Early defibrotide therapy and risk factors for post-transplant veno-occlusive disease/sinusoidal obstruction syndrome in childhood.

BACKGROUND: Veno-occlusive disease (VOD), also known as sinusoidal obstruction syndrome (SOS), is a life-threatening complications of hematopoietic cell transplantation (HCT). METHODS: We studied the impact of early defibrotide (DF) therapy on the outcomes of pediatric patients with VOD/SOS after transplantation, focusing on recent immunotherapies. A total of 111 pediatric patients who underwent HCT for malignant disease between February 2017 and March 2023 at Kyushu University Hospital were included. RESULTS: Among 111 patients of less than 20 years of age who underwent HCT for malignancy at a single institution between 2017 and 2023, VOD/SOS occurred in 25 (23%) patients. VOD/SOS developed more frequently in the post-DF era (2020-2023, n = 58) than in the pre-DF era (31% vs. 13%, p = .04). The proportion of patients with relapsed/refractory acute lymphoblastic leukemia (ALL) was higher in the post-DF era than in the pre-DF era (44% vs. 8%, p = .04). Early DF therapy that was started at two European Society for Blood and Marrow Transplantation diagnostic criteria reduced the severity of VOD/SOS (p < .01) in comparison to non-early therapy started at less than two criteria. A multivariate analysis indicated that a history of cytokine release syndrome (odds ratio [OR] = 10.4, p = .01) and juvenile myelomonocytic leukemia (OR = 8.98, p = .04), but not an endothelial activation and stress index (EASIX) score of greater than 0.85, were independent risk factors for VOD/SOS. CONCLUSIONS: Early DF therapy improves the severity and survival outcomes of post-transplant VOD/SOS in children. However, its incidence is increasing in the era of immunotherapy for progressive diseases.

Evaluation of erythrocyte membrane oxidation due to their exposure to shear flow generated by extracorporeal blood pump.

Several similarities have been found between shear stress-induced erythrocyte damage and physiological aging of erythrocytes in terms of elevated mechanical fragility, increased erythrocyte aggregation, and decreased membrane surface charge. Accordingly, we hypothesized that blood pump circulation, which generates shear stress, would accelerate erythrocyte aging, manifesting as oxidation. Therefore, the purpose of this study was to investigate the effect of blood pump circulation on erythrocyte oxidation. Fresh porcine blood was acquired from a slaughterhouse and anticoagulated with sodium citrate. About 500 mL of anticoagulated whole blood was circulated for 180 min in an in vitro test circuit comprising a BP-80 blood pump with a pump speed and a pump pressure head of 100-120 mmHg. A blood sample was taken at the start of the circulation and 180 min afterward. The hemolysis level and oxidation amount of the erythrocyte membrane were analyzed and compared between samples. Hemolysis increased with the prolongation of shear exposure inside the pump circuit. After 180 min of blood pumping in circuit, the oxidation level of the erythrocyte membrane showed an increase of 0.1 nmol/mg protein. Moreover, the membrane oxidation levels of sheared erythrocytes were greater than those of control erythrocytes. These results suggest that blood pump circulation accelerates erythrocyte aging and give us a greater understanding of the effects of blood pump perfusion.

The shear rate promotes pinocytosis of extracellular dextran in platelets.

BACKGROUND: Several conventional studies focused on platelet pinocytosis for possible utilization as drug delivery systems. Although platelet pinocytosis is important in such utilization, the impact of the shear rate on pinocytosis is unclear. OBJECTIVE: Our objective was to investigate the relationship between shear rate and platelet pinocytosis in vitro. In addition, this study addressed the change in platelet aggregation reactivity with adenosine diphosphate (ADP) stimulation after pinocytosis. METHOD: Porcine platelet-rich plasma was mixed with fluorescein isothiocyanate (FITC)-conjugated dextran and incubated for 15 min under shear conditions of 0, 500, and 1500 s-1. After incubation, confocal microscopic scanning and three-dimensional rendering were performed to confirm the internalization of FITC-dextran into platelets. The amount of FITC-dextran accumulated via platelet pinocytosis was compared using flow cytometry at each shear rate. In addition, light transmission aggregometry by ADP stimulation was applied to platelets after pinocytosis. RESULTS: The amount of intracellular FITC-dextran increased with higher shear rates. Platelets with increased amounts of intracellular FITC-dextran did not show changes in the aggregation reactivity to ADP. CONCLUSIONS: A higher shear rate promotes platelet pinocytosis, but enhanced pinocytosis does not affect aggregation sensitivity, which is stimulated by ADP.

