Role of Piezo1 in modulating the RANKL/OPG ratio in mouse osteoblast cells exposed to Porphyromonas gingivalis lipopolysaccharide and mechanical stress.

AIMS: Excessive occlusal force with periodontitis leads to rapid alveolar bone resorption. However, the molecular mechanism by which inflammation and mechanical stress cause bone resorption remains unclear. We examined the role of Piezo1, a mechanosensitive ion channel expressed on osteoblasts, in the changes in the receptor activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) ratio in mouse MC3T3-E1 osteoblast-like cells under Porphyromonas gingivalis lipopolysaccharide (P.g.-LPS) and mechanical stress. METHODS: To investigate the effect of P.g.-LPS and mechanical stress on the RANKL/OPG ratio and Piezo1 expression, we stimulated MC3T3-E1 cells with P.g.-LPS. After 3 days in culture, shear stress, a form of mechanical stress, was applied to the cells using an orbital shaker. Subsequently, to investigate the role of Piezo1 in the change of RANKL/OPG ratio, we inhibited Piezo1 function by knockdown via Piezo1 siRNA transfection or by adding GsMTx4, a Piezo1 antagonist. RESULTS: The RANKL/OPG ratio significantly increased in MC3T3-E1 cells cultured in a medium containing P.g.-LPS and undergoing mechanical stress compared to cells treated with P.g.-LPS or mechanical stress alone. However, the expression of Piezo1 was not increased by P.g.-LPS and mechanical stress. In addition, phosphorylation of MEK/ERK was induced in the cells under P.g.-LPS and mechanical stress. MC3T3-E1 cells treated with P.g.-LPS and mechanical stress when cocultured with RAW264.7 cells induced their differentiation into osteoclast-like cells. The increased RANKL/OPG ratio was suppressed by either Piezo1 knockdown or the addition of GsMTx4. Furthermore, GsMTx4 inhibited the phosphorylation of MEK/ERK. CONCLUSION: These findings suggest that P.g.-LPS and Piezo1-mediated mechanical stress induce MEK/ERK phosphorylation and increase RANKL expression in osteoblasts. Consequently, this leads to the differentiation of osteoclast precursor cells into osteoclasts.

Social networking service messages improve novice trainees' motivation and performance of skills.

PURPOSE: We examined the usefulness of positive social networking service (SNS) messages to improve motivation and performance during off-the-job training. METHODS: Subjects were sixth-year medical students who completed a 4-week clinical clerkship in our department involving two separate tasks. Time taken to perform the tasks was recorded on Days 1, 14, and 28. All trainees voluntarily practiced the task until Day 14. The trainees were classified into two groups according to the results of their time measurements on Day 14. The slow time group was intervened with SNS messages (SNS group) and the fast time group was not intervened (non SNS group, nSNS). The SNS group received messages from the moderator daily or every other day. The time to complete the skills practiced in the first (Days 1-14) and second half (Days 15-28) were recorded for each group. RESULTS: On Day 14, the time for both tasks of the nSNS group was significantly faster than the SNS group. However, there was no significant time difference on Day 28. During Days 15-28, the SNS group had significantly more practice days than the nSNS group (5.3 vs. 3.8 days, p = .023). On questionnaire, all SNS group participants indicated that the messages increased their motivation to practice. CONCLUSIONS: SNS messages using smartphones might have increased motivation for task training and improved the performance of tasks in off-the-job training for novice trainees.

Regeneration of the ureter using a scaffold-free live-cell structure created with the bio-three-dimensional printing technique.

Ureteral strictures, which can be caused by ureteral injury, radiation therapy, ureterolithiasis, urinary tract infections, and ureteral endometriosis, typically require ureteral reconstruction. Although tissue engineering, autologous alternative tissue transplantation, and surgical techniques applying various flaps have been carried out for ureteral regeneration, all with some success, each method has its advantages and disadvantages. As an alternative, we created the first artificial ureter structures using only live cells and grafted them into healthy rat ureters. Spheroids were created using normal human dermal fibroblasts and human umbilical vein endothelial cells and subsequently laminated using a bio-three-dimensional printer. After molding the laminated spheroids into tubular structures, the artificial ureters were transplanted into live rats. After 2-12 weeks, the animals were sacrificed and their gross and pathological features were examined. In the artificial ureteral lumen of rats with Grade 0-1 hydronephrosis, regeneration of the ureteral epithelium was observed, the thickness of which increased over the course of the experiment. Regeneration of the muscular layer was also observed, extending from the normal ureteral side toward the artificial ureter structure over time. However, complete regeneration was not observed at the end of 12 weeks. Although ureteral peristalsis was noted in all cases, it was weaker than expected. Therefore, we achieved short-segment ureteral regeneration using a cell-only structure. This finding suggests that by applying alternative strategies to this method, such as changing the cell type and composition, regeneration over the entire length of the ureter may be possible in the future. STATEMENT OF SIGNIFICANCE: Until now, ureteral regeneration techniques have been dominated by the use of high-molecular-weight compounds and autologous tissues, and there have been no reports of regeneration using structures made entirely of cells. This is the first report of ureteral regeneration using a tubular structure made from stacked spheroids. Although this study only attained short-segment ureteral regeneration, regeneration of the ureter over a much longer proportion of its length can be achieved in the future by applying other strategies, such as changing the cell type. This study provides a foundation to achieve the future goal of complete regeneration.

