymph-node metastasis, and stage. Interpretation MicroRNAs are expressed differentially in gastric cancers, and histological subtypes are characterised by specific microRNA signatures. Unique microRNAs are associated with progression and prognosis of gastric cancer. Funding National Cancer Institute.

Oxidative stress is a critical mediator in liver injury of steatohepatitis. The transcription factor Nrf2 serves as a cellular stress sensor and is a key regulator for induction of hepatic detoxification and antioxidative stress systems. The involvement of Nrf2 in defense against the development of steatohepatitis remains unknown. We aimed to investigate the protective roles of Nrf2 in nutritional steatohepatitis using wild-type (WT) and Nrf2 gene-null ( Nrf2-null) mice. WT and Nrf2-null mice were fed a methionine- and choline-deficient (MCD) diet for 3 and 6 wk, and the liver tissues were analyzed for pathology and for expression levels of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. In WT mice fed an MCD diet, Nrf2 was potently activated in the livers, and steatohepatitis did not develop over the observation periods. However, in Nrf2-null mice fed an MCD diet, the pathological state of the steatohepatitis was aggravated in terms of fatty changes, inflammation, fibrosis, and iron accumulation. In the livers of the Nrf2-null mice, oxidative stress was significantly increased compared with that of WT mice based on the increased levels of 4-hydroxy-2-nonenal and malondialdehyde. This change was associated with the decreased levels of glutathione, detoxifying enzymes, catalase, and superoxide dismutase activity. Correlating well with the liver pathology, the mRNA levels of factors involved in fatty acid metabolism, inflammatory cytokines, and fibrogenesis-related genes were significantly increased in the livers of the Nrf2-null mice. These findings demonstrate that Nrf2 deletion in mice leads to rapid onset and progression of nutritional steatohepatitis induced by an MCD diet. Activation of Nrf2 could be a promising target toward developing new options for prevention and treatment of steatohepatitis.

Background Small airways appear to have an important role in asthma. Hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) has ultrafine particles and accordingly greater deposition in the small airways than chlorofluorocarbon (CFC)-BDP. Impulse oscillometry systems (IOS), a new and non-invasive measure of pulmonary function, can examine the resistance of total (R5), large (R20), and small airways (R5–R20) separately, and low-frequency reactance area (AX), also considered a measure of small airways dysfunction. Methods Mild-to-moderate asthmatics who were inhaled corticosteroid naive were randomized to receive 200 mcg HFA-BDP bid (n = 26) or 400 mcg CFC-BDP bid (n = 12) for 12 weeks in an open-label manner. Following baseline measurements, IOS and spirometry were repeated every 4 weeks, and methacholine challenge to separately assess airway sensitivity and airway reactivity and lung volumes at 12 weeks. Results Moderate correlations were found between R5–R20 or AX and spirometry and lung volume indices of small airways, and between R20 and peak expiratory flow at baseline. The two groups did not significantly differ in baseline clinical or functional parameters. At 12 weeks, all IOS indices improved in the HFA-BDP group, whereas all but R5–R20 improved with CFC-BDP. R5–R20 and AX progressively improved with HFA-BDP; these changes achieved statistical significance at 12 weeks versus the CFC-BDP group. Other IOS and spirometry indices failed to show such trends. HFA-BDP significantly attenuated methacholine airway sensitivity; the degree of this attenuation strongly correlated with R5–R20 and AX baseline values, and with improvement of AX with treatment. Conclusion HFA-BDP is an effective treatment of small airways in asthma. Prolonged treatment provides a progressive effect over time, which is associated with an attenuation of airway responsiveness.

The predictive value of combined 123iodine-labelled 15-( p-iodophenyl)-3 R,S-methyl pentadecanoic acid imaging (123I-BMIPP) and early technetium-99m (99mTc)-tetrofosmin imaging was compared with combined 123I-BMIPP and delayed 99mTc-tetrofosmin or 123I-BMIPP and thallium-201 (201Tl) imaging for functional outcome of stunned myocardium after acute myocardial infarction (AMI) in 37 patients with AMI. All patients underwent successful percutaneous coronary intervention with/without stenting within 24 h of symptoms. Resting 201Tl, 99mTc-tetrofosmin and 123I-BMIPP imaging were performed within 10 days of hospital admission; 99mTc-tetrofosmin imaging was also performed 6 months later. Segments were mismatched when the 123I-BMIPP score was greater than the 99mTc-tetrofosmin or 201Tl scores, and were matched when all scores were the same. Left ventricular function was estimated using wall motion score. Sensitivity and regional wall motion were significantly better in mismatching 99mTc-tetrofosmin-early/123I-BMIPP segments than mismatching 201Tl/123I-BMIPP or 99mTc-tetrofosmin-delayed/123I-BMIPP segments. It is concluded that mismatching of 123I-BMIPP and early 99mTc-tetrofosmin uptake can predict improvement in wall motion of stunned myocardium better than the other two imaging combinations.