Differences in incidence rate and onset timing of undiagnosed finger symptom among shoulder surgeries related to complex regional pain syndrome.

The purpose of this study was to clarify the difference in onset timing and incidence of undiagnosed finger symptom (UDFS) between various shoulder surgical procedures. In this study, UDFS symptoms included the following four symptoms in the fingers;edema, limited range-of-motion, skin color changes, and abnormal sensations. UDFS cases were defined as those presenting with at least one UDFS. In result, the incidence rate of UDFS cases was 7.1% overall (58/816 shoulders), 7.4% (32/432) in arthroscopic rotator cuff repair (ARCR), 9.0% (11/122) in open rotator cuff repair (ORCR), 1.4% (2/145) in arthroscopic subacromial decompression (ASD), 13.2% (5/38) in open reduction and internal fixation (ORIF), 11.1% (3/27) in humeral head replacement, 4.8% (1/21) in anatomical total shoulder arthroplasty, and 12.9% (4/31) in reverse total shoulder arthroplasty cases. The Rate was significantly higher with ARCR compared to ASD (p<.01). About onset timing in weeks postoperatively, the ORIF group had a statistically earlier symptom onset than the Rotator cuff repair (ARCR + ORCR) group (2.4 weeks vs. 6.0 weeks, p<.01). When classifying the onset timing into before and after the removal of the abduction pillow, the ORIF group showed a statistically higher rate of onset before brace removal than the Rotator cuff repair groups (p<.01). Differences in UDFS among shoulder surgeries were demonstrated in this study. J. Med. Invest. 70 : 415-422, August, 2023.

Ultrasound assessment of sarcopenia in patients with rheumatoid arthritis.

OBJECTIVES: To evaluate the efficacy of ultrasound (US) as a diagnostic tool for sarcopenia in patients with rheumatoid arthritis (RA). METHODS: Female RA patients aged >50 years and matched controls were cross-sectionally assessed. Sarcopenia was diagnosed based on the 2019-updated Asian Working Group for Sarcopenia definition. The cross-sectional area (CSA) and echo intensity (EI) of the biceps brachii, rectus femoris, and EI of the vastus lateralis were examined bilaterally. Correction for subcutaneous fat and calculation of the recorrected EI (rcEI) were performed. We performed logistic regression using both muscle rcEI and CSA with receiver operating curve analysis to evaluate the discriminative performance per muscle group. RESULTS: Seventy-eight consecutive RA patients and 15 age-and sex-matched controls were assessed. Sarcopenia was diagnosed in 34 RA patients (43.6%). The rcEI of examined muscles were significantly higher, whereas CSA were significantly lower in sarcopenic RA patients than in non-sarcopenic patients and matched controls. The combined discriminative performance of rcEI and CSA was superior to those of rcEI or CSA alone. CONCLUSIONS: This study suggests the use of US for the diagnosis of sarcopenia in RA patients. The diagnostic performance increases when both echogenicity and CSA are considered together rather than individually.

Erythrocyte morphological symmetry analysis to detect sublethal trauma in shear flow.

The viscoelastic properties of red blood cells (RBC) facilitate flexible shape change in response to extrinsic forces. Their viscoelasticity is intrinsically linked to physical properties of the cytosol, cytoskeleton, and membrane-all of which are highly sensitive to supraphysiological shear exposure. Given the need to minimise blood trauma within artificial organs, we observed RBC in supraphysiological shear through direct visualisation to gain understanding of processes leading to blood damage. Using a custom-built counter-rotating shear generator fit to a microscope, healthy red blood cells (RBC) were directly visualised during exposure to different levels of shear (10-60 Pa). To investigate RBC morphology in shear flow, we developed an image analysis method to quantify (a)symmetry of deforming ellipsoidal cells-following RBC identification and centroid detection, cell radius was determined for each angle around the circumference of the cell, and the resultant bimodal distribution (and thus RBC) was symmetrically compared. While traditional indices of RBC deformability (elongation index) remained unaltered in all shear conditions, following ~100 s of exposure to 60 Pa, the frequency of asymmetrical ellipses and RBC fragments/extracellular vesicles significantly increased. These findings indicate RBC structure is sensitive to shear history, where asymmetrical morphology may indicate sublethal blood damage in real-time shear flow.

Expression profile of seven polyamine oxidase genes in rice (Oryza sativa) in response to abiotic stresses, phytohormones and polyamines.

