[Proton-pump inhibitor use and hyponatremia].

AIM: Proton-pump inhibitors (PPIs) are widely used. However, reports of their adverse effects are increasing. Older patients are prone to developing hyponatremia due to various factors. The special environment of a geriatric healthcare facility tends to subject these patients to long-term medication use. Therefore, we hypothesized that nursing home residents receiving PPIs will present hyponatremia. METHODS: The residents of Shonan Silver Garden, a long-term care health facility for older adults, were divided into two groups: a control group (n=61) which did not receive proton-pump inhibitors and a PPI group (n=29), which received proton-pump inhibitors for at least 6 months. The PPI group was further divided into the lansoprazole group (LPZ group) and the other PPI group. Other PPI users were excluded due to small numbers. The blood test results were compared between the control and LPZ groups. In the LPZ group, blood samples were taken 1 month after the discontinuation of lansoprazole, and serum Na level was compared to the level before discontinuation. RESULTS: Blood Na levels in the PPI were lower than those in the control group, and hyponatremia (<136 mEq/L) was more frequent in the LPZ group than in the control group. There were no significant differences in other blood test parameters between the control and LPZ groups. At one month after the discontinuation of lansoprazole, serum Na levels were significantly increased; however, they remained lower than those in the control group. CONCLUSION: A higher rate of hyponatremia was induced in older residents of long-term care facilities who took lansoprazole for >6 months in comparison to those who did not take lansoprazole.

Diminished responsiveness to dobutamine as an inotrope in mice with cecal ligation and puncture-induced sepsis: attribution to phosphodiesterase 4 upregulation.

Dobutamine has been used in septic shock for many years as an only inotrope, but its benefit has been questioned. We weighed the effects of dobutamine and milrinone as inotropes in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. CLP-induced septic mice exhibited significant cardiac inflammation, as indicated by greatly increased mRNAs of proinflammatory cytokines and robust infiltration of inflammatory cells in the ventricular myocardium. Elevations of plasma cardiac troponin-I showed cardiac injury in CLP mice. Noninvasive echocardiographic assessment of cardiac function revealed that despite preserved left ventricular function in the presence of fluid replacement, the dobutamine inotropic response was significantly impaired in CLP mice compared with sham-operated controls. By contrast, milrinone exerted inotropic effects in sham-operated and CLP mice in an equally effective manner. Surface expression levels of ß1-adrenoceptors and α-subunits of three main G protein families in the myocardium were unaffected by CLP-induced sepsis. Plasma cAMP levels were significantly elevated in both sham-operated and CLP mice in response to milrinone but only in sham-operated controls in response to dobutamine. Of phosphodiesterase (PDE) isoforms, PDE4D, but not PDE3A, both of which are responsible for cardiac cAMP hydrolysis, was significantly upregulated in CLP mouse myocardium. We define a novel mechanism for the impaired responsiveness to dobutamine as an inotrope in sepsis, and understanding the role of PDE4D in modulating cardiac functional responsiveness in sepsis may open the potential of a PDE4D-targeted therapeutic option in septic patients with low cardiac output who have a need for inotropic support.NEW & NOTEWORTHY Advisability of the usefulness of dobutamine in septic shock management is limited. Here, we reveal that the effect of dobutamine as a positive inotrope is impaired in mice with cecal ligation and puncture-induced sepsis without changes in cardiac ß1-adrenoceptor signaling as a result of cAMP breakdown achieved by upregulated phosphodiesterase 4D.

[Early Results of Complex Fractionated Atrial Electrogram Mapping Guided Atrial Fibrillation Surgery].

