Higher Frequency of Premature Atrial Contractions Correlates With Atrial Fibrillation Detection after Cryptogenic Stroke.

BACKGROUND: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM). METHODS: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS2 score. RESULTS: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P<0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively. CONCLUSIONS: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.

Methiothepin downregulates SNAP-23 and inhibits degranulation of rat basophilic leukemia cells and mouse bone marrow-derived mast cells.

In the present study, we found that methiothepin (a nonselective 5-hydroxytryptamine [5-HT] receptor antagonist) inhibited antigen-induced degranulation in rat basophilic leukemia cells and mouse bone marrow-derived mast cells. Although antigen stimulation induces release of histamine and serotonin (5-HT) by exocytosis and mast cells express several types of 5-HT receptor, the detailed role of these receptors remains unclear. Here, pretreatment of cells with methiothepin attenuated increased intracellular Ca2+ concentration, phosphorylated critical upstream signaling components (Src family tyrosine kinases, Syk, and PLCγ1), and suppressed TNF-α secretion via inhibition of Akt (a Ser/Thr kinase activated by PI3K)and ERK phosphorylation. Furthermore, it inhibited PMA/ionomycin-induced degranulation; this finding suggested that methiothepin affected downstream signaling. IκB kinase ß phosphorylates synaptosomal associated protein 23, which regulates the fusion events of the secretory granule/plasma membrane after mast cell activation, resulting in degranulation. We showed that methiothepin blocked PMA/ionomycin-induced phosphorylation of synaptosomal associated protein 23 by inhibiting its interaction with IκB kinase ß. Together with the results of selective 5-HT antagonists, it is suggested that methiothepin inhibits mast cell degranulation by downregulating upstream signaling pathways and exocytotic fusion machinery through mainly 5-HT1A receptor. Our findings provide that 5-HT antagonists may be used to relieve allergic reactions.

Effects of lysophosphatidic acid (LPA) signaling via LPA receptors on cellular functions associated with ATP reduction in osteosarcoma cells treated with ethidium bromide.

Lysophosphatidic acid (LPA) signaling via LPA receptors (LPA1 to LPA6) exhibits a variety of malignant properties in cancer cells. Intracellular ATP depletion leads to the development of necrosis and apoptosis. The present study aimed to evaluate the effects of LPA receptor-mediated signaling on the regulation of cancer cell functions associated with ATP reduction. Long-term ethidium bromide (EtBr) treated (MG63-EtBr) cells were established from osteosarcoma MG-63 cells. The intracellular ATP levels of MG63-EtBr cells were significantly lower than that of MG-63 cells. LPAR2, LPAR3, LPAR4 and LPAR6 gene expressions were elevated in MG63-EtBr cells. The cell motile and invasive activities of MG63-EtBr cells were markedly higher than those of MG-63 cells. The cell motile activity of MG-63 cells was increased by LPA4 and LPA6 knockdowns. In cell survival assay, cells were treated with cisplatin (CDDP) every 24 h for 3 days. The cell survival to CDDP of MG63-EtBr cells was lower than that of MG-63 cells. LPA2 knockdown decreased the cell survival to CDDP of MG-63 cells. The cell survival to CDDP of MG-63 cells was inhibited by (2 S)-OMPT (LPA3 agonist). Moreover, the cell survival to CDDP of MG-63 cells was enhanced by LPA4 and LPA6 knockdowns. These results indicate that LPA signaling via LPA receptors is involved in the regulation of cellular functions associated with ATP reduction in MG-63 cells treated with EtBr.

Effects of adrenaline and vasopressin on cerebral microcirculation at baseline and during global brain ischemia and reperfusion in rabbits.

