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In this retrospective study, based on recent studies reporting the superiority of sublobar resection to lobectomy for peripheral small size non-small cell lung cancer (NSCLC), we investigated the optimal pathological factors for predicting noninvasive cancer and the selection of operative procedure.Patients with peripheral NSCLC of ≤2 cm who underwent surgery at our hospital between January 2010 and June 2020 were included in this study. We evaluated the relationship between pathologically noninvasive cancer and predictive factors according to the area under the curve (AUC) and accuracy, and the cutoff value was set to investigate indications for sublobar resection.The comparison of the AUCs revealed that the maximum standardized uptake value and consolidation to tumor (C/T) volume ratio were better predictors than the C/T ratio. Among the three factors, the C/T volume ratio showed the best accuracy. The patients were divided into two groups (low and high) using the cutoff value of the C/T volume ratio and compared according to the surgical procedure (lobectomy vs. segmentectomy). In the low-group, there was no significant difference in the prognosis. In the high-group, the 5-year recurrence-free survival rate of the patients who received lobectomy was 87.8%, while that of patients who received segmentectomy was 75.8% (p = 0.08).The C/T volume ratio was the best preoperative pathologically noninvasive predictive factor. Sublobar resection should be performed with caution in cases with significant solid components on three-dimensional images.

Supplementary Movie 2 from Adaptor Molecule Crk Is Required for Sustained Phosphorylation of Grb2-Associated Binder 1 and Hepatocyte Growth Factor–Induced Cell Motility of Human Synovial Sarcoma Cell Lines

Supplementary Movie S1A from Oligodendrocyte Lineage Transcription Factor 2 Inhibits the Motility of a Human Glial Tumor Cell Line by Activating RhoA

Supplementary Figure S1(A-D) from Adaptor Molecule Crk Is Required for Sustained Phosphorylation of Grb2-Associated Binder 1 and Hepatocyte Growth Factor–Induced Cell Motility of Human Synovial Sarcoma Cell Lines

Supplementary Figures S1-S3 from Oligodendrocyte Lineage Transcription Factor 2 Inhibits the Motility of a Human Glial Tumor Cell Line by Activating RhoA

Supplementary Movie S2B from Oligodendrocyte Lineage Transcription Factor 2 Inhibits the Motility of a Human Glial Tumor Cell Line by Activating RhoA

Supplementary Movie 1 from Adaptor Molecule Crk Is Required for Sustained Phosphorylation of Grb2-Associated Binder 1 and Hepatocyte Growth Factor–Induced Cell Motility of Human Synovial Sarcoma Cell Lines

Background and aim Early-life stress is thought to affect aggressive behavior in humans and rodents. Laboratory experiments have demonstrated that Sansoninto (SST; 酸棗仁湯 suān zǎo ren tāng), a traditional herbal medicine, attenuates stress-induced abnormal behavior in rodents. However, it is unknown whether SST attenuates stress-induced aggressive behavior. The current study examined the effects of SST on aggressive behavior of mice who suffered from social isolation (SI) stress in adolescence. Experimental procedure Five-week old mice were socially isolated for 6 weeks, and SST administration was started at 4 weeks after starting SI. Aggressive behavior and locomotor activity were examined in SST-treated mice. The content of dopamine and its metabolites in the hypothalamus were examined using high-performance liquid chromatography analysis. Gene expression analyses of monoamine oxidase-B (MAO-B), catechol-O-methyltransferase (COMT), and tyrosine hydroxylase in the hypothalamus were performed using quantitative reverse transcription polymerase chain reaction. Results and conclusion SST attenuated SI-induced aggressive behavior and increased levels of homovanillic acid, a metabolite of dopamine. However, SST did not affect dopamine levels. SI enhanced locomotion in a novel environment and increased COMT mRNA levels. In contrast, SST-treated mice showed no significant enhancement of locomotion. SST attenuated the increase in COMT mRNA levels. Given that the dopaminergic system has been implicated in aggressive behavior, these findings suggest that SST toned down dopaminergic signaling, resulting in amelioration of aggression. SST may be useful for treatment of aggressive behavior in patients with neurotic symptoms.