Polyamine levels are controlled by biosynthesis, intra- and inter-cellular flux by the respective transporters, and catabolism. The catabolism is catalyzed by two groups of enzymes. One is copper-containing amine oxidases and the other is polyamine oxidases (PAOs). In Oryza sativa, seven PAO genes exist and they are termed as OsPAO1 to OsPAO7. However, their physiological function has not been elucidated yet. Here, we examined the expressional changes of seven OsPAO genes upon abiotic and oxidative stress, phytohormone, and exogenous polyamines application. The transcript of extracellular polyamine oxidase OsPAO2 and OsPAO6 are strongly induced upon wounding, drought, salinity, oxidative stress (H2O2), and exogenous application of jasmonic acid, spermidine, spermine, thermospermine and negatively regulated upon indole acetic acid, isopentenyl adenine (iPT), gibberellic acid (GA), abscisic acid; OsPAO7 is to iPT, GA and all polyamines; OsPAO4 and OsPAO5 are mildly responsive to heat, cold, oxidative stress. These results suggest that polyamine oxidase encoding extracellular enzyme may play a pivotal role during exogenous stimulus to protect the plant cell. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01006-1.

Correlation of Coronary Artery Abnormalities with Fever Pattern in Patients with Kawasaki Disease.

OBJECTIVE: To investigate the incidence of coronary artery abnormalities (CAAs) by fever pattern after intravenous immunoglobulin (IVIG) therapy in patients with Kawasaki disease. STUDY DESIGN: This retrospective cohort study included 172 patients with Kawasaki disease aged ≤12 years who underwent IVIG therapy and had no CAAs before treatment. Resistance to initial IVIG was defined as persistent fever ≥37.5 °C for ≥24 hours after therapy or the recurrence of Kawasaki disease after initial defervescence. The patients were divided into 3 groups: IVIG responders, nonresponders with persistent fever, and nonresponders with recurrent fever. CAAs were evaluated 2 or 4 weeks and 12 months after onset and were defined by a coronary artery z-score ≥2.5. RESULTS: The incidence of CAAs within 12 months after onset was significantly higher in nonresponders with persistent fever (27%) compared with the other 2 groups. On multivariate logistic regression analysis, being a nonresponder with persistent fever was an independent risk factor for having CAAs within 12 months after the onset of Kawasaki disease (OR, 6.48; P = .007). CONCLUSIONS: In patients with Kawasaki disease resistant to IVIG therapy, persistent fever, but not recurrent fever, was found to be a risk factor for the incidence of CAAs. Aggressive additional therapy may be beneficial to prevent CAA formation in patients with Kawasaki disease with persistent fever.

Force-responsive ordered carbonaceous frameworks synthesized from Ni-porphyrin.

Force-responsive ordered carbonaceous frameworks (OCFs) are synthesized for the first time. Carbonization of Ni porphyrin monomers having eight polymerizable ethynyl groups yields OCFs with atomically dispersed divalent Ni species and developed micropores. The highest specific surface area (673 m2 g-1) among the OCFs has been achieved. The OCFs thus synthesized comprise non-stacked graphene sheets, affording a unique mechanical flexibility that enables force-driven reversible phase transition.

The weather condition and epidemics as triggers for febrile seizure: A single-center retrospective observational study.

OBJECTIVE: The objective of this study was to investigate the association between the weather and epidemic condition and risk of febrile seizures (FSs) in Japan. STUDY DESIGN: This single-center, retrospective study included 560 children (age, 6-60 months) with FSs who were transported to our center by ambulance from January 2011 through December 2018. The weather (temperature, atmospheric pressure, relative air humidity, amount of rainfall, sunshine duration, and air concentration of nitrogen dioxide [NO2] and sulfur dioxide [SO2]) and epidemic (influenza virus infection, infectious gastroenteritis, and exanthem subitum) conditions in this region were compared between the periods (days or weeks) with the transportation of children with FS to our hospital and those without such transportation. RESULTS: In the univariate analyses, neither daily or weekly weather condition nor weekly epidemic condition was correlated to FS transportation. Furthermore, the multiple logistic regression analysis suggested that epidemic influenza virus infection (odds ratio [OR], 1.34; 95% confidence interval [CI], 1.08-1.73) and infectious gastroenteritis (OR, 1.64; 95% CI, 1.09-2.54) were the independent risk factors for FS occurrence and weather condition was not associated with FS risk. CONCLUSIONS: Febrile seizure incidence may be increased by epidemic febrile infections but not by weather condition.

Shear-dependent platelet aggregation size.