BACKGROUND: During cardiopulmonary resuscitation, the brain becomes ischemic. Adrenaline and vasopressin have been recommended for use during cardiopulmonary resuscitation. We aimed to investigate the direct effects of adrenaline and vasopressin on the cerebral microvasculature at baseline and during ischemia and reperfusion in rabbits. METHODS: The closed cranial window method was used to visualize the cerebral microcirculation and changes in the pial arteriole diameter in rabbits. Adrenaline and vasopressin were administered topically on the brain tissue. First, the effects of adrenaline and vasopressin on pial arterioles were evaluated in 7 rabbits that were given 4 different concentrations of adrenaline, and another 7 rabbits that received 4 different concentrations of vasopressin. Second, the effects of adrenaline and vasopressin were determined during the global brain ischemia and reperfusion, which was induced by clamping the brachiocephalic, left common carotid, and left subclavian arteries for 15 min. An additional 21 rabbits were randomly assigned to receive artificial cerebrospinal fluid (aCSF) (n = 7), adrenaline 10-5 mol/L (n = 7), or vasopressin 10-7 mol/L (n = 7). Each drug was continuously infused from 5 min after the initiation of ischemia until 120 min after reperfusion. The pial arteriole diameters were recorded before and during ischemia, and after reperfusion. RESULTS: At baseline, adrenaline and vasopressin did not affect the cerebral pial arterioles. During ischemia, vasopressin, but not aCSF and adrenaline constricted the pial vessels. Late in the reperfusion phase, pial diameter became reduced in the vasopressin and aCSF groups whereas pial diameter was higher in the animals treated with adrenaline. CONCLUSIONS: Adrenaline and vasopressin did not affect pial arterioles at baseline. During reperfusion, adrenaline may counteract the cerebral vasoconstriction.

Influence of pneumoperitoneum and head-down maneuver on the cerebral microvasculature in rabbits.

BACKGROUND: With recent advances in robot-assisted techniques, an increasing number of surgeries are being performed with pneumoperitoneum and head-down maneuver (HDM) that may affect the cerebral microcirculation. For the first time, this study investigated the direct influence of pneumoperitoneum and HDM on the cerebral microvasculature in rabbits. METHODS: Adult male rabbits were randomly allocated to the following groups (n = 7 each): control, pneumoperitoneum alone (P), and pneumoperitoneum with HDM (P + HDM) for 120 min. A closed cranial window was installed above the parietal bone to visualize the pial microvasculature. Pial arteriolar diameter and hemodynamic and blood gas parameters were measured during the 140-min observation period. Brain edema was assessed by evaluation of the brain water content at the end of the experiment. RESULTS: Rabbits in the P and P + HDM groups exhibited a similar degree of immediate pial arteriolar dilation following the initiation of both P and P + HDM (P: 1.11 ± 0.03, p = 0.0044 and P + HDM: 1.07 ± 0.02, p = 0.0004, relative changes from the baseline value by defining the baseline as one). In the P + HDM group, pial arteriole diameter returned to the baseline level following the discontinuation of pneumoperitoneum and HDM (1.05 ± 0.03, p = 0.0906, vs. baseline). In contrast, the pial arterioles remained dilated as compared to the baseline level in the P group after discontinuation of pneumoperitoneum. There were no changes in pial arteriole diameter in the animals in the control group. Heart rate, blood gas parameters, and brain water content were not significantly different between the groups. CONCLUSION: The pial arterioles dilated immediately after pneumoperitoneum with or without HDM. The pial arterioles remained dilated 20 min after discontinuation of pneumoperitoneum alone but constricted upon discontinuation of pneumoperitoneum plus HDM. Pneumoperitoneum and HDM for 2 h did not cause brain edema.

Factors associated with the new appearance of cerebral microbleeds after endovascular treatment for unruptured intracranial aneurysms.