Targeting cytotoxins or immunotoxins to tumor cell surface receptors represents a new approach for the treatment of cancers. We tested the antitumor activity of a cytotoxin (IL-4-PE) composed of an interleukin-4 (IL-4) targeting moiety and a truncated form of Pseudomonas exotoxin A against human biliary tract carcinoma (BTC). Immunohistochemical analysis showed that cultured BTC cell lines and cancerous epithelia in BTC tissue (e.g., gallbladder carcinoma, extrahepatic cholangiocarcinoma, and intrahepatic cholangiocarcinoma) expressed receptors for IL-4 in situ at high densities. However, normal epithelial cells in gallbladder and bile duct tissues did not express these IL-4 receptors. Eight BTC cell lines expressed IL-4R on the cell surface as determined by radiolabeled ligand binding assays. When these cells were treated with IL-4-PE, significant cytotoxicity was observed as determined by the inhibition of protein synthesis. The concentration of agent causing 50% inhibition of protein synthesis (IC(50)) was found to be less than 10 ng/mL in 4 of the 8 BTC cell lines studied. The antitumor activity of IL-4-PE was assessed for human BTC cells implanted subcutaneously in immunodeficient mice. By intratumoral injection of IL-4-PE, complete disappearance of the established tumors was observed in 40% of animals. Intraperitoneal administration of IL-4-PE at tolerated doses to animals with peritoneally disseminated BTC exhibited significantly prolonged survival compared to untreated animals (>14 weeks vs. 5 weeks in treated and untreated mice, respectively). These results indicate that IL-4 receptor-targeted cytotoxin is a potent agent that may provide a new therapeutic option for BTC.

In the progression of repetitive balloon inflations during percutaneous transluminal coronary angioplasty (PTCA), the heart becomes more tolerant to ischemia. The study reported here analyzed the effects of theophylline and nicorandil on this intriguing phenomenon. Twenty-one patients with stable angina pectoris due to a significant stenosis at the left anterior descending; artery were subjected to PTCA. The balloon was inflated twice for two minutes each with a three-minute reperfusion period. Theophyylline, an adenosine receptor antagonist, was intravenously administered (0.6mg/kg/hr) to six patients during PTCA (theophylline group). Nicorandil, a hybrid between nitrate and an ATP-sensitive potassium channel opener, was intravenously administered (6 mg/hr) to nine patients during PTCA (nicorandil group). The rest of the patients served as controls (ischemic preconditioning group, n = 6). Cardiac adaptation to the second ischemia was observed in the ischemic preconditioning group, judging from lactate metabolism and electrocardiography. In both the theophylline and nicorandil groups, the difference between the two ischemic events was abolished. In the nicorandil group, the severity of the first ischemia was less than that of the ischemic preconditioning group. In conclusion, signal transduction through the adenosine receptor and opening of the ATP-sensitive potassium channels might play key roles, interactively or independently, in the cardioprotection observed in the process of PTCA.

Background TGF-β1 can modulate airway inflammation and exaggerate airway remodeling. A polymorphism of a promoter region of TGFB1 , C-509T, might be associated with the development of asthma, but its pathophysiologic relevance remains poorly understood. Objective We investigated relations of the C-509T polymorphism to airflow obstruction, sputum eosinophilia, and airway wall thickening, as assessed by means of computed tomography, in 85 patients with stable asthma. Methods The CC, CT, and TT genotypes were examined by means of PCR and restriction enzyme fragment length polymorphism. At a selected bronchus, 3 indices of airway wall thickness were measured with an automatic method. Results The CC, CT, and TT genotypes were found in 22, 46, and 17 patients, respectively. Serum TGF-β1 levels were significantly associated with the polymorphism and were increased in the CT/TT genotypes. FEV 1 and sputum eosinophil percentages were also significantly associated with the polymorphism and were both decreased in the CT/TT genotypes. The polymorphism was unrelated to airway wall thickness. Conclusion In addition to increased serum TGF-β1 levels, the T allele of the C-509T polymorphism is related to increased airflow obstruction but attenuated eosinophilic inflammation. The former relation is not attributed to thickening of the central airway walls. The latter relation might reflect the anti-inflammatory effect of TGF-β1. The C-509T polymorphism has a complex role in asthma pathophysiology, presumably because of the diverse functions of TGF-β1 and its various interactions with cells and humoral factors in vivo .

Patients with cough variant asthma, a common cause of chronic cough, may develop wheezing. We examined the determinants of this phenomenon and achievement of remission in 42 patients. During 4 years after diagnosis, wheezing developed in 13 of the patients. Early inhaled corticosteroid treatment was inhibitory against the development of wheezing by univariate analysis and by multivariate analysis with an odds ratio of 0.12 (95% confidence interval, 0.02 to 0.87, p = 0.037). Remission was achieved in 7 patients, who were younger than those without remission by univariate analysis (p = 0.048). Early treatment with inhaled corticosteroid may prevent the progression of cough variant asthma to classic asthma.

This study was designed to examine whether theophylline, an adenosine receptor antagonist, affects cardiac adaptation to ischemia during progression of repetitive balloon inflations of percutaneous transluminal coronary angioplasty (PTCA). Theophylline abolished this cardiac adaptation, suggesting that endogenous adenosine is a key mediator for cardiac adaptation during PTCA.