The aim of this study was to investigate whether low-dose valganciclovir (VGCV) prophylaxis for cytomegalovirus (CMV) infection increased the risk of developing neutropenia in heart transplant recipients (HTRs). Forty-three HTRs receiving VGCV were divided into two groups: those who received VGCV prophylaxis (n = 22) and those who did not (n = 21). Neutropenia was defined as an absolute neutrophil count ˂1500/µL and was monitored for approximately one year post-transplantation. In the prophylaxis group, 77.3% (17/22) of HTRs experienced neutropenia, which was significantly higher than that in the no prophylaxis group (42.9% [9/21], p = 0.031). No significant differences in the duration of VGCV administration and cumulative dose up to the first neutropenia episode were observed between the groups. Meanwhile, the cumulative dose of mycophenolate mofetil was significantly higher in the prophylaxis group than in the no prophylaxis group (p = 0.018); the daily maintenance dose and regularly measured area under the concentration-time curve (AUC) of mycophenolic acid did not significantly differ between groups. In conclusion, the risk of developing neutropenia was higher in HTRs receiving low-dose VGCV prophylaxis than it was in those not receiving prophylaxis, probably not attributed to dosing period and cumulative dose of VGCV until the onset of neutropenia.

Sleep-disordered breathing (SDB) is associated with an increased risk of adverse events in patients with heart failure (HF); however, its impact in patients implanted with a left ventricular assist device (LVAD) remains unclear. We aimed to investigate the prevalence of SDB in patients with LVAD and its impact on their clinical outcomes. Fifty consecutive patients with LVAD who underwent portable sleep monitoring between September 2017 and April 2018 were prospectively enrolled, and they were followed up for 170 ± 36 days. According to their respiratory disturbance indexes (RDIs), they were categorized into the SDB group (RDI ≥ 15, n = 12) and the non-SDB group (RDI 15, n = 38). The incidence of adverse events during the follow-up period was investigated after enrollment. Multivariate logistic regression analysis revealed significant differences in SDB in LVAD-implanted patients in terms of the logarithmic transformation brain natriuretic peptide (BNP) values (p = 0.005). The optimal BNP cut-off value for SDB prediction in LVAD-implanted patients was 300 pg/mL (sensitivity: 58.3%, specificity: 94.7%). During follow-up, ventricular tachyarrhythmias (VTas) occurred significantly more frequently in the SDB group (4 [33%] vs. 2 [5%] patients, p = 0.02); Atrial tachyarrhythmia (ATa) also tended to occur more frequently in the SDB group (2 [25%] vs. 2 [2%] patients, p = 0.07). SBD was prevalent in 24% of the LVAD-implanted patients with advanced HF. Furthermore, SDB was significantly associated with high BNP levels and was also potentially associated with subsequent incidence of VTa in patients with LVAD.

Aims The outcomes of patients with hypertrophic cardiomyopathy with left ventricular systolic dysfunction (HCM‐LVSD) undergoing left ventricular assist device (LVAD) implantation remain unclear. We retrospectively evaluated the clinical impact of LVAD implantation on clinical outcomes, including haemodynamics and brain natriuretic peptide (BNP) levels, in patients with HCM‐LVSD, in comparison with those with dilated cardiomyopathy (DCM). Methods and results In this retrospective, single‐centre, observational study conducted in Japan, the medical records of patients who underwent LVAD implantation in the National Cerebral and Cardiovascular Center between 2011 and 2020 were reviewed. We enrolled 96 patients with DCM (average age: 43.5 years; 73 men) and 24 patients with HCM‐LVSD (average age: 48.3 years; 16 men). The HCM‐LVSD group had smaller left ventricles with thicker ventricular walls than the DCM group, which became more prominent after LVAD implantation. Preoperatively, BNP values were comparable between both groups; however, 3 months post‐implantation, they were significantly higher in the HCM‐LVSD group. Pulmonary artery pulsatility index, right ventricular stroke work index, and cardiac index were lower, and right atrial pressure was higher, in the HCM‐LVSD group, suggesting subclinical impairment of right ventricular function. The HCM‐LVSD group demonstrated equivalent outcomes, including overall survival, cerebrovascular accidents, right ventricular failure, LVAD‐related infections, arrhythmia, and aortic insufficiency, post‐implantation. Conclusions Despite a decreased right ventricular function with higher BNP values, patients with HCM‐LVSD and DCM showed comparable outcomes post‐LVAD implantation.