PURPOSE: Endovascular treatment of unruptured intracranial aneurysms may increase cerebral microbleeds (CMBs) in postprocedural T2*-weighted MRIs, which may be a risk for future intracerebral hemorrhage. This study examined the characteristics of postprocedural CMBs and the factors that cause their increase. METHODS: The patients who underwent endovascular treatment for unruptured intracranial aneurysms from April 2016 to February 2018 were retrospectively analyzed. Treatment techniques for endovascular treatment included simple coiling, balloon-assisted coiling, stent-assisted coiling, or flow diverter placement. To evaluate the increase in CMBs, a head MRI including diffusion-weighted imaging and T2*-weighted MRIs was performed on the preprocedural day; the first postprocedural day; and at 1, 3, and 6 months after the procedure. RESULTS: Among the 101 aneurysms that were analyzed, 38 (37.6%) showed the appearance of new CMBs. In the multivariate analysis examining the causes of the CMB increases, chronic kidney disease, a higher number of preprocedural CMBs, and a higher number of diffusion-weighted imaging-positive lesions on the first postprocedural day were independent risk factors. Furthermore, a greater portion of the increased CMBs was found in cortical and subcortical lesions of the treated vascular perfusion area within 1 month after the procedure. CONCLUSION: In endovascular treatment for unruptured intracranial aneurysms, CMBs tended to increase in patients with small vessel disease before the procedure, and it was also implicated in hemorrhagic changes after periprocedural microinfarction.

Involvement of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/peroxisome proliferator-activated receptor γ pathway for induction and maintenance of neuropathic pain.

Peripheral nerve injury induces neuropathic pain, which is characterized by the tactile allodynia and thermal hyperalgesia. N-type voltage-dependent Ca2+ channel (VDCC) plays pivotal roles in the development of neuropathic pain, since mice lacking Cav2.2, the pore-forming subunit of N-type VDCC, show greatly reduced symptoms of both tactile allodynia and thermal hyperalgesia. Our study on gene expression profiles of the wild-type and N-type VDCC knockout (KO) spinal cord and several pain-related brain regions after spinal nerve ligation (SNL) injury revealed altered expression of genes encoding catalytic subunits of phosphatidylinositol-3 kinase (PI3K). PI3K/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling is considered to be very important for cancer development and drugs targeting the molecules in this pathway have been tested in oncology trials. In the present study, we have tested whether the changes in expression of molecules in this pathway in mice having spinal nerve injury are causally related to neuropathic pain. Our results suggest that spinal nerve injury induces activation of N-type VDCC and the following Ca2+ entry through this channel may change the expression of genes encoding PI3K catalytic subunits (p110α and p110γ), Akt, retinoid X receptor α (RXRα) and RXRγ. Furthermore, the blockers of the molecules in this pathway are found to be effective in reducing neuropathic pain both at the spinal and at the supraspinal levels. Thus, the activation of PI3K/Akt/mTOR/peroxisome proliferator activated receptor gamma (PPARγ) pathway would be a hallmark of the induction and maintenance of neuropathic pain.

The effect of glutamate on ghrelin release in mice.

Ghrelin is abundantly produced in the stomach. Here, we found that glutamate decreased ghrelin expression and release in ghrelin-producing cells, and decreased levels of food intake and plasma acyl-ghrelin in mice. Treatment with siRNA of G protein-coupled receptor, family C, group 5, member B (GPRC5B) in ghrelin-producing cell lines completely blocked the effect of glutamate-induced ghrelin suppression. In addition, glutamate inhibited ghrelin release via the extracellular signal-regulated kinase (ERK) activity pathway, and stimulated CREB2 mRNA expression in ghrelin-producing cell lines. These results suggest that glutamate inhibits ghrelin release via ERK-CREB2 pathway. These results suggest that the GPRC5B-ERK-CREB2 pathway is involved in the inhibition of ghrelin expression and secretion in ghrelin cells.

Comparison of methods of steroid administration combined with tonsillectomy for IgA nephropathy patients.

BACKGROUND: IgA nephropathy (IgAN) is a chronic glomerular disease that causes end-stage renal disease in 20-40 % of patients within 20 years. The efficacy of tonsillectomy combined with steroid pulse (SP) administration (TSP) for clinical remission of IgAN has been reported. Particularly in Japan, TSP has been performed widely. However, the optimum method for steroid administration in TSP has not been established. METHODS: We retrospectively compared clinical remission in IgAN patients treated with tonsillectomy combined with two different steroid administration methods: (1) three courses of SP therapy and oral prednisolone administered on alternate days (group 3A; n = 25); and (2) one course of SP therapy and oral prednisolone administered on consecutive days (group 1C; n = 22). RESULTS: There was no significant difference in the clinical remission rates between the two groups at 12 (48.0 vs. 40.9 %, P = 0.77) and 24 months after starting treatment (68.0 vs. 72.7 %, P = 0.76) and at the final observation (76.0 vs. 81.8 %, P = 0.73). The mean period from starting treatment to remission of hematuria in group 3A was significantly shorter than that in group 1C (5.7 ± 4.4 vs. 9.9 ± 5.9 months, P = 0.03). Dyslipidemic patients treated for the first time with statin after the SP therapy were more present in group 3A at 24 months (P = 0.02). CONCLUSIONS: In IgAN patients, treatment of group 3A may be effective for inducing rapid remission of hematuria. Further studies are needed to establish an appropriate protocol for TSP.

