Extracellular aaRSs drive autoimmune and inflammatory responses in rheumatoid arthritis via the release of cytokines and PAD4.

OBJECTIVES: Recent studies demonstrate that extracellular-released aminoacyl-tRNA synthetases (aaRSs) play unique roles in immune responses and diseases. This study aimed to understand the role of extracellular aaRSs in the pathogenesis of rheumatoid arthritis (RA). METHODS: Primary macrophages and fibroblast-like synoviocytes were cultured with aaRSs. aaRS-induced cytokine production including IL-6 and TNF-α was detected by ELISA. Transcriptomic features of aaRS-stimulated macrophages were examined using RNA-sequencing. Serum and synovial fluid (SF) aaRS levels in patients with RA were assessed using ELISA. Peptidyl arginine deiminase (PAD) 4 release from macrophages stimulated with aaRSs was detected by ELISA. Citrullination of aaRSs by themselves was examined by immunoprecipitation and western blotting. Furthermore, aaRS inhibitory peptides were used for inhibition of arthritis in two mouse RA models, collagen-induced arthritis and collagen antibody-induced arthritis. RESULTS: All 20 aaRSs functioned as alarmin; they induced pro-inflammatory cytokines through the CD14-MD2-TLR4 axis. Stimulation of macrophages with aaRSs displayed persistent innate inflammatory responses. Serum and SF levels of many aaRSs increased in patients with RA compared with control subjects. Furthermore, aaRSs released PAD4 from living macrophages, leading to their citrullination. We demonstrate that aaRS inhibitory peptides suppress cytokine production and PAD4 release by aaRSs and alleviate arthritic symptoms in a mouse RA model. CONCLUSIONS: Our findings uncovered the significant role of aaRSs as a novel alarmin in RA pathogenesis, indicating that their blocking agents are potent antirheumatic drugs.

Change over Time in the Risk of Death among Japanese COVID-19 Cases Caused by the Omicron Variant Depending on Prevalence of Sublineages.

To assess temporal changes to the risk of death in COVID-19 cases caused by the Omicron variant, we calculated age-standardized case fatality rates (CFR) in patients aged ≥40 years over nine diagnostic periods (3 January to 28 August 2022) in ten Japanese prefectures (14.8 million residents). Among 552,581 study subjects, we found that there were 1836 fatalities during the isolation period (up to 28 days from date of onset). The highest age-standardized CFR (0.85%, 95% confidence interval (CI):0.78-0.92) was observed in cases diagnosed in the second 4-week period (January 31 to February 27), after which it declined significantly up to the 6th 4-week period (0.23%, 95% CI: 0.13-0.33, May 23 to June 19). The CFR then increased again but remained at 0.39% in the eighth period (July 18 to August 28). The CFR in cases with the BA.2 or BA.5 sublineages in the age range 60-80 years was significantly lower than that with BA.1 infections (60 years: 0.19%, 0.02%, 0.053%, respectively; 70 years: 0.91%, 0.33%, 0.39%; ≥80 years: 3.78%, 1.96%, 1.81%, respectively). We conclude that the risk of death in Japanese COVID-19 patients infected with Omicron variants declined through February to mid-June 2022.

Ascending aortic aneurysm exposed to direct impingement of eccentric flow jets through a tilting-disc valve prosthesis.

Single-leaflet tilting-disc aortic valve prostheses are known to generate eccentric transvalvular flow jets. These prostheses are routinely inserted with the major valve opening directed toward the non-coronary sinus to achieve more favorable hemodynamic performance. From the viewpoint of blood flow dynamics, the structural and functional properties of tilting-disc aortic valves resemble those of congenital bicuspid aortic valves with right- and left-coronary leaflet fusion, which have been associated with aortopathy in the ascending aorta. Here we describe the case of a patient who had undergone aortic valve replacement in 1987 with a Björk-Shiley tilting-disc valve and required reoperation for ascending aortic aneurysm 29 years later. Eccentric flow jets through the tilting-disc valve directly impinged on the posterior wall of the ascending aorta including the aortotomy suture line, possibly contributing to the development of the saccular aneurysm in the ascending aorta.

To repair or not to repair: a case report of atrioventricular groove hematoma during mitral valve surgery.