OBJECTIVE: Although the Cox-maze operation is the standard surgical procedure for permanent atrial fibrillation(AF), conversion to sinus rhythm is limited by patient characteristics, including the duration of AF, atrial size, and voltage of fibrillation waves. A surgical strategy based on structural alteration of the electrical substrates of AF is required to achieve better outcomes of AF surgery. Complex fractionated atrial electrogram (CFAE) plays an important role in the electrical substrate of AF. We performed AF surgery guided by preoperative CFAE mapping using a 3-dimensional (3D) mapping system. This study evaluated the early results of our procedure. METHODS: From January 2015 to August 2016, 8 patients (mean age:66.5±6.4 years) underwent CFAE mapping-guided AF surgery. In the preoperative electrophysiological study using 3D mapping, CFAE was defined by a low voltage electrogram (0.05~0.25 mV) with a highly fractionated potential (short cycle length <120 msec). First, right atrial CFAE sites were ablated by using a catheter ablation system. Several days after right-sided CFAE ablation, a modified Cox-maze operation was performed with additional cryoablation of CFAE sites. RESULTS: There were 1~3 (mean:2.5 ±0.8) CFAE sites in the right atrium and 2~4 (mean:2.4±0.7) sites in the left atrium. Mean CFAE mapping time was 87.6±24.6 minutes, fluoroscopy time was 53.1±22.2 minutes, and volume of contrast agent was 44±3 ml. Concomitant cardiac surgery included mitral valve plasty in 6 patients, and aortic valve replacement and mitral valve replacement in 1 patient each. The mean time for CFAE mapping-guided AF surgery was 25.7±5.6 minutes. At discharge, 7 patients were in sinus rhythm and 1 patient still had AF, but sinus rhythm recovered at 3 months postoperatively without anti-arrhythmic medication. After a mean follow-up of 11.7±8.5 months, all patients remained in sinus rhythm. CONCLUSIONS: Early results suggest that CFAE mapping-guided atrial fibrillation surgery is feasible and effective. Although the long-term effect of CFAE ablation on maintenance of sinus rhythm and atrial function should be evaluated, this novel method could provide an alternative strategy for the surgical treatment of AF.

Current topics in surgery for multiple ventricular septal defects.

In this review article, we describe several topics, including the sandwich technique, the transatrial re-endocardialization technique, the limited apical left ventriculotomy approach and device closure. The sandwich technique was introduced for the closure of muscular ventricular septal defects (VSD) by sandwiching the septum between two felt patches placed in the left and right ventricle. This technique requires neither the transection of muscular trabeculae nor ventriculotomy. Although the sandwich technique has resulted in the improvement of surgical outcomes, cases of postoperative cardiac dysfunction have been reported. Multiple smaller VSDs have been closed with transatrial re-endocardialization. Septal dysfunction may be avoided through this technique, in which the septal trabeculae are approximated in two layers of superficial, endocardial running sutures. Recently, a number of reports have recommended a limited apical left ventriculotomy approach. With this technique, a much shorter incision of around 1 cm at the apex of the left ventricle may be sufficient for achieving the complete closure of apical muscular VSDs. The transcatheter or perventricular device closure of muscular VSDs has increasingly been performed with good results. Although favorable early and mid-term results of device closure have been reported, this method is not always safer or less invasive than surgical closure. Long-term evaluations should be performed to determine whether the right and left ventricular functions are affected by treatment with relatively large devices in the heart.

Independent component analysis of hyperspectral data measured from overlapping latent fingermarks: Forensic potential of independent component images.

Overlapping fingermark images are sometimes discarded because fingermark collation for the individual fingermarks is difficult. Fluorescence hyperspectral data (HSD) measured using the models of double overlapping fingermarks obtained under the excitation of a high-power, continuous wave, green laser is suitable for obtaining individual fingermark images. However, there are limitations such as the problems on each spectrum of the individual fingermark and the forensic value of the obtained images. In this study, independent component analysis (ICA) was applied to the fluorescence HSD obtained from the models of doubly overlapping fingermarks, to obtain independent component (IC) spectra and the corresponding IC images. Forensic value of the obtained IC images was examined, considering the possibility of fingermark collation in masked fashion to the model sample information. The IC images obtained from the HSD had enough potential to enable extracting twelve minutiae required for fingermark collation if the image quality was good.