Spatiotemporal properties of multiple-color channels in the human visual system.

Psychophysical and neurophysiological evidence argues for neural channels in V1 selectively sensitive to intermediate hues between the cardinal axes of opponent-color space. The present study examined if these multiple-color channels are selective for other visual features analyzed by V1 such as orientation, spatial frequency, and motion direction. Using a conventional masking paradigm, we measured detection thresholds for an isoluminant grating modulated along a particular hue angle either in the presence or absence of a bandpass noise mask that varied in hue angle, orientation, spatial frequency, and motion direction. In line with previous studies, thresholds for the test grating were selectively elevated by noise masks with hue angles similar to that of the test. Hue-selective masking was substantially reduced if test and mask were oriented orthogonally or differed in spatial frequency, but thresholds remained elevated if the mask drifted in the direction opposite to that of the test. Masking also revealed components selective for hue angle, but not for orientation. The results support the notion that multiple-color channels partly involve visual units selective for orientation and spatial frequency but largely nonselective for motion direction.

Lewis Acid Catalyzed Asymmetric Three-Component Coupling Reaction: Facile Synthesis of α-Fluoromethylated Tertiary Alcohols.

A chiral dicationic palladium complex is found to be an efficient Lewis acid catalyst for the synthesis of α-fluoromethyl-substituted tertiary alcohols using a three-component coupling reaction. The reaction transforms three simple and readily available components (terminal alkyne, arene, and fluoromethylpyruvate) to valuable chiral organofluorine compounds. This strategy is completely atom-economical and results in perfect regioselectivities and high enantioselectivities of the corresponding tertiary allylic alcohols in good to excellent yields.

Comparison on removal performance of virus, antibiotic-resistant bacteria, cell-associated and cell-free antibiotic resistance genes, and indicator chemicals by ozone in the filtrated secondary effluent of a sewage treatment plant.

Due to the widespread appearance of viruses, antibiotic-resistant bacteria (ARBs), and antibiotic resistance genes (ARGs) in the aquatic environment, more powerful oxidation processes such as ozonation are needed to enhance the efficiency of their inactivation and removal during wastewater treatment. However, information is lacking on the elimination rates of viruses, ARBs, cell-associated ARGs (ca-ARGs), and cell-free ARGs (cf-ARGs) during ozonation. This study examined the kinetics and dose-dependent inactivation of a virus (MS2 coliphage) and an ARB (Ampicillin-resistant [AmpR] E. coli) and the removal of ca- and cf-ARGs (plasmid-encoded blaTEM) by ozonation in a filtered secondary effluent (SE) of a municipal sewage treatment plant (STP). In addition, the ozonation kinetics of carbamazepine (CBZ) and metoprolol (MTP)-ubiquitous organic micropollutants with different removal rate constants-were also investigated in order to monitor their effectiveness as indicators for the abovementioned biological risk factors. Our results showed that ozonation was an efficient way to remove MS2, AmpRE. coli, ARGs, CBZ, and MTP. We investigated the kinetics of their inactivation/removal with respect to exposure in terms of CT (dissolved ozone concentration C and contact time T) value, and found their inactivation/removal constants were in the following order: MS2 (8.66 ×103 M-1s-1) ≈ AmpRE. coli (8.19 ×103 M-1s-1) > cf-ARG (3.95 ×103 M-1s-1) > CBZ (3.21 ×103 M-1s-1) > ca-ARG (2.48×103 M-1s-1) > MTP (8.35 ×102 M-1s-1). In terms of specific ozone dose, > 5-log inactivation of MS2 was observed at > 0.30 mg O3/mg DOC, while > 5-log inactivation of AmpRE. coli was confirmed at 1.61-2.35 mg O3/mg DOC. Moreover, there was almost no removal of ca-ARG when the specific ozone dose was < 0.68 mg O3/mg DOC. However, 2.86-3.42-log removal of ca-ARG was observed at 1.27-1.31 mg O3/mg DOC, while 1.14-1.36-log removal of cf-ARG was confirmed at 3.60-4.30 mg O3/mg DOC. As alternative indicators, > 4-log removal of CBZ was observed at > 1.00 mg O3/mg DOC, while > 2-log removal of MTP was confirmed at > 2.00 mg O3/mg DOC. Thus, it was observed that inactivation of E. coli needs a greater ozone dose to achieve the same level of inactivation of AmpRE. coli; for ARGs, cf-ARG can persist longer than ca-ARG if low dosages of ozone are applied in the filtrated SE, CBZ might act as an indicator with which to monitor the inactivation of viruses and ARBs, while MTP might act as an indicator with which to monitor removal of ARGs. Moreover, cf-ARG cannot be neglected even after ozonation due to the possibility that ca-ARGs can become cf-ARGs during ozonation and be discharged with the final effluent, posing a potential risk to the receiving environment.