Dravet syndrome (DS) is an infantile-onset epileptic encephalopathy. More than 80% of DS patients have a heterozygous mutation in SCN1A, which encodes a subunit of the voltage-gated sodium channel, Nav

Acquired coarctation of the aorta (CoA) following total aortic arch replacement (TAR) is a rare complication inducing left ventricular (LV) dysfunction probably due to increased LV afterload and secondary hypertension caused by increased upper body and decreased renal blood flow. We describe a case of a 35-year-old male who developed atypical CoA with severe LV dysfunction with LV ejection fraction of 10%, but without secondary hypertension after TAR using conventional elephant trunk (ET) technique for acute aortic dissection. Computed tomography revealed near-occlusive CoA due to narrowed distal ET. Because the myocardial histological findings were mild, and he had no cardiac failure history, we determined that LV function might be reversible. He underwent thoracic endovascular aortic repair (TEVAR), resulting in restored LV function. However, as the descending aortic false lumen distally to the end of ET was rapidly dilated, probably due to increased cardiac output and lower body blood flow, he underwent descending aortic replacement 3 months after TEVAR. In conclusion, a narrowed distal ET may cause LV dysfunction early after TAR, even without secondary hypertension. TEVAR may be a useful therapeutic option for a narrowed distant ET but can induce distal aortic dilatation.

This study aimed to investigate whether persistently high 1-h postchallenge glucose (PG) levels in a 75 g oral glucose tolerance test (75 g OGTT), as well as persistently low 1-h PG levels, are a risk factor for reclassification from normal glucose tolerance (NGT) into impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) among participants continually observed for 11 years. This single-center retrospective study used the electronic records of all participants undergoing Ningen Dock (health checkup) at Kiryu Kosei General Hospital between 2008 and 2018. In 2008, 361 of 523 participants who received Ningen Dock had NGT. Of the 361 participants, 109 received 75 g OGTT yearly for 11 years (2008–2018), and 72 of these 109 participants showed either persistently high 1-h PG (> 155 mg/dL) or persistently low 1-h PG (

Background With the advent of high‐resolution chest imaging, the number of patients diagnosed with multiple primary lung cancers is increasing. For the treatment of multiple lung cancers, a surgical procedure that preserves pulmonary function while ensuring curability is required. Methods The study population included 85 patients with synchronous multiple primary lung cancer who received surgical resection between January 2010 and September 2020. Patients with synchronous lung cancer within the same lobe were excluded, and only patients with ≥2 involved lobes were included. The postoperative pulmonary function was examined at 3–6 months after the surgery. Results Sixty‐seven patients had cancers within the ipsilateral lobe, and 18 patients had cancers in bilateral lobes. Seventy‐six patients (89.4%) underwent combination surgery with limited resection (e.g., segmentectomy and wedge resection). The preoperative pulmonary functions (mean VC/%VC, mean FEV1/%FEV1, and mean %DLCO) were 3.06 L/100.2%, 2.23 L/96.1%, and 117.2%, respectively, and the postoperative pulmonary functions were 2.45 L/81.4%, 1.87 L/81.2%, and 102.6%. In each parameter, the predicted reductions of pulmonary function were almost the same as the predicted values. The 5‐year survival rate was 85.0%. The 5‐year survival rate according to the most advanced pathological stage was 94.9% for stage I disease, and 62.6% for stage ≥II, which was a significant difference (p, Our method could adequately predict the postoperative pulmonary function, and the prognosis was good when combined with limited resection.

