The impact of micronutrient deficiency on pregnancy complications and development origin of health and disease.

Due to the spread of the western style diet, which is characterized by high intake of processed food, micronutrients (vitamins and minerals) deficiency is increasing in the Japanese population of all ages and genders. During pregnancy, the elevated demand for micronutrients put pregnant women at even higher risk of micronutrients deficiency. Some micronutrients are relatively famous such that women with reproductive age are recommended to take folic acid supplementation for the prevention of neural tube defect. However, it is not generally known that folate is also important for fetal growth throughout the pregnancy course and for prevention of pregnancy complications, and that pregnant women should continue to take supplementation during pregnancy and lactation. The types of micronutrients and the duration of supplementation are both important factors to maintain normal pregnancies. This review focused on four micronutrients that are commonly deficient in Japanese pregnant women, folate, vitamin B12, vitamin D, calcium, and magnesium. The detrimental effects of homocysteine accumulation associated with the above micronutrient defects and its link to catechol-o-methyltransferase insufficiency are described. We also discussed possible molecular mechanisms of pregnancy complications and the development origin of health and disease (DOHaD) regarding micronutrient deficiencies from the point of view of one carbon metabolism.

Characteristics of labor-onset hypertension persist after neuraxial labor analgesia.

AIM: This study aimed to investigate the rate of labor-onset hypertension (LOH) under neuraxial labor analgesia and the effect of neuraxial labor analgesia on LOH. METHODS: A retrospective study was conducted in a tertiary university hospital from 2015 to 2016. Patients who were admitted to the hospital for vaginal delivery under combined spinal and epidural anesthesia were selected. LOH was defined as the elevation of systolic blood pressure (BP) to ≥140 mmHg or diastolic BP to ≥90 mmHg for the first time after the onset of labor. Cases of LOH that persisted after neuraxial labor analgesia (prolonged LOH) were further analyzed to determine the hypertension severity and therapeutic intervention rate. RESULTS: Among 775 patients, 213 (28.4%) developed LOH. Prolonged LOH was observed in 30 patients (3.9%). LOH severity and the likelihood of prolonged LOH were positively correlated. Therapeutic intervention was administered only to the patients with prolonged LOH, that is, to 100% of those with emergent hypertension, to 21.1% of those with severe hypertension during labor, and to 36.8% of those with severe hypertension, to 55.6% of those with mild hypertension in the post-partum period. CONCLUSION: The rate of LOH was reduced significantly after neuraxial labor analgesia. Patients with prolonged LOH should be carefully followed up during labor and in the post-partum period because such patients often require antihypertensive therapy.

Deficiency in Dipeptidyl Peptidase-4 Promotes Chemoresistance through the CXCL12/CXCR4/mTOR/TGFß Signaling Pathway in Breast Cancer Cells.

Dipeptidyl peptidase (DPP)-4, a molecular target of DPP-4 inhibitors, which are type 2 diabetes drugs, is expressed in a variety of cell types, tissues and organs. DPP-4 has been shown to be involved in cancer biology, and we have recently shown that a DPP-4 inhibitor promoted the epithelial mesenchymal transition (EMT) in breast cancer cells. The EMT is known to associate with chemotherapy resistance via the induction of ATP-binding cassette (ABC) transporters in cancer cells. Here, we demonstrated that deficiency in DPP-4 promoted chemotherapy resistance via the CXCL12/CXCR4/mTOR axis, activating the TGFß signaling pathway via the expression of ABC transporters. DPP-4 inhibition enhanced ABC transporters in vivo and in vitro. Doxorubicin (DOX) further induced ABC transporters in DPP-4-deficient 4T1 cells, and the induction of ABC transporters was suppressed by either the CXCR4 inhibitor AMD3100, the mTOR inhibitor rapamycin or a neutralizing TGFß (1, 2 and 3) antibody(N-TGFß). Knockdown of snail, an EMT-inducible transcription factor, suppressed ABC transporter levels in DOX-treated DPP-4-deficient 4T1 cells. In an allograft mouse model, however, the effects of DOX in either primary tumor or metastasis were not statistically different between control and DPP-4-kd 4T1. Taken together, our findings suggest that DPP-4 inhibitors potentiate chemotherapy resistance via the induction of ABC transporters by the CXCL12/CXCR4/mTOR/TGFß signaling pathway in breast cancer cells.

