A Rare Case of Platypnea-Orthodeoxia Syndrome in a Patient With Undiagnosed Atrial Septal Defect.

Platypnea-orthodeoxia syndrome (POS) is a rare condition characterized by dyspnea and oxygen desaturation that worsens in the upright position and improves when lying down. We report the case of a 67-year-old male who presented with a 14-month history of dyspnea in the sitting/standing position. Despite treatment for suspected asthma, his symptoms persisted, and he was referred to our hospital for further evaluation. Physical examination and arterial blood gas analysis confirmed the presence of POS, with a significant decrease in PaO2 and SpO2 when moving from a supine to an upright position. Contrast-enhanced CT showed no obvious embolism nor arteriovenous fistula, and ventilation-perfusion scintigraphy demonstrated ventilation-perfusion mismatch with a right-to-left shunt fraction of 9.4%, without any focal defect. Transthoracic echocardiography with a microbubble test demonstrated a right-to-left shunt that increased in the upright position. Transesophageal echocardiography revealed an atrial septal defect (ASD) with an atrial septal aneurysm and the presence of an inferior vena cava valve, causing a bidirectional shunt. The patient was diagnosed with POS secondary to ASD and was referred for percutaneous closure of the defect. Following the procedure, the shunt resolved, and the patient's orthostatic oxygen desaturation improved. This case highlights the importance of considering POS in patients with positional dyspnea and the value of performing diagnostic tests, such as echocardiography, in different positions to identify the underlying cause. Early recognition and appropriate management of POS can significantly improve patients' quality of life and prevent complications associated with chronic hypoxemia.

Dapagliflozin administration to a mouse model of type 2 diabetes induces DNA methylation and gene expression changes in pancreatic islets.

Decreased pancreatic ß-cell volume is a serious problem in patients with type 2 diabetes mellitus, and there is a need to establish appropriate treatments. Increasingly, sodium/glucose cotransporter 2 (SGLT2) inhibitors, which have a protective effect on pancreatic ß-cells, are being prescribed to treat diabetes; however, the underlying mechanism is not well understood. We previously administered SGLT2 inhibitor dapagliflozin to a mouse model of type 2 diabetes and found significant changes in gene expression in the early-treated group, which led us to hypothesize that epigenetic regulation was a possible mechanism of these changes. Therefore, we performed comprehensive DNA methylation analysis by methylated DNA immunoprecipitation using isolated pancreatic islets after dapagliflozin administration to diabetic model mice. As a result, we identified 31 genes with changes in expression due to DNA methylation changes. Upon immunostaining, cystic fibrosis transmembrane conductance regulator and cadherin 24 were found to be upregulated in islets in the dapagliflozin-treated group. These molecules may contribute to the maintenance of islet morphology and insulin secretory capacity, suggesting that SGLT2 inhibitors' protective effect on pancreatic ß-cells is accompanied by DNA methylation changes, and that the effect is long-term and not temporary. In future diabetes care, SGLT2 inhibitors may be expected to have positive therapeutic effects, including pancreatic ß-cell protection.

Clinical Association Between Immune-related Adverse Events and Treatment Efficacy in Patients With Non-small-cell Lung Cancer Treated With Nivolumab-Ipilimumab-based Therapy.

BACKGROUND/AIM: Nivolumab and ipilimumab combination therapy has been extensively explored for the treatment of advanced non-small-cell lung cancer (NSCLC) through the pivotal phase III trials CheckMate 227 and CheckMate 9LA. However, the relationship between immune-related adverse events (irAEs) and the effectiveness of nivolumab plus ipilimumab-based therapy in a real-world clinical setting remains uncertain. PATIENTS AND METHODS: We performed a retrospective analysis of 28 patients with advanced or recurrent NSCLC who underwent treatment with nivolumab plus ipilimumab, with or without platinum-doublet chemotherapy, from February 2021 to January 2023. The primary objective was to elucidate the clinical association between irAEs and treatment efficacy associated with nivolumab plus ipilimumab-based therapy. RESULTS: Among the 28 patients, 22 (78.6%) experienced irAEs. The median progression-free survival (PFS) was significantly longer for patients with irAEs than for those without (p=0.0158), as was overall survival (OS) (p=0.000394). The severity of irAEs had no significant influence on PFS or OS. The objective response rate tended to be higher in patients with irAEs than in those without (50.0% versus 0.0%, respectively; p=0.0549). Multivariate analysis indicated that irAE occurrence was an independent factor for improved PFS (hazard ratio=0.2084, p=0.01383) and OS (hazard ratio=0.0857, p=0.001588). Interstitial lung disease was inferior to other irAE profiles for both PFS and OS. CONCLUSION: Patients with advanced NSCLC experiencing irAEs demonstrated superior clinical outcomes when treated with nivolumab plus ipilimumab-based therapy compared with those without irAEs. However, immune-related interstitial lung disease may be less linked with PFS and OS than other irAE profiles.