Downsizing and lowering engine speed is effective for fuel economy. However, such measures lead to severe lubrication condition and increase the risk of seizure because of higher load for the sliding surface. The bearing of the small end of a connecting rod is one of the sliding parts used under the severest lubrication conditions. Therefore, clarifying the mechanism of its seizure is an important subject. In the previous study, it is shown that higher the cylinder pressure thicker the oil film between the piston pin and bearing of the small end of the connecting rod. It derived a hypothesis that cylinder pressure causes a deformation of the pin and thicker oil film at around the center of the bearing and heavy contact at the bearing end. This study aimed clarifying the mechanism of the seizure occurring at around the piston pin. The calculated results showed that oil film could be generated by deformation of the piston pin. Further, oil film thickness was measured by laser induced fluorescence method for investigating the effect of pin stiffness. Measured result showed lower the stiffness of the piston pin thicker the oil film. It was found that the deformation of piston pin caused thick oil films. The fact that seizure occurred often the engine operation with the low stiffness piston pin also proved the hypothesis adequate.

Acute calcineurin inhibitor (CNI) nephrotoxicity is a common complication associated with CNI exposure. However, it can be difficult to diagnose. Herein, we report a case of acute CNI nephrotoxicity after heart transplant that was visualized using kidney Doppler ultrasonography.A 38-year-old female patient underwent heart transplant 5 years after the use of left ventricular assist device support because of advanced heart failure due to ischemic cardiomyopathy. Corticosteroids, tacrolimus, and mycophenolate mofetil were administered as immunosuppressive regimens postoperatively. The patient gradually developed kidney dysfunction despite a favorable perioperative clinical course and hemodynamics. Serum creatinine increased to 1.89 mg/dL on postoperative day (POD) 9, and the kidney Doppler ultrasonography examination showed severely reduced blood flow in the renal and renal segmental arteries, indicating acute CNI nephrotoxicity due to vasoconstriction of the renal arterioles. After the cessation of tacrolimus, kidney function returned to baseline levels within 2 days, and the kidney Doppler ultrasonography examination on POD 19 revealed a significant increase in blood flow in the renal and renal segmental arteries. Basiliximab followed by everolimus were administered as alternative immunosuppressants. No organic stenosis of the renal artery was detected on the kidney magnetic resonance angiography, and the patient was discharged on POD 51, without any other adverse events, including rejection.Although CNIs are widely used after heart transplant, acute nephrotoxicity should always be considered. After heart transplant, a kidney Doppler ultrasonography should be performed routinely and promptly if there are any clinical manifestations related to kidney function.

Background Implantable left ventricular assist devices (LVAD) have improved quality of life and survival in patients with advanced heart failure. However, LVAD-specific infections and predicting which patients will develop infections remain challenging. This study investigated whether changes in body mass index (BMI) during hospitalization following LVAD implantation are associated with LVAD-specific infections within 1 year of implantation.Methods and Results:Patients (n=135) undergoing LVAD implantation were retrospectively divided into 2 groups based on changes in BMI from LVAD implantation to discharge: those with and without decreases in BMI. Each group was further subdivided according to baseline albumin concentrations (high [>3.7 g/dL] and low [≤3.7 g/dL]). Twenty patients developed LVAD-specific infections within 1 year. Receiver operating characteristic curve analysis resulted in a ∆BMI cut-off of less than -0.128 kg/m2. In multivariate analysis, younger patients and those with decreases in BMI had significantly higher rates of LVAD-specific infection (P=0.010 and P=0.035, respectively). LVAD-specific infection rates were significantly higher for patients with low albumin and decreases in BMI than for patients with low albumin but no decrease in BMI. Conclusions Decreases in BMI during hospitalization after LVAD implantation and younger age were independently associated with LVAD-specific infection within 1 year. Strict patient management may be needed to avoid decreases in BMI during hospitalization after LVAD implantation, particularly in patients with low baseline albumin concentrations.