Successful management of obstetric disseminated intravascular coagulation using a portable fibrinogen-measuring device.

The importance of fibrinogen replacement therapy in obstetric disseminated intravascular coagulation is well recognized. However, fibrinogen measurement in conventional laboratories has been a time-consuming task. Recently, a Japanese manufacturer developed a portable device that enables immediate fibrinogen measurement at the point of care. This report describes a case in which this device was used for the successful management of obstetric disseminated intravascular coagulation.

AMP-Activated Protein (AMPK) in Pathophysiology of Pregnancy Complications.

Although the global maternal mortality ratio has been consistently reduced over time, in 2015, there were still 303,000 maternal deaths throughout the world, of which 99% occurred in developing countries. Understanding pathophysiology of pregnancy complications contributes to the proper prenatal care for the reduction of prenatal, perinatal and neonatal mortality and morbidity ratio. In this review, we focus on AMP-activated protein kinase (AMPK) as a regulator of pregnancy complications. AMPK is a serine/threonine kinase that is conserved within eukaryotes. It regulates the cellular and whole-body energy homeostasis under stress condition. The functions of AMPK are diverse, and the dysregulation of AMPK is known to correlate with many disorders such as cardiovascular disease, diabetes, inflammatory disease, and cancer. During pregnancy, AMPK is necessary for the proper placental differentiation, nutrient transportation, maternal and fetal energy homeostasis, and protection of the fetal membrane. Activators of AMPK such as 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), resveratrol, and metformin restores pregnancy complications such as gestational diabetes mellitus (GDM), preeclampsia, intrauterine growth restriction, and preterm birth preclinically. We also discuss on the relationship between catechol-O-methyltransferase (COMT), an enzyme that metabolizes catechol, and AMPK during pregnancy. It is known that metformin cannot activate AMPK in COMT deficient mice, and that 2-methoxyestradiol (2-ME), a metabolite of COMT, recovers the AMPK activity, suggesting that COMT is a regulator of AMPK. These reports suggest the therapeutic use of AMPK activators for various pregnancy complications, however, careful analysis is required for the safe use of AMPK activators since AMPK activation could cause fetal malformation.

Occurrence of Potentially Lethal Arrhythmia due to Sudden Exposure of an Overt Accessory Pathway 8 Years After Catheter Ablation of a Concealed Accessory Pathway.

Although the efficacy of catheter ablation of the accessory pathway (AP) has been established, there are subgroups of APs with an intermittent conduction property, which is sometimes difficult to diagnose accurately. A 57-year-old man with a history of catheter ablation was referred to our clinic due to frequent faintness. He had undergone concealed AP ablation 8 years previously and bilateral circumferential pulmonary vein isolation (CPVI) 6 years previously. During regular electrocardiogram monitoring, it was suggested that irregular wide QRS tachycardia, which was considered to be atrial fibrillation with antegrade AP conduction, was the cause of the present symptoms. In the present electrophysiological study, we noticed a residual antegrade AP in the left lateral wall that was not observed during the previous session. We achieved abolition of overt accessory conduction, bilateral CPVI, and superior vena cava isolation with several radiofrequency applications without any recurrence. We also confirmed the absence of dormant conduction in the AP and the left atrium-PV connection with 20 mg adenosine triphosphate. This case demonstrated the possibility of sudden exposure of overt AP conduction late after catheter ablation of the concealed AP and the importance of confirming the absence of dormant conduction by means of adenosine triphosphate, which has the potential benefit of revealing latent AP conduction.

Cause of the "power-on reset" phenomenon other than electric magnetic interference in a patient with a pacemaker.

A 67-year old male with a dual-chamber pacemaker visited for a regular check-up. An unfamiliar message emerged on the display just after placing the programmer wand. We could recognize that the pacemaker had already been in the safe back-up mode of DDI, and the programmer prompted a re-initialization request. We are so surprised because there was no indication of device malfunction the day before in daily monitoring and a 12-lead electrocardiogram revealed normally working in the DDD mode just before checking the device. The pacemaker was immediately re-programmed to the former setting. This phenomenon has not recurred for 12 months.