Comprehensive circulating microRNA profile as a supersensitive biomarker for early-stage lung cancer screening.

PURPOSE:  Less-invasive early diagnosis of lung cancer is essential for improving patient survival rates. The purpose of this study is to demonstrate that serum comprehensive miRNA profile is high sensitive biomarker to early-stage lung cancer in direct comparison to the conventional blood biomarker using next-generation sequencing (NGS) technology combined with automated machine learning (AutoML). METHODS: We first evaluated the reproducibility of our measurement system using Pearson's correlation coefficients between samples derived from a single pooled RNA sample. To generate comprehensive miRNA profile, we performed NGS analysis of miRNAs in 262 serum samples. Among the discovery set (57 patients with lung cancer and 57 healthy controls), 1123 miRNA-based diagnostic models for lung cancer detection were constructed and screened using AutoML technology. The diagnostic faculty of the best performance model was evaluated by inspecting the validation samples (74 patients with lung cancer and 74 healthy controls). RESULTS: The Pearson's correlation coefficients between samples derived from the pooled RNA sample ≥ 0.98. In the validation analysis, the best model showed a high AUC score (0.98) and a high sensitivity for early stage lung cancer (85.7%, n = 28). Furthermore, in comparison to carcinoembryonic antigen (CEA), a conventional blood biomarker for adenocarcinoma, the miRNA-based model showed higher sensitivity for early-stage lung adenocarcinoma (CEA, 27.8%, n = 18; miRNA-based model, 77.8%, n = 18). CONCLUSION: The miRNA-based diagnostic model showed a high sensitivity for lung cancer, including early-stage disease. Our study provides the experimental evidence that serum comprehensive miRNA profile can be a highly sensitive blood biomarker for early-stage lung cancer.

Aortic valve replacement in a patient with self-reported systemic multiple metal allergy.

We report our experience with aortic valve replacement in a patient with severe aortic stenosis who had self-reported allergies to multiple metals. The patient was a 74-year-old man. He developed palmoplantar pustulosis after using a dental prosthesis, and a patch test revealed reactions to several metals; therefore, he was diagnosed with systemic metal allergy. His condition progressed to severe aortic stenosis, and bioprosthetic aortic valve replacement was planned. The Avalus valve (Medtronic, Minneapolis, MN, USA) was selected for aortic valve replacement, since the patient reported having allergies to several metals. While most devices used in cardiac surgery contain some amount of metal, the Avalus bioprosthetic valve does not contain metal in the stent and has been extremely useful for aortic valve replacement in patients with suspected metal allergies.

[Septic cardiomyopathy: pathophysiology and potential new therapeutic approaches].

Sepsis is the leading cause of death in critically ill patients, and its incidence continues to rise. Sepsis was defined as a systemic inflammatory response syndrome with an identifiable focus of infection, but therapeutic strategies aimed at eliminating the inflammatory response have only modest clinical benefit. The development of a failure of one or more organs poses a major threat to the survival of patients with sepsis, and mortality in sepsis is most often attributed to multiple organ dysfunction. Accordingly, sepsis has been recently redefined as life-threatening organ dysfunction due to a dysregulated host response to infection. Cardiac dysfunction is a well-recognized important component of septic multiple organ failure and can compromise the balance between oxygen supply and demand, ultimately leading to the development of multiple organ failure. The existence of cardiac dysfunction in sepsis is associated with much higher mortality when compared with septic patients without heart problems. Dobutamine, a ß1-selective adrenoceptor agonist, has been used in septic shock for many years as an only inotrope, but limited clinical outcome measures have been provided as to advisability of the usefulness of dobutamine in septic shock management. Here we provide an overview on the possible mechanisms underlying intrinsic myocardial depression during sepsis and discuss the perspective of several inotropes for sepsis-associated cardiac dysfunction.

Cardioprotective and functional effects of levosimendan and milrinone in mice with cecal ligation and puncture-induced sepsis.