Exocyst complex component 3-like 1 (EXOC3L1), which regulates insulin secretion, is ubiquitously present in heart, lung, liver, spleen, kidney, muscle, cerebellum, pituitary, adrenal grand, and pancreatic islets. Its deduced amino acid sequence has 31% identity and 53% similarity with Sec6, so they are considered isoforms. Since Sec6 suppresses apoptosis via HSP27, we investigated the involvement of EXOC3L1 expression in apoptosis. We found that overexpressed EXOC3L1 in Chinese hamster ovary cells significantly reduced cultured cell numbers. It also significantly increased apoptotic DNA ladder, caspase 3 activity, and cleavage of caspase 3 compared with the control. Thus, although Sec6 reduces apoptosis by increasing HSP27 phosphorylation, overexpressed EXOC3L1 alone can spontaneously induce apoptosis without apoptotic stimulators or inducers.

Background Catheter ablation (CA) has been reported to be an effective therapeutic option for ventricular arrhythmias, even in patients with a left-ventricular assist device (LVAD). However, the issues of right-to-left shunting due to iatrogenic atrial septal defect (iASD) associated with procedures for CA have not been well documented. We describe a rare case of refractory hypoxia associated with right-to-left shunting via iASD after CA through the transseptal approach in an LVAD patient. Case summary A 52-year-old Asian man with a continuous-flow implantable LVAD and progressive right ventricular (RV) dysfunction was admitted because of refractory ventricular tachycardia (VT) and subsequent right heart failure. Since VT could not be controlled by intravenous administration of multiple antiarrhythmic drugs, VT ablation via the transseptal approach was performed. Ventricular tachycardia was terminated to the sinus rhythm after VT ablation; however, hypoxia associated with significant right-to-left shunting across the iASD was detected. Intensive medical management, such as an adjusted mechanical ventilator to increase pulmonary vascular compliance and adjustment of LVAD pump speed, as well as the use of intravenous inotropes to support impaired RV function successfully stabilized the haemodynamic and improved hypoxia for the disappearance of right-to-left shunting. Echocardiography at 7 months after CA showed that the significant iASD and right-to-left shunting had disappeared. Discussion The evaluation of RV function prior to VT ablation via the transseptal approach is important in the postoperative management of patients with LVAD, because RV dysfunction may cause refractory hypoxia due to iASD.

Triiodothyronine reduces sodium glucose cotransporter 2 expression in the kidney and increased glucose excretion in urine of alloxan-induced diabetic rats. Free thyroxine is also negatively associated with islet beta-cell function in euthyroid subjects. However, the influence of sodium glucose cotransporter 2 inhibitor on thyroid function in patients with type 2 diabetes mellitus has not been established.We investigated thyroid function in patients with type 2 diabetes mellitus in the presence or absence of sodium glucose cotransporter 2 inhibitor in a multicenter retrospective study conducted between 2019 and 2021. All participants visited the hospital monthly for type 2 diabetes mellitus treatment and plasma glucose and glycated hemoglobin level measurements. Furthermore, thyroid-stimulating hormone, free triiodothyronine, and free thyroxine levels were measured annually.Free triiodothyronine level and the free triiodothyronine:free thyroxine ratio in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor. Free triiodothyronine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly higher than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.040). Free thyroxine levels in the group treated with sodium glucose cotransporter 2 inhibitor were significantly lower than the levels in the group not treated with sodium glucose cotransporter 2 inhibitor (p = 0.002). Thyroid-stimulating hormone levels did not differ significantly between the two groups.Our findings show that sodium glucose cotransporter 2 inhibitor affects free triiodothyronine levels free thyroxine levels, and the free triiodothyronine:free thyroxine ratio.