Gross Hematuria after the COVID-19 mRNA Vaccination: Nationwide Multicenter Prospective Cohort Study in Japan.

BACKGROUND: In the past three years, cases of gross hematuria (GH) after the vaccination for coronavirus disease 2019 (COVID-19) in IgA nephropathy (IgAN) patients have been frequently reported worldwide. However, the post-event renal prognosis of these patients, their clinical backgrounds, and underlying mechanisms remain unknown. Therefore, we conducted a nationwide multicenter prospective cohort study in Japan. METHODS: We analyzed laboratory findings at the time of the first presentation to the hospital, and 3 and 6 months after in patients with GH after the vaccination, and histopathological findings in their kidney biopsy specimens. Moreover, changes in pathological biomarkers of IgAN such as galactose-deficient IgA1 (Gd-IgA1) and its immune complexes (ICs) were also evaluated. RESULTS: During the study period, 127 newly presenting with GH after the vaccination were enrolled, with a clear female bias (73.2%). GH was observed after the second or subsequent vaccinations in most patients (92.9%). Of the 37 patients undergoing kidney biopsy prior to the vaccination, 36 patients had been diagnosed with IgAN/IgA vasculitis (IgAV). In remaining 90 patients, 69 of the 70 who newly underwent kidney biopsy were diagnosed with IgAN (N=67)/IgAV (N=2). Their histopathology did not show a high incidence of acute lesions such as endocapillary hypercellularity and crescentic lesions. Most cases showed a temporary increase in proteinuria, but no sustained worsening in renal function. Among the biomarkers measured, serum Gd-IgA1 and ICs were comparable throughout the observation period, however, only urinary Gd-IgA1 was increased at the time of GH. CONCLUSIONS: We found that GH after the vaccination is more likely to occur in IgAN/IgAV patients, with a female bias, but without progressive exacerbation of renal function. Although further investigation is needed regarding causal relationship between vaccination and GH, this study provides many insights into the molecular mechanisms of GH.

Atrial Fibrillation Detection and Ischemic Stroke Recurrence in Cryptogenic Stroke: A Retrospective, Multicenter, Observational Study.

BACKGROUND: Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM-detected AF. METHODS AND RESULTS: We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time-dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection (P=0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41-5.28]). In a time-dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70-4.47]). CONCLUSIONS: The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM-detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM-detected AF.

Genetic and phenotypic analyses of mcr-harboring extended-spectrum ß-lactamase-producing Escherichia coli isolates from companion dogs and cats in Japan.