Applicability of 3-Dimensional Quantitative Coronary Angiography-Derived Computed Fractional Flow Reserve for Intermediate Coronary Stenosis.

BACKGROUND: Quantitative flow ratio (QFR) is a newly developed image-based index for estimating fractional flow reserve (FFR).Methods and Results:We analyzed 151 coronary arteries with intermediate stenosis in 142 patients undergoing wire-based FFR measurement using dedicated software. Predefined contrast flow QFR, which was derived from 3-dimensional quantitative coronary angiography (3-D QCA) withThrombolysis in Myocardial Infarction (TIMI) frame counts, was compared with FFR as a reference. QFR had good correlation (r=0.80, P<0.0001) and agreement (mean difference: 0.01±0.05) with FFR. After applying the FFR cut-off ≤0.8, the overall accuracy rate of QFR ≤0.8 was 88.0%. On receiver operating characteristics analysis, the area under the curve was 0.93 for QFR. In contrast, 3-D QCA-derived anatomical indices had insufficient correlation with FFR and diagnostic performance compared with QFR. CONCLUSIONS: QFR had good correlation and agreement with FFR and high diagnostic performance in the evaluation of intermediate coronary stenosis, suggesting that QFR may be an alternative tool for estimating myocardial ischemia.

The PKM2 activator TEPP-46 suppresses kidney fibrosis via inhibition of the EMT program and aberrant glycolysis associated with suppression of HIF-1α accumulation.

AIMS/INTRODUCTION: Tubulointerstitial fibrosis is a hallmark of diabetic nephropathy and is associated with an epithelial-to-mesenchymal transition (EMT) program and aberrant glycolysis. Dimeric pyruvate kinase (PK) M2 (PKM2) acts as a key protein kinase in aberrant glycolysis by promoting the accumulation of hypoxia-inducible factor (HIF)-1α, while tetrameric PKM2 functions as a pyruvate kinase in oxidative phosphorylation. The aim of the research is to study the effect of PKM2 tetramer activation on preventing kidney fibrosis via suppression of aberrant glycolysis and the EMT program. MATERIALS AND METHODS: In vivo: Streptozotocin (STZ) was utilized to induce diabetes in 8-week-old CD-1 mice; 4 weeks after diabetes induction, proteinuria-induced kidney fibrosis was developed by intraperitoneal injection of bovine serum albumin (BSA: 0.3 g/30 g BW) for 14 days; The PKM2 activator TEPP-46 was also administered orally simultaneously. In vitro: HK2 cells were co-treated with high-glucose media or/and TGF-ß1 and TEPP46 for 48 h, cellular protein was extracted for evaluation. RESULTS: Diabetic mice developed kidney fibrosis associated with aberrant glycolysis and EMT; BSA injection accelerated kidney fibrosis in both the control and diabetic mice; TEPP-46 rescued the kidney fibrosis. In HK2 cells, TEPP-46 suppressed the EMT program induced by TGF-ß1 and/or high-glucose incubation. TEPP-46-induced PKM2 tetramer formation and PK activity resulted in suppression of HIF-1α and lactate accumulation. Specific siRNA-mediated knockdown of HIF-1α expression diminished high glucose-induced mesenchymal protein levels. CONCLUSION: PKM2 activation could restore the tubular phenotype via suppression of the EMT program and aberrant glycolysis, providing an alternative target to mitigate fibrosis in diabetic kidneys.

Dietary Magnesium Insufficiency Induces Salt-Sensitive Hypertension in Mice Associated With Reduced Kidney Catechol-O-Methyl Transferase Activity.

[Figure: see text].

Metformin Mitigates DPP-4 Inhibitor-Induced Breast Cancer Metastasis via Suppression of mTOR Signaling.