BACKGROUND: Atrioventricular groove hematomas during mitral valve surgery range from simple hematomas to complex atrioventricular disruptions that cause frank rupture with massive bleeding and subsequent mortality. A small or moderate-sized hematoma is reported to be present in the left atrioventricular groove in 10 to 30% of all patients immediately after mitral valve replacement. Despite the fact that atrioventricular groove hematomas are inherently unstable and unpredictable, conservative strategies are recommended due to the high mortality associated with additional surgical repair. Such conservative strategies, however, would not resolve the potential risk of rupture, and there also appears to be a certain degree of uncertainty to be overcome using the current advances in cardiac surgery. CASE PRESENTATION: We present a case of atrioventricular hematoma during double valve replacement which was treated with conservative management. A left ventricular pseudoaneurysm developed after surgery, but spontaneously resolved completely within six months. After reflecting on our case, we developed a check sheet, including the anesthesiologist's transesophageal echocardiography findings, for reasonable intraoperative decision-making regarding conservative management vs. additional surgical repair. Our check sheet helps organize the pathophysiological understanding of the injury and integrates partial findings from complementary viewpoints, and can be used to accurately assess intense situations and develop a common understanding among surgical team members. CONCLUSIONS: Our case involved an atrioventricular groove hematoma that occurred during mitral valve surgery and caused a left ventricular pseudoaneurysm. Conservative strategies yielded positive results. We hope our experience and original check sheet will be of value to surgical teams facing similar situations.

Familial campomelic dysplasia due to maternal germinal mosaicism.

Campomelic dysplasia is an autosomal dominant skeletal dysplasia caused by heterozygous SOX9 mutations. Most patients are sporadic due to a de novo mutation. Familial campomelic dysplasia is very rare. We report on a familial campomelic dysplasia caused by maternal germinal mosaicism. Two siblings showed the classic campomelic dysplasia phenotype with a novel SOX9 mutation (NM_000346.3: c.441delC, p.(Asn147Lysfs*36)). Radiological examination of the mother showed mild skeletal changes. Then, her somatic mosaicism of the mutation was ascertained. This is the first report of molecularly confirmed maternal germinal mosaicism for a SOX9 mutation. We suggest that a meticulous clinical examination of the parents, even if they are superficially healthy, is needed to avoid overlooking germinal mosaicism of SOX9 mutations.

[Thoracic Endovascular Aortic Aneurysm Repair in a Young Patient with Descending Aortic Injury;Report of a Case].

A 15-year-old boy was referred to our emergency room due to a penetrating injury of the back. Computed tomography( CT) demonstrated a descending aortic injury at the Th9/10 level, bilateral hemothorax, and spinal cord injury. Although surgical treatment was indicated, multiple organ injury complicated open surgical repair, which required cardiopulmonary bypass with full heparinization. Therefore, the patient was scheduled to undergo thoracic endovascular aortic repair (TEVAR). A 23×33-mm Excluder aortic extension cuff was chosen for the small, 15-mm diameter aorta. The aortic extension was delivered and deployed in the descending aorta. Postoperative CT demonstrated neither endoleak nor collapse of the stent-graft. TEVAR for traumatic aortic aneurysm appears to be safe and effective, and an aortic extension for an abdominal aortic aneurysm may be utilized as an alternative device if the patient is young and the aorta is small.

Early detection and response for measles and rubella cases through the (Nursery) School Absenteeism Surveillance System in Ibaraki Prefecture.

Objectives In Ibaraki Prefecture, all (nursery) schools have joined the (Nursery) School Absenteeism Surveillance System (hereafter denoted as (N)SASSy), which is operated by the Japan School Health Association to monitor the prevalence of infectious diseases, the early detection and response for outbreaks, and prevention of large outbreaks. Prefectural government officers also utilize it as a control measure for infectious diseases. In particular, when cases of measles or rubella are registered, (N)SASSy sends e-mails automatically to prefectural government officers to activate control measures. This paper summarizes administrative responses by prefectural government officers for measles or rubella cases using (N)SASSy and discusses the future challenges.Methods We summarized registration, detection, and first response data for measles or rubella cases in (N)SASSy and compared the number of detected and reported cases enforced by the Infectious Diseases Control Law from January 1, 2013 to December 31, 2014.Results The public health center questioned hospitals/clinics and (nursery) schools about all registered measles or rubella cases in (N)SASSy on the same day to check the entered information. In the past 2 years, there were 5 measles and 56 rubella cases in 2013 and 1 measles and 19 rubella cases in 2014 registered with (N)SASSy. All cases were checked and investigated by the public health center. Of all cases detected by (N)SASSy, 7 rubella cases in 2013 and 1 rubella case in 2014 were reported based on the law. No measles cases were reported in the 2 years. The results of investigations and laboratory tests were given as feedback to the (nursery) schools. If the case did not case definition determined by the law, we changed the status in (N)SASSy to suspected or discarded cases.Conclusion Since (N)SASSy assists prefectural government officers with earlier detection of and response for infectious diseases, it definitely contributes to infection control. Immediate feedback of the laboratory test results to the (nursery) schools was also useful to confirm cases of measles or rubella. As data entry in (nursery) schools is needed for stable operation and utilization of (N)SASSy, it is important that workshops for (N)SASSy are held for (nursery) school teachers every year to maintain accuracy. Our future challenges include the coordination among (nursery) schools, hospitals/clinics, and prefectural government and their applications for infection control.