Background: The involvement of digits in patients with multiple trigger digits often displays specific patterns. We aimed to determine the patterns of involvement of digits in multiple trigger digits and their association with patient-related factors and compare them to those of patients with a single trigger digit. Methods: All patients with trigger digits treated over a 2-year period were retrospectively examined in June 2020. Data regarding the age at occurrence of initial trigger digit, sex, occupation, presence of diabetes mellitus, carpal tunnel syndrome and de Quervain disease, and hand dominance was determined. The data obtained from patients with multiple trigger digits was compared with those with a single trigger digit. Additionally, we investigated the patterns of involvement of the first two affected digits in patients with multiple trigger digits and their association with patient-related factors and compared them to those in patients with a single trigger digit. Results: Three hundred and eighty-seven and 577 patients with multiple and single trigger digits, respectively, were studied. Their median age was 60 (range: 17–92) years. The incidence of concomitant diabetes mellitus was 150% higher in patients with multiple trigger digits than in those with a single trigger digit. Symmetric occurrence and adjacent occurrence patterns were observed in 42.4 % and 28.4% of the 387 patients, respectively. Initial onset in the fifth and sixth decades of life, female sex and a time lag between occurrences were significantly associated with symmetric occurrence. Male sex and simultaneous occurrence in two digits were significantly associated with adjacent occurrence. Diabetes mellitus was not associated with each occurrence pattern. Conclusions: We have confirmed the presence of two involvement patterns in patients with multiple trigger digits: symmetric and adjacent. Our data will help in the prevention, early detection and management of multiple trigger digits. Level of Evidence: Level III (Therapeutic)

Panax ginseng C.A.Mey. (Araliaceae) cultivation suffers from the inability to cultivate the same fields continuously for long durations due to replant failure. The main cause of replant failure is considered to be the annual change in the soil microbial flora, especially the invasion and settlement of pathogenic microorganisms of soil-borne diseases. We analyzed the soil bacterial and fungal flora and inter-annual changes in their composition over 5 years in ginseng cultivation fields on Daikonshima Island, Shimane Prefecture of Western Japan by DNA metabarcoding using next-generation sequencing. Bacteria such as Sphingomonas sp., Bacillus sp., and Betaproteobacteria and the fungus Mortierella sp. were consistently detected throughout the cultivation period. The inter-annual compositional changes of the bacterial flora, especially two members of the family Burkholderiaceae, one member of the phylum Actinobacteria, one member of the genus Candidatus Koribacter, and one member of the genus Sphingomonas, corresponded to the cultivation period, whereas those of the fungal flora showed random changes, suggesting that the growth of ginseng may be greatly affected by changes in the bacterial flora. Therefore, a greater understanding of the bacterial flora could provide valuable information for the cultivation of ginseng. The absence of pathogenic microorganisms associated with soil-borne diseases, which have been reported as causative agents of the main diseases of ginseng, in all soil sampling sites throughout the entire cultivation period in this study proves, for the first time, that traditional cultivation management employing empirical methods and chemical control is an effective approach to control these pathogens. Therefore, the DNA metabarcoding of the bacterial flora could provide valuable information for cultivation management, specifically in detecting and controlling soil-borne pathogens responsible for ongoing cultivation damage in long-term cultivation of medicinal plants.