The biological influence of antidiabetic drugs on cancer cells and diabetic cancer patients has not yet been completely elucidated. We reported that a dipeptidyl peptidase (DPP)-4 inhibitor accelerates mammary cancer metastasis by inducing epithelial-mesenchymal transition (EMT) through the CXCL12/CXCR4/mTOR axis. Metformin has been shown to inhibit the mTOR signaling pathway. In this study, we investigated whether metformin mitigates breast cancer metastasis induced by a DPP-4 inhibitor via suppression of mTOR signaling. In cultured mouse mammary and human breast cancer cells, metformin suppressed DPP-4 inhibitor KR62436 (KR)-induced EMT and cell migration via suppression of the mTOR pathway associated with AMPK activation. For the in vivo study, metformin intervention was performed in an allograft 4T1 breast cancer model mouse with or without KR. We also analyzed mice transplanted with shRNA-mediated DPP-4 knockdown 4T1 cells. Treatment with metformin inhibited the lung metastasis of DPP-4-deficient 4T1 mammary tumor cells generated by either KR administration or DPP-4 knockdown. Immunostaining of primary tumors indicated that DPP-4 suppression promoted the expression of EMT-inducing transcription factor Snail through activation of the CXCR4-mediated mTOR/p70S6K pathway in an allograft breast cancer model; metformin abolished this alteration. Metformin treatment did not alter DPP-4-deficiency-induced expression of CXCL12 in either plasma or primary tumors. Our findings suggest that metformin may serve as an antimetastatic agent by mitigating the undesirable effects of DPP-4 inhibitors in patients with certain cancers. IMPLICATIONS: Metformin could combat the detrimental effects of DPP-4 inhibitor on breast cancer metastasis via mTOR suppression, suggesting the potential clinical relevance. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/19/1/61/F1.large.jpg.

Applicability of quantitative flow ratio for rapid evaluation of intermediate coronary stenosis: comparison with instantaneous wave-free ratio in clinical practice.

Quantitative flow ratio (QFR) is an image-based fractional flow reserve (FFR) computed by three-dimensional quantitative coronary angiography and estimated flow velocity. Several studies have reported that QFR was rapidly computed within approximately 5 min and had a good diagnostic performance as compared with FFR. However, studies comparing QFR with instantaneous wave-free ratio (iFR) as an index with a prognostic value comparable to that of FFR are limited. Thus, we investigated the applicability of QFR with respect to iFR, both being easy-to-measure indices not requiring pharmacological hyperaemic induction. We computed QFR in prospectively enrolled 150 coronary lesions (including 50 lesions for onsite QFR analysis) in consecutive patients with intermediate stenosis evaluated by iFR. The correlation and diagnostic performance of QFR were compared using iFR as a reference. The mean QFR and iFR were 0.81 ± 0.12 and 0.89 ± 0.11, respectively. QFR and iFR exhibited a good correlation in all subjects (R = 0.70, p < 0.0001) and the onsite-analysed vessels (R = 0.74, p < 0.0001). In the receiver-operating characteristics analysis, the area under the curve of QFR predicting iFR ≤ 0.89 was 0.91. Applying the cut-off value of QFR ≤ 0.80 and iFR ≤ 0.89, the sensitivity, specificity, positive and negative predictive values were 85%, 83%, 72%, and 91%, respectively, in all subjects, and 82%, 82%, 78%, and 85%, respectively, in the onsite-analysed vessels. QFR including onsite analysis demonstrated a good correlation with iFR and a diagnostic performance comparable to that of iFR in consecutive patients with intermediate coronary stenosis, suggesting its potential as a rapidly derived index for evaluating myocardial ischaemia in clinical settings.

Inhibition of Dipeptidyl Peptidase-4 Accelerates Epithelial-Mesenchymal Transition and Breast Cancer Metastasis via the CXCL12/CXCR4/mTOR Axis.