The emergence of mcr plasmid-mediated colistin-resistant extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales among companion dogs and cats poses a risk of the animals acting as reservoirs for cross-species transmission. However, current knowledge of mcr-harboring ESBL-producing Enterobacterales in companion dogs and cats is still limited; thus, the genetic and phenotypic characteristics of the bacterial isolates and plasmids, in companion dogs and cats, remain to be elucidated. Here, we identified mcr gene-harboring ESBL-producing Escherichia coli isolates during whole-genome sequencing of ESBL-producing E. coli isolates from a dog and a cat in Osaka, Japan. Colistin-resistant MY732 isolate from a dog carried two plasmids: mcr-1.1-harboring IncI2 plasmid and blaCTX-M-14-harboring IncFIB plasmid. Conjugation assays revealed that both plasmids can be co-transferred even though the IncFIB plasmid lacked a conjugal transfer gene cassette. The other isolate MY504 from a cat harbored two bla genes and mcr-9 on the identical IncHI2 plasmid. This isolate was not resistant to colistin, which is likely to be due to deletion of the regulatory two-component QseBC system associated with the mcr-9 expression. To the best of our knowledge, this is the first report of a colistin-resistant ESBL-producing E. coli isolate harboring mcr-1 from a companion dog in Japan. Given that the mcr gene-harboring IncI2 and IncHI2 plasmids in this study shared high homology with plasmids from human or animal-derived Enterobacterales, companion dogs and cats may act as important reservoirs for cross-species transmission of the mcr gene in the community, in Japan.

Hemophagocytic Lymphohistiocytosis and Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis Possibly Caused by Enterococcus faecalis Infective Endocarditis.

Infection can induce hemophagocytic lymphohistiocytosis (HLH) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We herein report a 52-year-old man who had HLH and AAV simultaneously, possibly caused by Enterococcus faecalis infective endocarditis. The HLH diagnosis was based on the HLH-2004 criteria. AAV was diagnosed based on a positive result for proteinase-3 ANCA and necrotizing vasculitis of the small vessels on a skin biopsy. He eventually died and was sent for autopsy after combination treatment of valve replacement, antibiotics, and immunosuppressants, including corticosteroids. This case involved a challenging diagnosis and treatment of HLH with various complications in an adult.

Acute heart failure due to left common iliac arteriovenous fistula: A case of VEXAS syndrome.

We describe the case of a 78-year-old man presenting with multiple oedematous erythemas, fever, and arthralgia who subsequently developed neutrophil infiltration into the cartilage of the bilateral auricularis, consistent with relapsing polychondritis. A skin biopsy of the erythema on his right arm showed dense neutrophilic infiltration into the dermis, while a bone marrow aspirate revealed myelodysplastic syndromes with characteristic vacuoles in myeloid precursor cells. Although the patient achieved remission with high-dose oral prednisolone, the inflammatory symptoms relapsed, and he was resistant to colchicine and cyclosporine. The patient spontaneously developed left leg oedema and high-output cardiac failure caused by an arteriovenous fistula with a common iliac artery aneurysm. We successfully performed a two-stage surgery using internal iliac artery coil embolisation and endovascular aortic repair of the iliac aneurysm. We assumed the patient was suffering from large-vessel vasculitis such as giant cell arteritis or Takayasu's arteritis. We treated him with tocilizumab in addition to prednisolone, and the febrile events and elevated C-reactive protein levels improved. One year later, sequencing of ubiquitylation-initiating E1 enzyme using peripheral blood leucocytes revealed somatic variants (c.121A>C p.Met41Leu), confirming the diagnosis of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. This case suggests that arteriovenous fistula could be a complication of VEXAS syndrome with large-vessel vasculitis, and adequate surgical intervention and prompt diagnosis are essential for rescue. Although arteriovenous fistula is a rare complication of VEXAS syndrome, physicians should be aware of this complication to ensure prompt diagnosis and timely surgical intervention.

Left atrial appendage flow velocity predicts occult atrial fibrillation in cryptogenic stroke: a CRYPTON-ICM registry.