Comparison of Real-world Efficacy and Safety of Atezolizumab and Durvalumab in Combination With Chemotherapy for First-line Treatment of Extensive-stage Small-cell Lung Cancer.

BACKGROUND/AIM: The combination of programmed cell death ligand 1 inhibitors and platinum-based chemotherapy has become the standard treatment for first-line therapy in extensive-stage small-cell lung cancer (ES-SCLC). This study compared the efficacy and safety of atezolizumab plus chemotherapy and durvalumab plus chemotherapy in the treatment of ES-SCLC in clinical practice. PATIENTS AND METHODS: We retrospectively analyzed 40 patients with ES-SCLC treated with atezolizumab plus chemotherapy or durvalumab plus platinum-based chemotherapy at the Fukuoka University Hospital between October 2019 and November 2022. RESULTS: Among the 40 patients, 20 were treated with atezolizumab and 20 were treated with durvalumab. There was no significant difference in patient characteristics between the two groups; five patients who received atezolizumab and one who received durvalumab showed a performance status of 2 or higher. The median progression-free survival of patients who received atezolizumab or durvalumab was 5.6 and 5.4 months, respectively (p=0.881). The median overall survival of patients who received atezolizumab or durvalumab was 10.0 and 17.1 months, respectively (p=0.163). The objective response rate of the patients who received atezolizumab or durvalumab was 80.0% and 85.0%, respectively. There was no significant difference in the incidence of immune-related adverse events between the groups. CONCLUSION: This retrospective study was the first to compare the efficacy and safety of PD-L1 antibody, atezolizumab or durvalumab, in combination with carboplatin and etoposide in treatment-naïve ES-SCLC Japanese patients in a real-world setting. Both regimens, atezolizumab or durvalumab with carboplatin and etoposide, were effective and well-tolerated in Japanese ES-SCLC patients, in line with clinical trial findings.

A study of the effect of half-day climatotherapy on changes in salivary cortisol levels.

In our previous study setting, climatotherapy programme consisted of six sessions - four in the mid-mountain area and two in a flat park. For all sessions, the subjects underwent climatotherapy in the morning under slightly cool conditions. During each session, the subjects' blood pressure, pulse rate, skin temperature, blood lactate, salivary cortisol and mood profile were recorded, and meteorological data were collected at the sites. We hypothesised that exercise habits, changes in mood profile and effective temperatures during the session, and physical exertion during the climatic terrain cure would affect salivary cortisol levels. Subjects were 30 (spring) and 29 (autumn). Multiple linear regression analyses were performed to examine the determinants of the change in salivary cortisol levels. In the mountain setting, salivary cortisol was elevated, even though the sessions took place in the descending phase of the circadian salivary cortisol variation; however, the post-session cortisol increase was not significant. Increased post-session salivary cortisol was significantly associated with female gender, older age, higher BMI, lower body fat, less daily physical activity, increased blood lactate, increased 'Tension-Anxiety' and 'Depression-Dejection' moods, and decreased 'Anger-Hostility' mood. The increase in cortisol may have been due to older age, a predominance of females, and the increased blood lactate due to the mountainous terrain. In the flat park, the significant decrease in postsession salivary cortisol was related to the descending circadian phase of circadian cortisol variation and the low physical demands of the sessions.

A High Fibrosis-4 Index is Associated with a Reduction in the Estimated Glomerular Filtration Rate in Non-obese Japanese Patients with Type 2 Diabetes Mellitus.