Dravet syndrome (DS) is an intractable form of childhood epilepsy that occurs in infancy. More than 80% of all patients have a heterozygous abnormality in the SCN1A gene, which encodes a subunit of Na+ channels in the brain. However, the detailed pathogenesis of DS remains unclear. This study investigated the synaptic pathogenesis of this disease in terms of excitatory/inhibitory balance using a mouse model of DS. We show that excitatory postsynaptic currents were similar between Scn1a knock-in neurons (Scn1a+/− neurons) and wild-type neurons, but inhibitory postsynaptic currents were significantly lower in Scn1a+/− neurons. Moreover, both the vesicular release probability and the number of inhibitory synapses were significantly lower in Scn1a+/− neurons compared with wild-type neurons. There was no proportional increase in inhibitory postsynaptic current amplitude in response to increased extracellular Ca2+ concentrations. Our study revealed that the number of inhibitory synapses is significantly reduced in Scn1a+/− neurons, while the sensitivity of inhibitory synapses to extracellular Ca2+ concentrations is markedly increased. These data suggest that Ca2+ tethering in inhibitory nerve terminals may be disturbed following the synaptic burst, likely leading to epileptic symptoms.

Background In Japan, patients with heart failure who have a paracorporeal left ventricular assist device (pLVAD) and cannot be weaned from the VAD may undergo conversion to implantable continuous-flow LVAD (iLVAD) via a bridge-to-bridge (BTB) strategy for bridge-to-transplantation (BTT). This study aimed to evaluate the real-world clinical status of BTB strategies. Methods Among 134 patients who underwent iLVAD implantation for BTT, 34 patients underwent conversion from pLVAD to iLVAD (BTB group) and 100 patients underwent iLVAD implantation primarily (primary iLVAD group). The clinical characteristics and outcomes were compared between the two groups. Results No significant difference was found in the overall survival between the two groups (p = 0.26; log-rank test). However, the 1-year survival rate and the 1-year freedom from the composite events of death, stroke, systemic infection, and bleeding rate were lower in the BTB group than in the primary iLVAD group (survival rate, 88.2% vs. 99.0%, p = 0.0040; composite event-free survival rate, 26.1% vs. 49.8%, p = 0.030; log-rank test). Multivariate analysis indicated that the BTB strategy [hazard ratio (HR) 1.70, 95% confidence intervals (CI) 1.03–2.72; p=0.036] and serum total bilirubin levels at iLVAD implantation [HR 1.31, 95% CI 1.00–1.65; p=0.043] were independent predictors of 1-year composite events. Conclusions The BTB strategy is useful in providing long-term survival in patients with acute critical diseases. However, the early mortality rate after conversion is higher in patients who underwent the BTB strategy.

Summary: This review provides an updated overview of the emerging roles of neopterin derivatives in atherosclerosis. Neopterin, a metabolite of guanosine triphosphate, is produced by interferon-γ-activated macrophages and is expressed at high levels in atheromatous plaques within the human carotid and coronary arteries as well as in the aorta. Plasma concentrations of neopterin are higher in patients with carotid, cerebral, and coronary artery diseases as well as aortic aneurysm. The concentration of neopterin is positively correlated with the severity of coronary artery disease. However, a prospective cohort study showed that neopterin contributes to protection against plaque formation in carotid arteries in patients with atherosclerosis. Moreover, using both in vitro and in vivo experiments, a recent study has shown the atheroprotective effects of neopterin. Neopterin suppresses the expression of monocyte chemotactic protein-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in endothelial cells, and thereby suppresses the adhesion of monocytes to endothelial cells. It also suppresses the inflammatory phenotype of monocyte-derived macrophages. In addition, neopterin suppresses oxidized low-density lipoprotein-induced foam cell formation in macrophages and the migration and proliferation of vascular smooth muscle cells. Neopterin injection into apolipoprotein E-deficient ( Apoe-/-) mice suppresses the development of atherosclerotic lesions. A neopterin derivative tetrahydroneopterin (BH4), also known as a cofactor for nitric oxide (NO) synthases, suppresses atherosclerosis and vascular injury-induced neointimal hyperplasia in Apoe-/- mice. BH4 administration improves endothelial dysfunction in patients with coronary artery disease. These findings suggest that neopterin production may increase to counteract the progression of atherosclerosis, as neopterin contributes to atheroprotection. Otherwise, the increased neopterin levels in atherosclerosis may reflect a compensatory mechanism associated with inducible NO synthase upregulation in macrophages to supply BH4 for high output NO production caused by decreased endothelial NO synthase in atherosclerosis. Therefore, neopterin derivatives are a novel therapeutic target for atherosclerosis and related diseases.