Recurrence of idiopathic pulmonary hemosiderosis in adults with childhood onset: A case report and literature review.

We describe a rare case of a 20-year-old Japanese man with idiopathic pulmonary hemosiderosis (IPH) recurrence in adults with childhood onset (racIPH). IPH commonly occurs in children, and data regarding racIPH are lacking. A review of the literature showed that only five cases of racIPH have been reported (including the present case) and that racIPH shows features that are intermediate between childhood- and adult-onset IPH with respect to age and a lower frequency of smoking history. We also found that the degree of anemia was usually not severe, and a favorable response to corticosteroid therapy is expected in racIPH.

Spontaneous intraperitoneal renal rupture with urinoma formation in the fetus.

Spontaneous intraperitoneal renal rupture with urinoma formation in fetuses is an unusual condition that is caused by upper or lower urinary tract obstruction. We report the case of a neonatal male infant who presented with a spontaneous intraperitoneal right renal rupture accompanying ipsilateral ureterovesical junction obstruction (UVJO). Fetuses with UVJO accompanying contralateral multicystic dysplastic kidney should be observed carefully because of the risk of spontaneous renal rupture.

[Chronic active Epstein-Barr virus infection with multiple vascular lesions successfully treated by cord blood transplantation].

An 18-year-old woman presented with fever and liver dysfunction. Computed tomography showed lymphadenopathy, hepatosplenomegaly, and vascular lesions such as aneurysms and irregularities at multiple arteries, including coronary arteries. Based on the high copy number of Epstein-Barr virus (EBV)-DNA in the peripheral blood, EBV-infected CD4+T cells, and the proliferation of EBER-positive cells in the bone marrow, chronic active EBV infection (CAEBV) was diagnosed. Although the fever and liver dysfunction improved as a result of the initial immunosuppressive therapy and multiagent chemotherapy, EBV-DNA remained high. Moreover, she experienced repeated episodes of angina pectoris due to coronary arterial lesions. Therefore, cord blood transplantation was performed after reduced-intensity conditioning. EBV-DNA decreased quickly after initiating the conditioning and became undetectable at day 7 after the transplant. Vascular lesions did not progress after the transplant, and the patient's angina pectoris resolved. At 2.5 years after the transplant, she is alive without disease recurrence. The prognosis of CAEBV with vascular lesions is especially poor. Although the indication for allogeneic hematopoietic stem cell transplantation (HSCT) is difficult to determine in such cases, the clinical course of our case suggests that allogenic HSCT could be safely performed under appropriate management and could successfully control not only CAEBV but also vascular lesions.

[Efficacy of photocatalytic air purifiers in reducing dimethyl sulfide malodor following cryopreserved peripheral blood stem cell infusion].

Dimethyl sulfoxide (DMSO) is used as a cryoprotectant for peripheral blood stem cells (PBSC) preservation. Dimethyl sulfide (DMS) is a metabolite of DMSO secreted through patients' breath after PBSC infusion. It possesses malodor causing an unpleasant environment. We evaluated the efficacy of a photocatalyst environment purifier, which has the potential to lyse toxic substances, in reducing DMS malodor. High DMS concentration in the air after PBSC infusion rapidly decreased after operating the device. Our results suggest that photocatalytic reaction has the potential to reduce the DMS odor associated with PBSC infusion.

Acute Bromide Intoxication in a Patient with Preserved Renal Function.