Liver fibrosis is associated with non-alcoholic fatty liver disease (NAFLD), and one of the most important risk factors for NAFLD is type 2 diabetes (T2DM). The Fibrosis-4 (FIB-4) index, a noninvasive liver fibrosis score, has been found to be useful for estimating liver fibrosis. Because individuals with non-obese NAFLD were recently reported to be metabolically unhealthy and have a higher risk of T2DM than individuals with obese NAFLD, we hypothesized that the clinical factors related to a high FIB-4 index would differ between non-obese and obese Japanese T2DM patients. Accordingly, we examined the relationship between clinical factors and the FIB-4 index in non-obese and obese Japanese patients with T2DM. We divided 265 patients into two groups by BMI level - a non-obese group (n = 149) and an obese group (n = 116) - and examined the correlation between the FIB-4 index and clinical parameters. Single regression analysis revealed that a high FIB-4 index was correlated with a reduction in the estimated glomerular filtration rate and hypertension in the non-obese group. Importantly, multiple regression analysis showed that only a reduction in the estimated glomerular filtration rate was significantly associated with a high FIB-4 index in the non-obese group. These results demonstrated that non-obese T2DM patients with a high FIB-4 index might be at risk of kidney dysfunction. Our findings may enable the more appropriate treatment of T2DM patients based on BMI level.

CACNA2D1 regulates the progression and influences the microenvironment of colon cancer.

BACKGROUND: Calcium voltage-gated channel auxiliary subunit alpha 2/delta 1 (CACNA2D1), a gene encoding a voltage-gated calcium channel, has been reported as an oncogene in several cancers. However, its role in colon cancer (CC) remains unclear. This study aimed to investigate the function of CACNA2D1 and its effect on the microenvironment in CC. METHODS: Immunohistochemistry (IHC) analysis was performed on samples collected from 200 patients with CC who underwent curative colectomy. Knockdown experiments were performed using CACNA2D1 siRNA in the human CC cell lines HCT116 and RKO, and cell proliferation, cycle, apoptosis, and migration were then analyzed. The fibroblast cell line CCD-18Co was co-cultured with CC cell lines to determine the effect of CACNA2D1 on fibroblasts and the relationship between CACNA2D1 and the cancer microenvironment. Gene expression profiles of cells were analyzed using microarray analysis. RESULTS: IHC revealed that high CACNA2D1 expression was an independent poor prognostic factor in patients with CC and that CACNA2D1 expression and the stroma are correlated. CACNA2D1 depletion decreased cell proliferation and migration; CACNA2D1 knockdown increased the number of cells in the sub-G1 phase and induced apoptosis. CCD-18Co and HCT116 or RKO cell co-culture revealed that CACNA2D1 affects the cancer microenvironment via fibroblast regulation. Furthermore, microarray analysis showed that the p53 signaling pathway and epithelial-mesenchymal transition-associated pathways were enhanced in CACNA2D1-depleted HCT116 cells. CONCLUSIONS: CACNA2D1 plays an important role in the progression and the microenvironment of CC by regulating fibroblasts and may act as a biomarker for disease progression and a therapeutic target for CC.

Forensic application of three interstitial pneumonia markers: search for new pneumonia markers in dead bodies.

In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant-associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD.

Safety and Pharmacokinetics of Quizartinib Combination Therapy With Standard Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia: Results from Two Phase 1 Trials in Japan and China.

Quizartinib is a potent, oral, second-generation, selective type II FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor. It has shown improved overall survival in a randomized, multinational, Phase 3 (QuANTUM-First) study in patients with FLT3-internal tandem duplication (ITD)-positive newly diagnosed acute myeloid leukemia. We conducted 2 Phase 1b studies in Japan and China to evaluate the safety, pharmacokinetics, and efficacy of quizartinib in combination with standard induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Quizartinib was started at a dose level of 20 mg/day and then escalated to 40 mg/day, the dose used in the Phase 3 study. Seven patients were enrolled according to the 3 + 3 dose-escalation method in each study, including 3 patients who were FLT3-ITD positive. No dose-limiting toxicities were observed at dose levels up to 40 mg/day in both studies. Grade 3 or higher, quizartinib-related, treatment-emergent adverse events included febrile neutropenia, hematologic toxicities, and infections. QT prolongation on electrocardiogram was observed in 5 patients. The pharmacokinetics of quizartinib and its metabolite AC886 were similar between the studies and consistent with previous findings in the United States. We confirmed the tolerability of Japanese and Chinese patients to the dose of quizartinib and chemotherapy regimens used in the QuANTUM-First study.

A suicide case of liquid nicotine intoxication.