Dipeptidyl peptidase (DPP)-4 is a multifunctional glycoprotein involved in various biological and pathologic processes. DPP-4 has been widely recognized as a therapeutic target for type 2 diabetes mellitus but is also implicated in the development of human malignancies. Here, we show that inhibition of DPP-4 accelerates breast cancer metastasis via induction of CXCL12/CXCR4, which activates mTOR to promote epithelial-mesenchymal transition (EMT). In cultured cells, DPP-4 knockdown induced EMT and cell migration. Treatment with the DPP-4 inhibitor KR62436 (KR) promoted primary tumor growth and lung metastasis in a 4T1 tumor allograft mouse model; DPP-4 knockdown in 4T1 cells displayed similar phenotypes in vivo and in vitro. KR treatment enhanced the levels of CXCL12/CXCR4 and phosphorylated mTOR, which were associated with the induction of EMT in metastatic cancer cells. KR-induced EMT in cancer cells was inhibited by treatment with the CXCR4 inhibitor AMD3100 or the mTOR inhibitor rapamycin, and AMD3100 suppressed KR-induced metastasis in vivo. Our findings suggest that DPP-4 plays a significant role in cancer biology and that inhibition of DPP-4 promotes cancer metastasis via induction of the CXCL12/CXCR4/mTOR/EMT axis. SIGNIFICANCE: These findings reveal that inhibition of DPP-4 increases the metastatic potential of breast cancer. This is especially important given the potential use of DPP-4 inhibition as a therapeutic strategy for type 2 diabetes.

Clinical Factors Relevant to the Recurrence of Atrial Tachyarrhythmia after Extensive Defragmentation Followed by Thoracic Vein Isolation.

INTRODUCTION: The efficacy of thoracic vein isolation (TVI), an approach to trigger atrial fibrillation (AF), for the management of AF has been established. Our goal was to identify the predictors for late recurrence of atrial tachyarrhythmias (ATAs), for which the patients and procedural and/or echocardiographic parameters were retrospectively analyzed. Although substrate modification in the atrium for the treatment of AF ablation remains controversial, the background associated with the outcome has not been fully investigated. We retrospectively studied 33 patients with paroxysmal AF and 21 with persistent AF undergoing defragmentation followed by TVI. We evaluated the late/early recurrences, defined as ATA at 3 months after/within the single procedure. METHODS AND RESULTS: During a median follow-up period of 22 (11-37) months, 28 patients (52%) experienced a late recurrence. There was a higher incidence of late recurrences in the patients with disease durations of ≥12.4 months, which was the optimal cut-off point measured in the receiver operating characteristic curve analysis, or in those with left atrial diameter >50 mm or with earlier recurrences than the others (19% versus 72%, p=0.01; 0% versus 37%, p=0.02; or 13% versus 53%, p<0.0001 by the log-rank test, respectively). Moreover, there was a trend toward a higher atrial tachycardia (AT)-free rate in the patients with AF termination during the procedure (75% versus 54%, p=0.07 by the log-rank test). A multivariate analysis based on the Cox proportional hazard model showed that disease duration ≥12.4 months or early recurrence was highly associated with the outcomes (HR 3.72, 95%CI 1.42-12.79, p<0.006; HR 4.80, 95%CI 2.24-10.56, p<0.0001). CONCLUSION: The AF duration and early ATA recurrence are the peri-procedural factors significantly relevant to the outcome after extensive defragmentation followed by TVI.

Successful elimination of premature ventricular contractions by ablation of origin and preferential pathway.

However, the common strategy for eliminating premature ventricular contractions (PVCs) is to explore the exit site and ablate, which may be difficult in some cases. The origin and the preferential pathway, an insulated pathway connected to the exit, may also become targets for eliminating PVCs.

Interesting electrophysiological findings in a patient with coexistence of atrial tachycardia originating from coronary sinus and slow-fast atrioventricular nodal reentrant tachycardia.

Slow-fast atrioventricular nodal tachycardia (AVNRT) has various electrophysiological aspects due to atrioventricular (AV) nodal physiology. In addition, concomitantly another form of arrhythmia with AVNRT, especially atrial tachycardia (AT), was an infrequent arrhythmia. A 38-year-old female with narrow QRS tachycardia underwent electrophysiological study due to frequent faintness. The electrophysiological study disclosed the coexistence of AT originating from coronary sinus (CS) with slow-fast AVNRT. We easily diagnosed AT originating from CS and terminated with several radiofrequency ablations (RFA) around CS. The diagnosis of slow-fast AVNRT, however, was somewhat difficult due to the following findings: (1) small amount of adenosine triphosphate (ATP) could terminate slow-fast AVNRT reproducibly; (2) we could provoke slow-fast AVNRT only by RV pacing with isoproterenol infusion. With other electrophysiological findings, we diagnosed slow-fast AVNRT. Radiofrequency energy was delivered initially in the posteroseptal region, followed by inside CS, and finally in the middle septal region, which completed the slow pathway ablation. After the procedure, we could never provoke these arrhythmias. .