BACKGROUND Electrolyte imbalance is frequent in many situations, but severe hyperchloremia is markedly rare in the absence of renal impairment. We report a patient with preserved renal function who exhibited severe hyperchloremia and negative anion gap. CASE REPORT A 70-year-old female with preserved renal function presented with fatigue and impaired consciousness. Venous blood gas analysis was notable for a chloride level of 137 mEq/L and anion gap of -18.2 mEq/L. Careful history taking revealed that she had taken bromide-containing over-the-counter painkillers. Her symptoms and laboratory tests gradually improved after intravenous hydration and painkiller withdrawal. The serum level of bromide ions on admission was later found to be 4-times higher than that considered toxic. CONCLUSIONS It is important to recognize that hyperchloremia with a negative anion gap strongly suggests bromide intoxication, and that bromide intoxication can develop even in patients with preserved renal function. Careful history taking is essential to the diagnosis because some over-the-counter drugs that are widely available and a few prescription drugs contain bromides.

Immobilization of DNA on Quartz Crystal Microbalance Sensor Modified with Self-Assembled Monolayer of Thiol Derivative.

In this study, we investigated the direct detection of DNA, without pretreatment, using a quartz crystal microbalance (QCM) sensor. This sensor is modified by a self-assembled monolayer of a thiol derivative that has an amino group as the terminal functional group. Contact angle values and the attenuated total reflectance Fourier transform infrared (ATR/FT-IR) spectra of the QCM sensors after immersion into an ethanol solution of thiol derivatives clearly showed that self-assembled monolayers of the derivatives were formed on the QCM sensors. Although QCM measurements using unmodified and carboxylic group-modified sensors could not detect DNA-Na salt, the sensor modified with amino groups could detect the DNA. This system can be used for the analysis of the interaction between DNA and DNAbinding proteins.

Ethanol lock therapy in pediatric patients: A multicenter prospective study.

BACKGROUND: Ethanol lock therapy (ELT) has been performed for the purpose of preserving central venous catheters (CVC) in central venous catheter-related blood stream infection (CRBSI), but evidence for its effectiveness is not established. We conducted a multicenter, prospective study on the ELT protocol to ascertain its safety and effectiveness against CRBSI. METHODS: The subjects were patients aged over 1 year with potential for developing CRBSI who had long-term indwelling silicone CVCs. After culturing the catheterized blood, a 70% ethanol lock was performed daily for 2-4 h for 7 days. The effectiveness rate of ELT for single and multiple courses, the presence or absence of relapse of CRBSI within 4 weeks of treatment, and whether the CVC could be salvaged after 4 weeks were examined. RESULTS: From September 2014 to August 2018, 49 cases from six hospitals were enrolled in the study. Catheter blockage was seen in one case and the CVC was removed. A single course of ELT was effective in episodes 88% (42/48). In the remaining three episodes that failed after a single course of ELT, a second ELT was performed; however, all were ineffective. In episodes 93% (40/42), no CRBSI relapse was seen up to 4 weeks after the end of treatment. In episodes 84% (41/49), the catheter could be preserved for 4 weeks or more after the end of treatment. Facial flushing was seen in two cases as an adverse event; however, this was transient and soon disappeared. CONCLUSION: ELT is effective for 88% of CRBSI and 84% of catheters can be salvaged; therefore, this protocol is considered useful. TRIAL REGISTRATION: UMIN000013677.

Renal dysfunction and anemia associated with long-term imatinib treatment in patients with chronic myelogenous leukemia.

Knowledge of the toxicity profile of long-term treatment with imatinib is limited. In the present study, we sought to evaluate renal function and hemoglobin levels during long-term imatinib treatment. Eighty-two patients with chronic myelogenous leukemia in chronic phase who had been on imatinib for over 5 years were retrospectively analyzed. The mean estimated glomerular filtration rate (eGFR) was significantly decreased over 5 years (77 ± 17 to 62 ± 14 ml/min/1.73m², P < 0.001). Higher age and lower eGFR value at initiation of imatinib were significantly associated with development of renal dysfunction by multivariate analyses. Mean hemoglobin levels also significantly decreased over the 5-year period (12.9 ± 1.7 to 12.4 ± 1.3 g/dl, P < 0.01). The rate of decrease in eGFR correlated significantly with hemoglobin levels (correlation coefficient = - 0.249, P < 0.05). Serum erythropoietin (EPO) levels did not increase in 16 patients with both renal dysfunction and anemia (median, 31.9 mIU/ml). In patients who participated in a clinical trial of imatinib discontinuation, mean eGFR (50.0 ± 6.5 to 56.0 ± 10.2 ml/min/1.73m², P < 0.05) and hemoglobin levels (12.0 ± 1.7 to 14.0 ± 1.6 g/dl, P < 0.01) improved significantly at 1 year after discontinuation. These findings suggest that long-term imatinib results in a partially reversible continuous decline in renal function and decreased hemoglobin levels.

Invasive hepatic mucormycosis: A case report and review of the literature.