Levosimendan and milrinone may be used in place of dobutamine to increase cardiac output in septic patients with a low cardiac output due to impaired cardiac function. The effects of the two inotropic agents on cardiac inflammation and left ventricular (LV) performance were examined in mice with cecal ligation and puncture (CLP)-induced sepsis. CLP mice displayed significant cardiac inflammation, as indicated by highly increased pro-inflammatory cytokines and neutrophil infiltration in myocardial tissues. When continuously given, levosimendan prevented but milrinone exaggerated cardiac inflammation, but they significantly reduced the elevations in plasma cardiac troponin-I and heart-type fatty acid-binding protein, clinical markers of cardiac injury. Echocardiographic assessment of cardiac function showed that the effect of levosimendan, given by an intravenous bolus injection, on LV performance was impaired in CLP mice, whereas milrinone produced inotropic responses equally in sham-operated and CLP mice. A lesser effect of levosimendan on LV performance after CLP was also found in spontaneously beating Langendorff-perfused hearts. In ventricular myocytes isolated from control and CLP mice, levosimendan, but not milrinone, caused a large increase in the L-type calcium current. This study represents that levosimendan and milrinone have cardioprotective properties but provide different advantages and drawbacks to cardiac inflammation/dysfunction in sepsis.

Imatinib provides durable molecular and cytogenetic responses in a practical setting for both newly diagnosed and previously treated chronic myelogenous leukemia: a study in nagasaki prefecture, Japan.

To evaluate the efficacy of imatinib in a practical setting, we registered 43 patients with newly diagnosed chronic myelogenous leukemia (CML) (group I) and 56 patients with previously diagnosed CML (group II) at 11 hematology centers in Nagasaki prefecture, Japan, from December 2001 to July 2005 and analyzed the molecular responses. Cytopenia, fluid retention, and skin rash were major adverse events, along with elevation in creatine phosphokinase levels. With a follow-up of approximately 3.5 years, imatinib treatment led to 88.7% overall survival (OS) and 85.2% progression-free survival (PFS) rates for group I, and 79.8% OS and 76.6% PFS rates for group II; the rates were not significantly different despite a lower average imatinib dose in group II. The rates of complete cytogenetic response at 30 months and major molecular response at 24 months were 86.1% and 62.5%, respectively, in group I, and 77.9% and 58.3% in group II; the rates were not significantly different. As has been reported by other groups, these results demonstrate that imatinib treatment can provide excellent clinical and molecular effects for not only newly diagnosed but also previously treated CML patients in practical settings that cover a wider variety of patients than clinical trials.

Chemokine expression in human erythroid leukemia cell line AS-E2: macrophage inflammatory protein-3alpha/CCL20 is induced by inflammatory cytokines.

OBJECTIVE: Normal and malignant hematopoietic cells are shown to express and secrete various cytokines and chemokines, some of which are believed to play an important role in normal and abnormal hematopoiesis in an autocrine/paracrine manner. To explore the possibility of a cytokine/chemokine network participating in the pathophysiology of anemic disorders, we evaluated the ability of inflammatory cytokines to induce chemokine expression using erythroid progenitor cells. METHODS: Erythropoietin-dependent human leukemia cell line AS-E2 was used as a model of erythroid colony-forming unit (CFU-E) cells. The expression of mRNA of 8 chemokines was examined using RT-PCR, before and after TNF-alpha, IFN-gamma, and IL-1beta stimulation. For MIP-3alpha, the promoter activity was analyzed by luciferase assay and secretion was confirmed by ELISA. The expression of CCR6, the specific receptor for MIP-3alpha, was analyzed by RT-PCR and flow cytometry. RESULTS: Unstimulated AS-E2 cells constitutively expressed transcripts for MCP-4, IP-10, PF-4, IL-8, and MIP-3alpha. Stimulation with TNF-alpha, IFN-gamma, and IL-1beta upregulated MIP-3alpha mRNA expression and induced its protein secretion. Luciferase assay revealed that these cytokines could upregulate promoter activity of the MIP-3alpha gene, possibly through the NF-kappaB pathway. CCR6 mRNA was detected and its intracellular expression was confirmed. CONCLUSION: These data suggest that inflammatory cytokine-stimulated erythroid progenitors secrete MIP-3alpha, which may function in an autocrine/paracrine manner. Furthermore, the existence of intracellular CCR6 suggests the involvement in cytokine signaling of a MIP-3alpha-dependent internal autocrine mechanism. These mechanisms may play a role in pathophysiology of anemic disorders, such as secondary anemia and bone marrow failure syndromes.