Focal right atrial tachycardia with three foci in a patient with polymyositis.

Cardiac involvement secondary to polymyositis is not infrequent. In addition, it sometimes presents various forms of arrhythmia, including atrial tachycardia (AT). A 72-year-old female who had 5-years history of polymyositis was referred to our clinic with symptomatic supraventricular tachycardia with 2:1 atrioventricular conduction. Electrophysiological study revealed a total of three focal AT in right atrium with the origin of the basal right atrial appendage (AT1), coronary sinus ostium (AT2), and low lateral right atrium (AT3), respectively. Endocardial bipolar voltage mapping showed low voltage area in the limited area, partially overlapping with the focus of AT3. We finally terminated AT2 targeting an early fractionated potential and AT3 at early activation site with a support of flexibly-bended deflectable sheath while accidentally eliminating AT3 with the bumping of a catheter. With the additional applications, we completely eliminated all AT. AT were never provoked by any inductions with isoproterenol infusion. .

Successful angioplasty with intravascular ultrasound and optical frequency domain imaging guidance for tandem intramural hematoma caused by coronary artery spasm.

A 39-year-old woman with no coronary risk factors was admitted due to repetitive morning chest pain. Coronary angiography revealed subtotal occlusion of the distal obtuse marginal branch that was not recanalized by intracoronary nitroglycerin administration. Intravascular ultrasound and optical frequency domain imaging showed tandem intramural hematomas in the culprit vessel. We performed cutting balloon angioplasty successfully with dual intracoronary imaging modality guidance. The 4-month follow-up angiography revealed favorable vascular healing and the provocation test induced multiple spasms, including in the culprit vessel, by intracoronary acetylcholine administration. .

Primary Multiple Cardiac Myxomas in a Patient without the Carney Complex.

Cardiac tumors are rare, and multiple myxomas are even rarer. The latter phenomenon is mostly associated with the Carney complex, a dominantly inherited disease characterized by multiple primary cardiac myxomas, endocrinopathy, and spotty pigmentation of the skin. We report the rare case of a patient who did not have the Carney complex but had multiple primary cardiac tumors. A 78-year-old woman with a past history of breast cancer was referred to our hospital for further examination of multiple cardiac tumors. Echocardiography showed 4 tumors in the left atrium and left ventricle. We could not diagnose them preoperatively and decided to resect them surgically because they were mobile and could have caused embolism and obstruction. The postoperative pathological findings of all 4 tumors were myxomas, although the patient did not meet the diagnostic criteria of the Carney complex. Therefore, a rare case of multiple primary cardiac myxomas was diagnosed.

Detection of right to left shunting through a patent foramen ovale in Japanese patients with ischemic stroke by transesophageal echocardiography using a standardized Valsalva maneuver.

We attempted to clarify the usefulness of transesophageal echocardiography performed using a standardized Valsalva maneuver to detect the presence of a patent foramen ovale in Japanese patients with ischemic stroke. Four hundred ninety six patients with ischemic stroke who were admitted to the Yokohama City Brain and Stroke Center between September 1999 and February 2002 were enrolled for the study. All the enrolled patients underwent transesophageal echocardiography with contrast injection and color Doppler imaging. During the procedure, a standardized Valsalva maneuver was performed to induce right to left shunting through a patent foramen ovale. Other related structural abnormalities, such as atrial septal aneurysm and the Chiari network anomaly, were also detected by the test. Transesophageal echocardiography without the Valsalva maneuver revealed a functional right to left communication in only 8.2% of the ischemic stroke patients, whereas the procedure conducted using a standardized Valsalva maneuver to provoke shunting revealed a patent foramen ovale in 15.3% of the patients. The presence of an atrial septal aneurysm or the Chiari network anomaly was not sensitive or specific enough to predict the presence of a patent foramen ovale as diagnosed by transesophageal echocardiography using the standardized Valsalva maneuver. Our results suggest that the standardized Valsalva maneuver is a safe and useful technique to detect the presence of a patent foramen ovale, which is potentially known to be associated with paradoxical embolism.