A man in his 50 s, who was found vomiting and in a disturbed state when the emergency medical team arrived, then went into cardiopulmonary arrest during transport and died without responding to resuscitation. The hospital initially suspected that the death may have been caused by internal causes, but since the deceased had previously been transported to the hospital in a suicide attempt, the hospital called police regarding suspicions of unnatural death. The police investigation revealed two empty bottles of nicotine liquid for e-cigarettes in his house and a search history of "nicotine suicide" on his cellphone. In a forensic autopsy, he was found to be highly obese, and abundant fat deposits were observed in his organs. A stent was placed in the aorta, but no abnormality was found. There was no obvious stenosis or obstruction in the coronary arteries. Drug screening using liquid chromatography tandem mass spectrometry (LC-MS/MS) was performed on cardiac blood, urine, and stomach contents collected at autopsy, which revealed the presence of some medical products such as aripiprazole, nicotine, and cotinine. Further quantitative testing revealed high concentrations of nicotine in all samples. The left and right femoral venous blood concentrations were above the lethal dose, suggesting that arrhythmia or respiratory failure due to nicotine intoxication was the cause of death. With the widespread use of e-cigarettes, high concentrations of nicotine are readily available, and case reports of serious nicotine addiction are increasing. It is important to always consider addiction when conducting forensic evaluations in the medical field.

Benefits of an accelerated climatotherapy programme for busy people: comparisons according to area and season.

An accelerated climatotherapy programme was evaluated for use with busy people in mid-mountain and flat lowland areas. A total of 43 urban residents participated in this climatotherapy programme. Participants' blood pressure, pulse rate, peripheral skin temperature and levels of salivary amylase, salivary cortisol and blood lactate were measured, and they completed the Profile of Mood Status questionnaire. In the mid-mountain area, which had a cooler environment and long uphill paths, participants' percentage of maximum pulse rate (70.01%) to estimated maximum heart rate was higher than that (59.67%) of participants in the flat lowland area, suggesting that the mid-mountain area was suitable for endurance training. At both sites, the decrease in peripheral skin temperature during the climatic terrain cure suggested that our programme was properly implemented with a cool body surface in accordance with our purpose. Negative moods improved quickly, suggesting that the forest environment and the fresh-air rest cure may have relaxed participants. In late spring and early autumn, the mood of approximately 25% of participants improved to an Iceberg profile, which is associated with positive mental states and athletic peak performance, after climatotherapy. On the other hand, the weather in early spring and late autumn was more likely to facilitate maintenance of a cool body surface during the climatic terrain cure. With the support of individualized feedback provided after the climatotherapy sessions, three participants developed regular exercise habits, serving as a good example of the effectiveness of our climatotherapy programme to elicit behavioural change.

Xylobiose treatment strengthens intestinal barrier function by regulating claudin 2 and heat shock protein 27 expression in human Caco-2 cells.

BACKGROUND: Xylobiose, a non-digestible disaccharide, largely contributes to the beneficial physiological effects of xylooligosaccharides. However, there is insufficient evidence to assess the direct effect of xylobiose on intestinal barrier function. Here, we investigated the intestinal barrier function in human intestinal Caco-2 cells treated with xylobiose. RESULTS: In total, 283 genes were upregulated and 256 genes were downregulated in xylobiose-treated Caco-2 cells relative to the controls. We focused on genes related to intestinal barrier function, such as tight junction (TJ) and heat shock protein (HSP). Xylobiose decreased the expression of the TJ gene Claudin 2 (CLDN2) and increased the expression of the cytoprotective HSP genes HSPB1 and HSPA1A, which encode HSP27 and HSP70, respectively. Immunoblot analysis confirmed that xylobiose suppressed CLDN2 expression and enhanced HSP27 and HSP70 expression. A quantitative reverse transcription-PCR and promoter assays indicated that xylobiose post-transcriptionally regulated CLDN2 and HSPB1 levels. Additionally, selective inhibition of phosphatidyl-3-inositol kinase (PI3K) inhibited xylobiose-mediated CLDN2 expression, whereas HSP27 expression induced by xylobiose was sensitive to the inhibition of PI3K, mitogen-activated protein kinase kinase and Src. CONCLUSION: The results of the present study reveal that xylobiose suppresses CLDN2 and increases HSP27 expression in intestinal Caco-2 cells via post-transcriptional regulation, potentially strengthening intestinal barrier integrity; however, these effects seem to occur via different signaling pathways. Our findings may help to assess the physiological role of xylobiose. © 2023 Society of Chemical Industry.

SARS-CoV-2 spike receptor-binding domain is internalized and promotes protein ISGylation in human induced pluripotent stem cell-derived cardiomyocytes.

