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.

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.

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.

[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.

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.

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.

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.

Identification of dynamin-2-mediated endocytosis as a new target of osteoporosis drugs, bisphosphonates.

Nitrogen-containing bisphosphonates are pyrophosphate analogs that have long been the preferred prescription for treating osteoporosis. Although these drugs are considered inhibitors of prenylation and are believed to exert their effects on bone resorption by disrupting the signaling pathways downstream of prenylated small GTPases, this explanation seems to be insufficient. Because other classes of prenylation inhibitors have recently emerged as potential antiviral therapeutic agents, we first investigated here the effects of bisphosphonates on simian virus 40 and adenovirus infections and, to our surprise, found that viral infections are suppressed by bisphosphonates through a prenylation-independent pathway. By in-house affinity-capture techniques, dynamin-2 was identified as a new molecular target of bisphosphonates. We present evidence that certain bisphosphonates block endocytosis of adenovirus and a model substrate by inhibiting GTPase activity of dynamin-2. Hence, this study has uncovered a previously unknown mechanism of action of bisphosphonates and offers potential novel use for these drugs.

Decreased expression of microRNA-143 and -145 in human gastric cancers.

OBJECTIVE: Downregulation of specific microRNAs (miRNAs) occurs in human tumors, which suggests a function for miRNAs in tumor suppression. We investigated the role of the miRNAs miR-143 and miR-145 in gastric cancers. METHODS: The expression levels of miR-143 and miR-145 in the samples from 43 patients with gastric cancer were determined by real-time PCR using TaqMan assay. The growth inhibitory effect was estimated by the transfection of human gastric cancer cells with the miRNA. RESULTS: The expression levels of miR-143 and -145 were decreased in most human gastric cancers examined, as previously reported to occur in colon tumors. The transfection of human gastric MKN-1 cells with miR-145 resulted in a greater growth inhibitory effect than that with miR-143, results which were contrary to those in colon cancers. In MKN-1 cells, an additive effect on growth inhibition was shown by the combined transfection with miR-143 and miR-145; further, higher sensitivity to 5-fluorouracil was also observed following the transfection with miR-143 or miR-145. The possible candidate target messenger RNAs of miR-145 were identified to be insulin receptor substrate-1 and beta-actin. CONCLUSION: Taken together, these findings suggest that miR-143 and miR-145 act as anti-oncomirs common to gastrointestinal tumors.

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.

Phenotypic analysis of vertigo 2 Jackson mice with a Kcnq1 potassium channel mutation.

The KCNQ1 gene encodes a voltage-dependent potassium ion channel, and mutations in this gene are the most common cause of congenital long QT syndrome (LQTS). In the present study, we investigated the various phenotypic characteristics of vertigo 2 Jackson (C3H/HeJCrl-Kcnq1(vtg-2J)/J) mice with a Kcnq1 mutation. Both heterozygotes (vtg-2J/+) and homozygotes (vtg-2J/vtg-2J) showed prolonged QT intervals in electrocardiograms (ECGs) compared to C3H/HeJ control (+/+) mice. Furthermore, vtg-2J/vtg-2J mice showed gastric achlorhydria associated with elevation of their serum gastrin levels. The serum corticosterone levels were also significantly increased in vtg-2J/vtg-2J mice. In addition, vtg-2J/vtg-2J mice exhibited significantly higher blood pressure. These findings indicate that the Kcnq1 mutation in vtg-2J mice alters various physiological functions in the cardiac, gastric and adrenocortical systems, and suggest that vtg-2J mice may represent a useful model for studying Kcnq1 functions.

Identification of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible genes in human amniotic epithelial cells.