Abnormal cardiac axis as a prenatal marker of left pulmonary artery sling.

Left pulmonary artery sling (LPAS) is a rare vascular anomaly. The left pulmonary artery arises distally from the right pulmonary artery on the right side of the trachea and passes between the trachea and esophagus towards the left lung, compressing the lower trachea. LPAS is associated with congenital tracheal stenosis, which frequently requires early surgical intervention and has a poor prognosis due to severe airway obstruction after birth. Therefore, LPAS should be prenatally diagnosed to prepare for surgical intervention for tracheal stenosis. To the best of our knowledge, there are few reports on prenatal echocardiographic findings in LPAS. We report three prenatal cases of LPAS, which resulted in respiratory symptoms. We discuss fetal ultrasound findings and highlight the abnormal rotation of the fetal cardiac axis to the right as a useful sign in the prenatal screening of LPAS.

Utility of serum ferritin and lactate dehydrogenase as surrogate markers for steroid therapy for Mycoplasma pneumoniae pneumonia.

INTRODUCTION: Patients with severe mycoplasma pneumonia having very high serum interleukin-18 levels may require systemic corticosteroid treatment. However, we know of no laboratory markers that have been identified to assess the precise severity of Mycoplasma pneumoniae pneumonia. Thus, we investigated the usefulness of four clinical laboratory tests as severity indicators and surrogate markers for initiation of steroid therapy in these patients. PATIENTS AND METHODS: For 22 Japanese children (including 3 patients who needed systemic corticosteroid therapy) diagnosed with Mycoplasma pneumoniae pneumonia, white blood cell counts and serum concentrations of interleukin-18, C-reactive protein, lactate dehydrogenase, and ferritin were determined in the acute and recovery phases. RESULTS: In total, 8 and 14 patients were classified as moderate and mild pneumonia, respectively, according to clinical manifestations. The serum interleukin-18 level in the acute phase of the pneumonia group was significantly higher than that of age-matched controls. Furthermore, serum interleukin-18, lactate dehydrogenase and ferritin levels in the acute phase increased in parallel with the severity of the pneumonia. The serum ferritin level was also higher in the acute phase than in the recovery phase. Positive correlations between the levels of serum interleukin-18, lactate dehydrogenase and ferritin were observed in the acute phase. CONCLUSIONS: Serum lactate dehydrogenase and ferritin levels may be useful as indicators of the severity of pediatric Mycoplasma pneumoniae pneumonia for initiation of corticosteroid therapy.

[Minimally Invasive Aortic Valve Replacement for Aortic Stenosis after Renal Transplantation;Report of a Case].

A 41-year-old man was referred to our department for surgical treatment for aortic stenosis 7 years after renal transplantation. He had been diagnosed with aortic stenosis by echocardiography a year before. He had syncopal attack during exercise 2 months before and surgical treatment had been indicated. We successfully performed aortic valve replacement via right mini-thoracotomy in the 4th intercostal space. Cardiac surgery after renal transplantation is rare and many complications may happen. Minimally invasive cardiac surgery is considerated to be useful in minimizing mediastinitis in patients on immune suppressants.

Potent vasodilatory effect of fasudil on radial artery graft in coronary artery bypass operations.