Although an increased risk of myocarditis has been observed after vaccination with mRNA encoding severe acute respiratory syndrome coronavirus 2 spike protein, its underlying mechanism has not been elucidated. This study investigated the direct effects of spike receptor-binding domain (S-RBD) on human cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs). Immunostaining experiments using ACE2 wild-type (WT) and knockout (KO) iPSC-CMs treated with purified S-RBD demonstrated that S-RBD was bound to ACE2 and internalized into the subcellular space in the iPSC-CMs, depending on ACE2. Immunostaining combined with live cell imaging using a recombinant S-RBD fused to the superfolder GFP (S-RBD-sfGFP) demonstrated that S-RBD was bound to the cell membrane, co-localized with RAB5A, and then delivered from the endosomes to the lysosomes in iPSC-CMs. Quantitative PCR array analysis followed by single cell RNA sequence analysis clarified that S-RBD-sfGFP treatment significantly upregulated the NF-kß pathway-related gene (CXCL1) in the differentiated non-cardiomyocytes, while upregulated interferon (IFN)-responsive genes (IFI6, ISG15, and IFITM3) in the matured cardiomyocytes. S-RBD-sfGFP treatment promoted protein ISGylation, an ISG15-mediated post-translational modification in ACE2-WT-iPSC-CMs, which was suppressed in ACE2-KO-iPSC-CMs. Our experimental study demonstrates that S-RBD is internalized through the endolysosomal pathway, which upregulates IFN-responsive genes and promotes ISGylation in the iPSC-CMs.

Two medicolegal autopsy cases of multinodular and vacuolating neuronal tumor revealed by postmortem MRI.

The multinodular and vacuolating neuronal tumor (MVNT) is a recently recognized brain lesion. MVNT has a characteristic appearance in MRI images and is potentially epileptogenic. To the best of our knowledge, no report has yet described this pathological entity in the forensic medicine literature. We present two medicolegal autopsy cases where postmortem MRI (PMMR) was useful to detect this lesion. Case 1: a man in his 30s, with about a 7-year history of intractable epilepsy and known MVNT died suddenly. Although MVNT was not detected in the initial morphological evaluation during autopsy, PMMR of the formalin-fixed brain revealed the lesion in the left frontal lobe. Histopathology confirmed it as a MVNT. Case 2: a man in his 20s hanged himself to death. PMMR prior to autopsy revealed MVNT in his brain, and the diagnosis was confirmed by a detailed histopathological evaluation. In both cases, postmortem CT was not useful for evaluation. The cases suggested that MVNT can cause sudden, unexpected epileptic death, and pre- or post-autopsy PMMR may be useful to detect it.

Cancer Stem Cells of Esophageal Adenocarcinoma are Suppressed by Inhibitors of TRPV2 and SLC12A2.

BACKGROUND: The potential of membrane transporters activated in cancer stem cells (CSCs) as new therapeutic targets for cancer is attracting increasing interest. Therefore, the present study examined the expression profiles of ion transport-related molecules in the CSCs of esophageal adenocarcinoma (EAC). METHODS: Cells that highly expressed aldehyde dehydrogenase 1 family member A1 (ALDH1A1) were separated from OE33 cells, a human Barrett's EAC cell line, by fluorescence-activated cell sorting. CSCs were identified based on the formation of tumorspheres. Gene expression profiles in CSCs were examined by a microarray analysis. RESULTS: Among OE33 cells, ALDH1A1 messenger RNA levels were higher in CSCs than in non-CSCs. Furthermore, CSCs exhibited resistance to cisplatin and had the capacity to redifferentiate. The results of the microarray analysis of CSCs showed the up-regulated expression of several genes related to ion channels/transporters, such as transient receptor potential vanilloid 2 (TRPV2) and solute carrier family 12 member 2 (SLC12A2). The cytotoxicities of the TRPV2 inhibitor tranilast and the SLC12A2 inhibitor furosemide were higher at lower concentrations in CSCs than in non-CSCs, and both markedly reduced the number of tumorspheres. The cell population among OE33 cells that highly expressed ALDH1A1 also was significantly decreased by these inhibitors. CONCLUSIONS: Based on the present results, TRPV2 and SLC12A2 are involved in the maintenance of CSCs, and their specific inhibitors, tranilast and furosemide, respectively, have potential as targeted therapeutic agents for EAC.

Super Minimally Invasive Pulp Therapy for Severe Pulpitis: A Report of Two Cases.