BACKGROUND: An insertable cardiac monitor (ICM) and transesophageal echocardiography (TEE) are useful for investigating potential embolic sources in cryptogenic stroke, of which atrial fibrillation (AF) is a critical risk factor for stroke recurrence. The association of left atrial appendage flow velocity (LAA-FV) on TEE with ICM-detected AF is yet to be elucidated. METHODS: CRYPTON-ICM (CRYPTOgenic stroke evaluation in Nippon using ICM) is a multicenter registry of cryptogenic stroke with ICM implantation, and patients whose LAA-FV was evaluated on TEE were enrolled. The primary outcome was the detection of AF (> 2 min) on ICM. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off of LAA-FV, and factors associated with ICM-detected AF were assessed. RESULTS: A total of 307 patients (age 66.6 ± 12.3 years; 199 males) with median follow-up of 440 (interquartile range 169-726) days were enrolled; AF was detected in 101 patients. The lower-tertile LAA-FV group had older age, more history of congestive heart failure, and higher levels of B-type natriuretic peptide (BNP) or N-terminal proBNP (all P < 0.05). On ROC analysis, LAA-FV < 37.5 cm/s predicted ICM-detected AF with sensitivity of 26.7% and specificity of 92.2%. After adjustment for covariates, the lower tertile of LAA-FV (hazard ratio [HR], 1.753 [1.017-3.021], P = 0.043) and LAA-FV < 37.5 cm/s (HR 1.987 [1.240-3.184], P = 0.004) predicted ICM-detected AF. CONCLUSIONS: LAA-FV < 37.5 cm/s predicts AF. TEE is useful not only to evaluate potential embolic sources, but also for long-term detection of AF on ICM by measuring LAA-FV in cryptogenic stroke. http://www.umin.ac.jp/ctr/ (UMIN000044366).

Expression of plant genes for arbuscular mycorrhiza-inducible phosphate transporters and fungal vesicle formation in sorghum, barley, and wheat roots.

Sorghum shows strong growth stimulation on arbuscular mycorrhizal (AM) symbiosis, while barley and wheat show growth depression. We identified the AM-inducible phosphate transporter genes of these cereals. Their protein products play major roles in phosphate absorption from arbuscules, intracellular fungal structures. Unexpectedly, barley and wheat expressed the AM-inducible genes at high levels. Hence the cause of their growth depression appears to be unrelated to the transcription of these genes. Notably, fungal vesicles were formed significantly more in barley and wheat than in sorghum. This study yielded new clues for investigation of the mechanism underlying these various responses.

The role of central corticotrophin-releasing factor receptor signalling in plasma glucose maintenance through ghrelin secretion in calorie-restricted mice.

Under severe calorie restriction (CR), the ghrelin-growth hormone axis in mice is involved in the maintenance of plasma glucose levels. Ghrelin, a stomach-derived acylated peptide, is up-regulated by the sympathetic nerve in the negative energy status. Central corticotrophin-releasing factor receptor (CRF-R) signalling stimulates the sympathetic tone. The present study aimed to examine the effect of central CRF-R signalling on the maintenance of plasma glucose concentrations in severe calorie-restricted mice with the involvement of ghrelin. Intracerebroventricular injections of urocorin-1 and urocorin-2, which are natural ligands for CRF-R1 and CRF-R2, elevated plasma ghrelin concentrations and ghrelin elevation with an i.c.v. injection of urocorin-1 was cancelled by atenolol (ß1 adrenergic receptor antagonist) administration. We then established a mice model of 60% CR and found that the administration of [d-Lys3]-GHRP-6 (a ghrelin receptor antagonist) in mice under 60% CR reduced the plasma glucose concentration more compared to the vehicle mice. Similarly, the atenolol injection in mice under 60% CR significantly reduced the plasma glucose concentration, which was rescued by the co-administration of ghrelin. An i.c.v. injection of the alpha helical CRH, a non-selective corticotrophin-releasing factor receptor antagonist, in mice under 60% CR significantly reduced the plasma glucose concentration, although the co-administration of α-helical CRH with ghrelin maintained plasma glucose levels. These results suggest that central CRF-R signalling is involved in the maintenance of plasma glucose levels in mice under severe CR via the sympathetic-ghrelin pathway.