Mucormycosis generally develops under immunocompromised conditions, including hematological malignancies and solid organ or hematopoietic stem cell transplantation. Although mucormycosis usually affects the lungs and paranasal sinuses, sporadic cases of invasive mucormycosis of the liver have been reported. We hereby report a patient with myelofibrosis who developed hepatic mucormycosis diagnosed by post-mortem examination. An extensive literature review identified 13 reported cases of hepatic mucormycosis, including ours, without lung involvement. Most of the underlying diseases or conditions were hematological malignancies and solid organ transplantation. Three cases had splenic lesions and four had gastrointestinal lesions, suggesting the possibility of translocation to the liver and/or spleen from the gastrointestinal tracts. Hepatic mucormycosis should be recognized as one of the presentations of invasive mucormycosis, especially when hepatic nodules are found in immunocompromised patients such as those with hematological malignancy or recipients of solid organ transplantation.

Very Late Relapse of Acute Promyelocytic Leukemia 17 Years after Continuous Remission.

The prognosis of acute promyelocytic leukemia (APL) has been improved by the combination of all-trans retinoic acid (ATRA) with chemotherapy. Nonetheless, relapse occurs in a certain proportion of patients, mostly within three to four years after treatment. We herein report a patient treated with ATRA and chemotherapy achieving remission who relapsed approximately 17 years after the treatment. A literature review identified 5 additional reported cases of APL relapse after more than 10 years. None of them presented with generally established risk factors for relapse, such as a high leukocyte count. The potential for late relapse of APL occurring more than 10 years after treatment should be recognized.

Initial experience with a 3D printed model for preoperative simulation of the Nuss procedure for pectus excavatum.

The incidence of pectus excavatum has been estimated to be between 0.1% and 0.8% though a large autopsy series reports. After publication of the Nuss procedure for pectus excavatum, it became widely accepted. However, there are still some complications, such as over-correction and recurrence. To reduce differences in the procedure due to surgeons' experience level, preoperative simulation may be useful. Thus, we performed simulated surgery using a specific patient's three-dimensional (3D) chest wall model made by a 3D printer before operation. A 13-year-old male patient with a severe deformity of the chest underwent the Nuss procedure. As in the simulation, bars were inserted into the 5th and 7th intercostal spaces (ICS), leading to improvement of the chest wall. This simulation can increase surgeons' confidence to improve the deformity by determination of the number and insertion sites of bars.

Recurrent bacterial pneumonia due to immunoglobulin G2 subclass deficiency after allogeneic hematopoietic stem cell transplantation: Efficacy of immunoglobulin replacement.

Immunoglobulin (Ig) G2 subclass deficiency is known to be associated with recurrent bacterial respiratory infections caused by capsulated bacteria. We encountered a case of recurrent pneumonia due to Streptococcus pneumoniae after allogeneic hematopoietic stem cell transplantation (HSCT). IgG2 subclass level was specifically low, and prophylactic Ig replacement successfully prevented subsequent infections. However, the cessation of Ig replacement resulted in subsequent pneumonia. These findings suggested that IgG2 deficiency could be a cause of recurrent pneumococcal infection after allogeneic HSCT.

Comparison of fluorine-18 fluorodeoxyglucose positron emission tomography with gallium-67 scintigraphy in the initial clinical staging of diffuse large B-cell lymphoma.

Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has been recommended as a complementary tool for the staging of various malignancies, including malignant lymphoma. PET findings often shift patients to higher stages and may affect treatment outcomes. In this study, we retrospectively compared staging and treatment outcomes of newly diagnosed diffuse large B-cell lymphoma (DLBCL) assessed by PET (n = 153) or gallium-67 scintigraphy (Ga) (n = 95). In total, Ga upstaged two (2.1%) of 95 patients, whereas PET upstaged 13 (8.5%) of 153 patients. Bone/bone marrow (15 vs. 4%, P = 0.01) and muscle lesion (5 vs. 0%, P = 0.03) were identified more frequently in the PET group than in the Ga group. The estimated 3-year overall and progression-free survival rates did not differ significantly in the two groups at any stage. However, patients with stage III disease tended to have better progression-free survival in the PET group than in the Ga group [92.3 (95% CI 56.6-98.9%) vs. 58.3% (95% CI 27.0-80.1%), P = 0.086]. These results suggest that PET has a greater potential in detecting musculoskeletal lesions of DLBCL as extranodal lesions than Ga, and may contribute to the optimal staging.

A Neonatal Case of Glial Choristoma of the Tongue Causing Airway Obstruction.