In regions where preventive dentistry is widespread, tooth loss due to root fracture occurs approximately 10 times more frequently than that due to caries and periodontal disease. Root fracture is most likely to occur in non-vital teeth, where the dental pulp has been removed, often through a procedure known as pulpectomy. However, super minimally invasive pulp (SMIP) therapy has recently been reported as a novel treatment approach for pulpitis of any degree. In this study, SMIP therapy was performed to preserve the vitality of teeth in two patients with severe pulpitis. Case one involved a 35-year-old man with a history of hypertension who presented with intense spontaneous pain in tooth #34. The pain was particularly severe while sleeping at night and on exposure to cold water or heat, but it was absent on percussion. Following the detection of cervical caries and severe pulp exposure, SMIP therapy was administered, and the tooth was subsequently restored using glass ionomer cement. Case two involved an 18-year-old woman with no significant medical history who had deep caries in tooth #46. She experienced mild tooth pain when exposed to cold water, and examination revealed pulp exposure. We applied mineral trioxide aggregate over the dental pulp and restored the tooth using composite resin. The vitality of both teeth was maintained at the three-month follow-up. To our knowledge, this is the first report of SMIP therapy for teeth with severe pulpitis. SMIP therapy is an innovative treatment that may cause a paradigm shift from conventional dental treatment.

Recurrent ventricular arrhythmia due to aconite intoxication successfully treated with landiolol: A case report.

BACKGROUND: Ventricular arrhythmias, such as ventricular tachycardia and fibrillation, are the main causes of death in patients with aconite poisoning. CASE SUMMARY: A 51-year-old man presented to our emergency department because he was vomiting after ingesting aconite root to attempt suicide. On arrival, the patient was hemodynamically unstable, and his electrocardiogram revealed polymorphic ventricular extrasystoles and non-sustained ventricular tachycardia. Amiodarone was immediately administered for ventricular arrhythmia. However, the patient remained unresponsive. We administered continuous intravenous landiolol as the ventricular arrhythmia worsened, gradually suppressing it. The patient returned to sinus rhythm 16 h after arriving at the hospital. Some aconitum alkaloids act on voltage-gated Na+- channels and induce ventricular or supraventricular tachyarrhythmias. Landiolol suppresses sympathetic nerve activity through its blocking effect, preventing arrhythmia. CONCLUSION: Landiolol can be a therapeutic option for amiodarone-refractory ventricular arrhythmias caused by aconite intoxication.

Tazobactam/ceftolozane and tobramycin combination therapy in extensively drug-resistant Pseudomonas aeruginosa infections in severe burn injury: a case report.

BACKGROUND: Combination therapy with tazobactam/ceftolozane (TAZ/CTLZ) and high-dose aminoglycosides has been reported to be efficacious in extensively drug-resistant (XDR)-Pseudomonas aeruginosa infection. However, there are no reports of efficacy in XDR-P. aeruginosa infection for combination therapy with low-dose aminoglycosides and TAZ/CTLZ. Herein, we describe a rare case of severe burn injury patients with persistent bacteremia due to XDR-P. aeruginosa, which was successfully treated with TAZ/CTLZ and low-dose tobramycin (TOB). CASE PRESENTATION: A 31-year-old man was admitted to the intensive care unit with severe burn injury involving 52% of the total body surface area and a prognostic burn index of 79.5. The patient had recurrent bacterial infections since admission, and blood cultures collected on the 37th day of admission revealed the presence of P. aeruginosa strains that were resistant to all ß-lactams and amikacin (AMK). The results of the antimicrobial synergistic study showed no synergistic effect of low-dose meropenem (MEPM) and AMK combination therapy. The patient had acute renal failure, and it was difficult to increase the dose of MEPM and AMK, respectively. Thus, we initiated TAZ/CTLZ 1.5 g/8 h instead of the AMK and MEPM combination therapy on the 43rd day of hospitalization. Low-dose TAZ/CTLZ was continued because of prolonged renal dysfunction and resulted in a transient clinical improvement. However, the dosage of TAZ/CTLZ could be increased as the renal function improved, but despite an increased TAZ/CTLZ dose, bacteremia persisted, and the blood cultures remained positive. Thus, TOB was added to TAZ/CTLZ at low doses for synergistic effect against Gram-negative bacteria. Blood cultures collected after initiation of combination therapy with TAZ/CTLZ and low-dose TOB were negative on two consecutive follow-up evaluations. Thereafter, although the patient had several episodes of fever and increased inflammatory response, blood cultures consistently tested negative, and all of the wounds healed. On the 93rd day, due to the good healing progress, the patient was transferred to another hospital. CONCLUSIONS: TAZ/CTLZ and low-dose TOB combination therapy showed the potential for synergistic effects. Our present report suggests a novel synergistic treatment strategy for rare cases that are refractory to the treatment of infections, such as XDR-P. aeruginosa infection.