BACKGROUND: Exposure to dioxins results in a broad range of pathophysiological disorders in human fetuses. In order to evaluate the effects of dioxins on the feto-placental tissues, we analyzed the gene expression in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) treated primary cultures of human amniotic epithelial cells. METHODS: Human amniotic epithelial cells were dispersed by trypsin from amniotic membranes and cultured in DME/Ham's F12 medium supplemented with 10% FBS. Two weeks after plating, cells were treated with 50 nM TCDD or DMSO (control), further incubated for 48 hrs, and the gene expression was analyzed by DNA microarray technology and quantitative real-time PCR. RESULTS: Thirty eight TCDD-inducible genes, including cytochromeP4501A1 and cytochromeP4501B1, were identified. One of the remarkable profiles of the gene expression was the prominent up-regulation of interferon-inducible genes. The genes involved in the interferon gene expression and interferon signaling pathways were also up-regulated. Furthermore, the expression of genes related to collagen synthesis or degradation was enhanced by TCDD. CONCLUSION: Using DNA microarray and quantitative real-time PCR analyses, we identified TCDD-inducible genes, including interferon-inducible genes and genes related to collagen synthesis or degradation, in human amniotic epithelial cells.

Left-sided omental torsion with inguinal hernia.

We report a case of surgically proved left-sided torsion of the greater omentum that caused secondary by untreated inguinal hernia. Case A 36-year-old man presented to our hospital with abdominal pain. He had been diagnosed with a left inguinal hernia, but he had not received any treatments. Contrast-enhanced computed tomography (CT) of the abdomen showed a large fat density mass below the Sigmoid colon and left inguinal hernia with incarcerated fat. Exploratory laparotomy revealed torsion of the greater omentum with small bloody ascites. The greater omentum was twisted into one and a half circles and entered into a left inguinal hernia. An omentectomy with a repair of left inguinal hernia was performed. A resected omentum was submitted for pathological examination, which showed hemorrhagic infarction. Omental torsion is a rare cause of acute abdominal pain but should be included in the differential diagnoses of acute abdomen, especially in patients with untreated inguinal hernia.

[Effective treatment of unresectable advanced gastric cancer by TS-1-based chemotherapy with a sequential combination of cisplatin (CDDP) and paclitaxel (PTX)].

The patient was a 66-year-old female with Borrmann's type 4 gastric cancer complicated by metastasis to the liver and invasion of the head of the pancreas. Radical resection was not indicated, and only gastrojejunostomy was performed to bypass an existing pyloric obstruction. One course of chemotherapy was defined as 3 weeks of drug administration(TS-1 100 mg/body/day po for 21 days + CDDP 9 0 mg/body/day by iv drip on day 8), followed by a 2-week rest period. Chemotherapy was started 13 days after the operation, and it was possible to continue it for 7 courses. TS-1/CDDP therapy improved the patient's general condition. The tumor marker levels were also decreased. However, the efficacy of treatment began to decline,and ascites gradually developed during the fourth course of therapy. The treatment regimen was then switched to TS-1 100 mg/body/day po for 14 days, followed by a 14-day rest period, combined with PTX 9 0 mg/body/day iv drip on day 1 and day 15, while the ascites was being controlled. The ascites decreased significantly after the change in regimen, and the new regimen was continued for 6 courses. However, PTX was switched to CPT-11 because of gradual progression of peripheral neuropathy as a side effect of chemotherapy, and the patient subsequently died without any improvement in symptoms. This report describes a case of advanced gastric cancer treated by combination chemotherapy with TS-1 as a key drug, which resulted in a long survival (1 year and 5 months)and improvement in quality of life.

[A case of recurrent esophageal cancer successfully treated with weekly paclitaxel in combination with radiotherapy].

A 48-year-old man underwent subtotal esophagectomy for pStage III (pT 3 pN 3) thoracic esophageal carcinoma on June 20, 2002, in combination with chemotherapy (5-FU 500 mg/day day 1-14, CDDP 10 mg/day day 1-14, VDS 3 mg on days 1 and 8) before and after the operation. Recurrence was seen 7 months after the operation in right pleura and lower mediastinum. Chemo (same regimen)-radiotherapy (50 Gy) was then performed but without effect. Thereafter, lung and upper mediastinal metastases were found, and weekly administration of paclitaxel (70 mg/m2, day 1, 8, 15, q 4w) was initiated in combination with radiotherapy (40 Gy). Two cycles of treatment resulted in PR, and CR was achieved after the 8th cycle was completed. Although treatment was terminated after the 12 th cycle due to development of peripheral neuropathy (grade 2), CR was still maintained 8 months after the completion of treatment. These results suggested the effectiveness of the treatment in cases that show resistance to conventional 5-FU-based chemotherapy.