Glial choristoma is considered to be a type of brain heterotopia consisting of ectopic central nervous tissue. We herein report a neonate with glial choristoma of the tongue who developed respiratory distress due to airway obstruction. A male neonate presented with respiratory distress due to a soft mass on the midline region of the dorsal tongue base at birth. He was intubated using a flexible fiberoptic nasopharyngoscope. MRI showed a well-circumscribed mass measuring 25 × 23 × 27 mm in size in the same region. A histologic examination confirmed a pathological diagnosis of glial choristoma. He underwent tracheotomy at 22 days of age, and a subtotal resection of the tumor was performed at five months of age. The clinical behavior of oral glial choristoma varies depending on the age at onset as well as the location and size of the mass. The small size of the organ and the narrow operating field hamper the surgical approach in neonates. The optimal therapeutic strategy for neonatal cases of glial choristoma should thus be determined based on the condition of each individual patient.

Allogeneic hematopoietic stem cell transplantation following treatment with brentuximab vedotin for refractory Hodgkin lymphoma.

Brentuximab vedotin (BV) is a novel agent used for the treatment of relapsed or refractory Hodgkin lymphoma. We have described two patients with refractory Hodgkin lymphoma, who were successfully treated with BV followed by allogeneic hematopoietic stem cell transplantation (HSCT). Although both patients were resistant to conventional chemotherapies, they responded to four or five doses of BV given every 3 weeks. Then, the patients underwent bone marrow transplantation from unrelated donors after reduced-intensity conditioning consisting of fludarabine and melphalan. They remained progression-free for more than 3 years after the transplantation. These findings suggest that BV could be a promising bridging therapy to curative allogeneic HSCT for relapsed or refractory Hodgkin lymphoma. Further accumulation of such cases is warranted to evaluate the efficacy and safety of BV therapy prior to allogeneic HSCT.

Effects of calcineurin inhibitors on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation.

Calcineurin inhibitors (CIs) such as cyclosporine A (CSA) and tacrolimus often cause renal dysfunction, resulting in increased serum creatinine, hyperkalemia, and hyperuricemia. However, the effects of CIs on sodium excretion have not been fully elucidated. We retrospectively evaluated the effects of CI administration on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Fifty consecutive recipients each of allogeneic HSCT receiving either CSA or tacrolimus (100 patients in total) with available data for weekly fractional excretion of sodium (FENa) for a 4-week period after transplantation were enrolled in this retrospective analysis. No significant differences in patient characteristics were observed between CSA and tacrolimus groups except for the type of donor. FENa was significantly higher at the 3rd (1.25 ± 0.80) and 4th weeks (1.53 ± 1.06) after transplantation as compared with that at the 1st week (0.93 ± 0.51; P < 0.01, P < 0.001, respectively) in the tacrolimus group, but not at any time point in the CSA group. In addition, FENa was significantly higher in the tacrolimus group than the CSA group at the 4th week (1.53 ± 1.06 vs. 1.13 ± 0.80; P < 0.05). These results suggest that tacrolimus increases sodium excretion after allogeneic HSCT, and that this effect is minimal with CSA.

Hyponatremia associated with human herpesvirus-6 (HHV-6) encephalitis after allogeneic hematopoietic stem cell transplantation: A presentation different from HHV-6 myelitis.

Human herpesvirus-6 (HHV-6) encephalitis and myelitis following allogeneic hematopoietic stem cell transplantation (HSCT) is frequently life-threatening. We retrospectively evaluated the clinical significance of hyponatremia in cases of HHV-6 encephalitis/myelitis. Using an institutional database and medical records, we identified and retrospectively analyzed 16 cases of HHV-6 encephalitis and/or myelitis after allogeneic HSCT. HHV-6 encephalitis and myelitis were defined as the symptoms/signs with HHV-6-DNA in the cerebrospinal fluid. Seizure and memory disorder were defined as symptoms/signs of encephalitis, and dysesthesia and vesicorectal disorder as those of myelitis. Five patients developed encephalitis with or without myelitis, and 11 patients developed myelitis alone. Hyponatremia (median 129.1 mEq/L; range 125.9-130.1) was observed in all five patients with HHV-6 encephalitis at diagnosis, and values were significantly lower than those in patients with HHV-6 myelitis alone (median 137.6; range 134.0-142.2; P < 0.01). In three of the five patients with encephalitis, the decrease in sodium level preceded the clinical onset of encephalitis by one or two days. These results suggest that hyponatremia may be an important manifestation of HHV-6 encephalitis, but not of myelitis, and could be a useful tool for the early prediction or diagnosis of HHV-6 encephalitis.