BACKGROUND: The radial artery (RA) is a useful conduit for coronary artery bypass grafting (CABG) but is susceptible to vasospasm during harvesting. We evaluated the usefulness of fasudil, a Rho kinase inhibitor, in dilating the RA graft and increasing graft free flow (GFF) compared with the conventional graft-dilating agents papaverine and verapamil-nitroglycerin (VG). METHODS: Between June 2012 and January 2013, 45 patients with ischemic heart disease who underwent isolated CABG using the RA were enrolled and randomly assigned to fasudil (n = 15), papaverine (n = 15), or VG (n = 15). Fasudil (2.67 mmol/L), papaverine (1.0 mmol/L) mixed with heparinized blood, or VG (30 µmol/L each of verapamil and nitroglycerin) was injected intraluminally into the RA graft after harvesting. Main outcome measures were RA GFF, hemodynamic changes, and histopathologic examination of the RA. RESULTS: In the fasudil group, GFF increased significantly (p < 0.001) from 36.8 ± 20.4 at baseline to 148.0 ± 88.3 mL/min after injection. GFF increased significantly (p < 0.001) from 36.0 ± 19.0 to 72.3 ± 36.7 mL/min in the papaverine group and increased significantly (p < 0.001) from 39.5 ± 23.3 to 64.3 ± 29.9 mL/min in the VG group. The GFF was significantly higher (p = 0.001) in fasudil-treated RA than in papaverine- or VG-treated RA. Histopathologically, RA graft diameter was markedly increased after fasudil injection, and the structure of the multiple elastic lamellae was intact. Blood pressure did not change significantly after drug injection in all groups. CONCLUSIONS: Fasudil exhibited a very potent vasodilatory effect on the RA compared with conventional papaverine or VG, resulting in increased GFF. This agent is useful for dilating RA grafts in CABG.

Liver disease is frequently observed in Down syndrome patients with transient abnormal myelopoiesis.

Transient abnormal myelopoiesis (TAM) in neonates with Down syndrome (DS) is characterized by the transient appearance of blast cells, which resolves spontaneously. Approximately 20 % of patients with TAM die at an early age due to organ failure, including liver disease. We studied 25 DS-TAM patients retrospectively to clarify the correlation between clinical and laboratory characteristics and liver diseases. Early death (<6 months of age) occurred in four of the 25 patients (16.0 %), and two of those four patients died due to liver failure. Although physiologic jaundice improved gradually after a week, all DS patients had elevated D-Bil levels during the clinical course of TAM, except one who suffered early death. The median peak day of the WBC count, total bilirubin (T-Bil) and D-Bil levels was: day 1 (range day 0-57), day 8 (range day 1-55), and day 17 (range 1-53), respectively. Our results reveal that all patients with DS-TAM may develop liver disease irrespective of the absence or presence of symptoms and risk factors for early death. In patients of DS-TAM, careful observation of the level of D-Bil is needed by at least 1 month of age for the detection of liver disease risk.

DDX6 post-transcriptionally down-regulates miR-143/145 expression through host gene NCR143/145 in cancer cells.

In various human malignancies, widespread dysregulation of microRNA (miRNA) expression is reported to occur and affects various cell growth programs. Recent studies suggest that the expression levels of miRNAs that act as tumor suppressors are frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription, and disturbances in miRNA processing. MiR-143 and -145 are well-recognized miRNAs that are highly expressed in several tissues, but down-regulated in most types of cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that DEAD-box RNA helicase 6, DDX6 (p54/RCK), post-transcriptionally down-regulated miR-143/145 expression by prompting the degradation of its host gene product, NCR143/145 RNA. In human gastric cancer cell line MKN45, DDX6 protein was abundantly expressed and accumulated in processing bodies (P-bodies). DDX6 preferentially increased the instability of non-coding RNA, NCR143/145, which encompasses the miR-143/145 cluster, and down-regulated the expression of mature miR-143/145. In human monocytic cell line THP-1, lipopolysaccharide treatment promoted the assembly of P-bodies and down-regulated the expression of NCR143/145 and its miR-143/145 rapidly. In these cells, cycloheximide treatment led to a loss of P-bodies and to an increase in NCR143/145 RNA stability, thus resulting in up-regulation of miR-143/145 expression. These data demonstrate that DDX6 contributed to the control of NCR143/145 RNA stability in P-bodies and post-transcriptionally regulated miR-143/145 expression in cancer cells.

Fasudil is a superior vasodilator for the internal thoracic artery in coronary surgery.