Common neural processing regions for dynamic and static stereopsis in human parieto-occipital cortices.

We performed functional magnetic resonance imaging to identify the neural processing regions in the parieto-occipital cortices for human dynamic and static stereopsis. The subjects were ten ophthalmologists professionally trained to do microscopic surgery. Visual stimuli for dynamic or static stereopsis were performed with solid stereograms displayed in the image guides of a binocular visual stimulation device that we developed. The dorsal occipital portion and the superior parietal lobule (i.e. dorsal parieto-occipital portion) were activated not only in static stereopsis, but also in dynamic stereopsis. The activation showed a right hemispherical dominancy. On the other hand, the temporo-occipital junction (i.e. human MT (middle temporal area) / MST (medial superior temporal area) complex) was activated in dynamic stereopsis. This demonstrates that the dorsal parieto-occipital portion is a common neural processing region for dynamic and static stereopsis.

Long-term efficacy of imatinib in a practical setting is correlated with imatinib trough concentration that is influenced by body size: a report by the Nagasaki CML Study Group.

Imatinib has dramatically improved long-term survival of chronic myelogenous leukemia (CML) patients. To analyze its efficacy in a practical setting, we registered most of CML patients in Nagasaki Prefecture of Japan. Of these, 73 patients received imatinib as an initial therapy. The overall survival rate of these patients was 88.7% at 6 years, and the cumulative complete cytogenetic response rate was 82.5% at 18 months. These results are comparable with the data of other reports including the IRIS study; however, the administered imatinib dose was smaller in our study than that in other reports. To address these discrepancies, we measured the trough concentration of imatinib among 35 patients. Although 39% of the patients were administered less than 400 mg/day, the trough level was comparable to those of previous reports. The trough level of imatinib showed a significant relationship with its efficacy, and was clearly related to dose of imatinib administrated and dose of imatinib divided by body surface area (BSA). Considering the smaller BSA of Japanese patients as compared to those of foreign origin, the results suggest that a lower dose of imatinib could maintain enough trough level and provided excellent results for the treatment of CML in our registry.

Difference in clinical features between Japanese and German patients with refractory anemia in myelodysplastic syndromes.

Several reports indicate that there might be differences in clinical features between Asian and Western myelodysplastic syndrome (MDS) cases. We analyzed refractory anemia (RA) in French-American-British (FAB) classification cases diagnosed in Japan and Germany to perform a more exact comparison between Asian and Western MDS types. In the first step, we analyzed agreement of morphologic diagnosis between Japanese and German hematologists. Blood and bone marrow slides of 129 patients diagnosed with FAB-RA, FAB-RA with ringed sideroblasts (RARS), or aplastic anemia were selected randomly and evaluated separately by each group. The agreements of diagnoses according to FAB and World Health Organization (WHO) classifications were 98.4% and 83.8%, respectively. Second, we compared clinical features between 131 Japanese and 597 German patients with FAB-RA. Japanese patients were significantly younger than German patients. Japanese patients had more severe cytopenias. However, prognosis of Japanese patients was significantly more favorable than that of German patients. Japanese patients had a significantly lower cumulative risk of acute leukemia evolution than did German patients. Frequency of WHO-RA in Japanese patients with FAB-RA was significantly higher than that in German patients. In conclusion, our results indicate that the clinical features of Japanese patients with FAB-RA differ from those of German patients.