Objective: Because patients with diabetes mellitus (DM) were forced to stay indoors during the state of emergency, resulting in stress and a lack of physical activity, concerns about their glycemic control were raised. Patients and Methods: The 165 patients' glycated hemoglobin (HbA1c) levels were compared during the following periods: the 4 months that were selected as a representative condition 1 year before the COVID-19 pandemic (May 2018, March 2019, June 2019, and July 2019) and the latter 3 months as a 1-year follow-up during the COVID-19 pandemic (May 2019, March 2020, June 2020, and July 2020). Results: The patients' HbA1c levels were 7.32 ± 1.23, 7.44 ± 1.20, 7.16 ± 1.06, 7.01 ± 1.05, 7.23 ± 1.06, 7.45 ± 1.18, 7.15 ± 10.7, and 7.11 ± 1.17 in May 2018, March 2019, June 2019, July 2019, May 2019, March 2020, June 2020, and July 2020, respectively (expressed as mean ± standard deviation). Conclusion: The analysis showed that HbA1c levels did not worsen during the self-restraint period.

Inochinohaha White (IHW) is a Japanese herbal medicine for treating women with anxiety associated with premenstrual syndrome (PMS). In this study, we examined the effects of IHW on anxiety-like behavior in rats undergoing progesterone withdrawal (PWD), a model for PMS. Female rats were injected daily with progesterone for 21 days. Water and ethanol extracts of IHW (WE-IHW and EE-IHW, respectively) were administered orally 15 days after the initiation of progesterone injections. Anxiety-like behavior in an elevated plus maze was evaluated 48 h after the final injection of progesterone. PWD induced anxiety-like behavior, and EE-IHW (300 mg/kg), but not WE-IHW, significantly attenuated this behavior. Administration of the GABA agonists, diazepam or muscimol, significantly attenuated PWD-induced anxiety-like behavior. To investigate the underlying mechanisms of IHW action, we analyzed GABAA receptor expression in the amygdala of these rats. EE-IHW ameliorated the PWD-induced decrease in GABAA receptor β2-subunit mRNA, although β2-subunit protein was unchanged. Brain-derived neurotrophic factor (BDNF) has been reported to have anxiolytic effects and enhance GABAergic synaptic transmission. We found that EE-IHW increased BDNF levels in a dose-dependent manner. Our results suggest that EE-IHW attenuates PWD-induced anxiety-like behavior by increasing GABAA receptor-mediated signaling via increases in β2-subunit and BDNF in the amygdala.

Valproic acid (VPA) is widely prescribed to treat epilepsy. Maternal VPA use is, however, clinically restricted because of the severe risk that VPA may cause neurodevelopmental disorders in offspring, such as autism spectrum disorder. Understanding the negative action of VPA may help to prevent VPA-induced neurodevelopmental disorders. Astrocytes play a vital role in neurodevelopment and synapse function; however, the impact of VPA on astrocyte involvement in neurodevelopment and synapse function has not been examined. In this study, we examined whether exposure of cultured astrocytes to VPA alters neuronal morphology and synapse function of co-cultured neurons. We show that synaptic transmission by inhibitory neurons was small because VPA-exposed astrocytes reduced the number of inhibitory synapses. However, synaptic transmission by excitatory neurons and the number of excitatory synapses were normal with VPA-exposed astrocytes. VPA-exposed astrocytes did not affect the morphology of inhibitory neurons. These data indicate that VPA-exposed astrocytes impair synaptogenesis specifically of inhibitory neurons. Our results indicate that maternal use of VPA would affect not only neurons but also astrocytes and would result in perturbed astrocyte-mediated neurodevelopment.