BACKGROUND: The internal thoracic artery (ITA) is a very useful conduit for coronary artery bypass artery (CABG), with excellent long-term patency. With the purpose to dilate the ITA graft and increase graft free flow (GFF) intraoperatively, we evaluated the usefulness of intraluminal injection of fasudil, a Rho-kinase inhibitor, in comparison to the conventional graft dilating agent, papaverine. METHODS: Between June 2011 and January 2012, 30 patients with ischemic heart disease who underwent isolated CABG using ITA were enrolled. The patients were randomly assigned to 2 groups: the fasudil group (n = 15) in which fasudil solution 0.9 mg/dL was injected into the ITA, and the papaverine group (n = 15) in which papaverine solution (0.4 mg/mL) mixed with heparinized blood was used. Outcome measures were left ITA GFF, heart rate, and mean blood pressure during flow measurements, and histopathologic examination of the ITA. RESULTS: In the fasudil group, GFF increased significantly (p < 0.01) from 19.7 ± 15.2 mL/minute at baseline to 66.9 ± 31.7 mL/minute after fasudil injection. In the papaverine group, GFF increased significantly (p < 0.01) from 22.9 ± 17.3 mL/minute at baseline to 44.8 ± 26.7 mL/minute after papaverine injection. Blood pressure and heart rate did not change significantly after drug injection in both groups. The GFF was significantly higher (p = 0.038) in fasudil-treated ITA than in papaverine-treated ITA. Histopathologically, the diameter of the ITA was markedly increased after fasudil injection. Elastica van Gieson staining showed that the multiple elastic lamellae structure was intact. CONCLUSIONS: Fasudil exhibited very potent vasodilatory effect on the ITA compared with conventional papaverine resulting in increased GFF. This agent is a useful graft dilating agent.

Intraradial administration of fasudil inhibits augmented Rho kinase activity to effectively dilate the spastic radial artery during coronary artery bypass grafting surgery.

OBJECTIVES: Radial arteries are increasingly used as conduits for coronary artery bypass grafts. However, vasospasm continues to be a major concern in radial artery grafts. Rho kinase plays a critical role in vascular contraction through phosphorylation of the regulatory subunit myosin phosphatase targeting subunit 1 (MYPT1) of the myosin light chain phosphatase to inhibit myosin light chain phosphatase in vascular smooth muscle. The purpose of this study was to evaluate the inhibitory effects of fasudil, a clinically used Rho kinase inhibitor, on Rho kinase activity, myosin light chain phosphorylation, in vitro contraction, and in situ vasospasm in radial arteries of patients undergoing coronary artery bypass grafting surgery. METHODS: The inhibitory efficacy of fasudil on vasoconstrictor-induced contraction and phosphorylation of MYPT1 was examined in radial artery rings. In situ phosphorylation of MYPT1 was evaluated in nonspastic and spastic radial arteries, and the effects of intraluminal administration of fasudil and verapamil-glyceryl trinitrate (VG) on in situ free blood flow and phosphorylation of MYPT1 and myosin light chain were compared in spastic radial arteries. RESULTS: Both fasudil and VG nearly fully inhibited noradrenaline- and serotonin-induced contraction of radial artery rings. However, fasudil but not VG abolished MYPT1 phosphorylation. In spastic radial arteries phosphorylation of MYPT1 and myosin light chain was increased compared with that seen in nonspastic arteries. Intraradial administration of fasudil induced a much larger increase in in situ free blood flow compared with VG treatment. This antispastic effect of fasudil was accompanied by marked decreases in phosphorylation of MYPT1 and myosin light chain. CONCLUSIONS: Fasudil is a very effective Rho kinase inhibitor that deinhibits myosin light chain phosphatase and powerfully relieves vasospasm in situ in radial arteries.

Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells.

MiR-34a was identified as one of the down-regulated micro-RNAs (miRs) in human colorectal cancer 5-fluorouracil (5-FU)-resistant DLD-1 cells compared with those in the parental DLD-1 cells. Exposure to 5-FU at 30 µM activated phosphoinositide 3-kinase (PI3K)/Akt signaling markedly from 12h up to 48 h in the 5-FU-resistant cells compared with that in the parental cells and resulted in an overt difference in growth at those times. Furthermore, the expression of miR-34a in the 5-FU-resistant cells was sustained at a low-level, whereas it was up-regulated in the parental cells after the 5-FU treatment. Sirt1, which is one of the target genes for miR-34a and related to drug-resistance, was strikingly up-regulated in the 5-FU-resistant cells. The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3. Moreover, the silencing of Sirt1 significantly canceled the resistance to 5-FU in the 5-FU-resistant cells. These findings suggest that miR-34a targeting the Sirt1 and E2F3 genes could negatively regulate, at least in part, the resistance to 5-FU in human colorectal cancer DLD-1 cells.