Nonsurgical bleeding is the most frequent complication of left ventricular assist device (LVAD) support. Supraphysiologic shear rates generated in LVAD causes impaired platelet aggregation, which increases the risk of bleeding. The effect of shear rate on the formation size of platelet aggregates has never been reported experimentally, although platelet aggregation size can be considered to be directly relevant to bleeding complications. Therefore, this study investigated the impact of shear rate and exposure time on the formation size of platelet aggregates, which is vital in predicting bleeding in patients with an LVAD. Human platelet-poor plasma (containing von Willebrand factor, vWF) and fluorochrome-labeled platelets were subjected to a range of shear rates (0-10 000 s-1 ) for 0, 5, 10, and 15 minutes using a custom-built blood-shearing device. Formed sizes of platelet aggregates under a range of shear-controlled environment were visualized and measured using microscopy. The loss of high molecular weight (HMW) vWF multimers was quantified using gel electrophoresis and immunoblotting. An inhibition study was also performed to investigate the reduction in platelet aggregation size and HMW vWF multimers caused by either mechanical shear or enzymatic (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13-ADAMTS13, the von Willebrand factor protease) mechanism under low and high shear conditions (360 and 10 000 s-1 ). We found that the average size of platelet aggregates formed under physiological shear rates of 360-3000 s-1 (200-300 µm2 ) was significantly larger compared to those sheared at >6000 s-1 (50-100 µm2 ). Furthermore, HMW vWF multimers were reduced with increased shear rates. The inhibition study revealed that the reduction in platelet aggregation size and HWM vWF multimers were mainly associated with ADAMTS13. In conclusion, the threshold of shear rate must not exceed >6000 s-1 in order to maintain the optimal size of platelet aggregates to "plug off" the injury site and stop bleeding.

Weather condition, air pollutants, and epidemics as factors that potentially influence the development of Kawasaki disease.

Environmental factors have been suspected to have effects on the development of Kawasaki disease. However, the associations have been conflicting. The aim of this study was to investigate the effects of air pollution, weather conditions, and epidemic infections on the risks for Kawasaki disease in Japan. The concentrations of air pollutants (nitric oxide, nitrogen dioxide, and sulfur dioxide); ambient weather conditions (temperature, atmospheric pressure, relative air humidity, precipitation, sunshine duration, and wind velocity); and the epidemic conditions of 14 infectious diseases in hospitalized patients with Kawasaki disease were monitored from 2011 to 2018 in Beppu, Japan. The overdispersed generalized additive model was used to evaluate the effects, and a combination model with a distributed lag nonlinear model was used to estimate the cumulative effects. The incidence of Kawasaki disease had positive associations with preceding hot temperature and increased concentrations of nitric oxide and sulfur dioxide and a negative association with epidemic herpangina. The cumulative relative risk of Kawasaki disease at 5 lagged days of increased temperature was 1.76 (95% confidence interval: 1.01-3.07). This city-level observational study suggested that the incidence of Kawasaki disease was associated with air pollution and increased temperature and may be indirectly influenced by epidemic herpangina.

Short-term neurodevelopmental outcomes of focal febrile seizures.

OBJECTIVE: The effect of complex febrile seizures (FS), specifically focal FS, on long-term neurodevelopmental outcome is not well known. The aim of this study was to assess the association between complex FS and neurodevelopmental outcome. METHODS: A single-center, retrospective, cohort study was performed. The study included 282 children aged 6-60 months who experienced FS. Of these, 61 (22%) experienced recurrent FS, 33 (12%) prolonged FS, and 17 (6%) focal FS. The effect of these complex FS on subsequent need for special neurodevelopmental support was investigated. The neurodevelopmental status after FS was evaluated by a questionnaire. RESULTS: During a median follow-up period of 3 years post FS, 12 children (4.3%) required special neurodevelopmental support. Univariate analysis demonstrated a significant association between focal FS and the need for subsequent special neurodevelopmental support, as well as a correlation between prolonged FS and pre-existing neurodevelopmental abnormality. Multiple logistic regression analysis demonstrated that focal FS (odds ratio [OR]: 12.27; 95% confidence interval [CI]: 2.11-71.22) and pre-existing neurodevelopmental abnormality (OR: 262; 95% CI: 17-3944) were significantly associated with the need for subsequent special support. CONCLUSION: An association was found between focal FS and subsequent neurodevelopmental impairment; therefore, close follow-up with particular attention to neurodevelopmental status is required for children who experience focal FS.

Change in the strategy for prophylactic diazepam use for febrile seizures and the impact on seizure recurrence within 24 h.

PURPOSE: To investigate the association between reduced prophylactic diazepam usage and short-term recurrence of febrile seizures (FSs) after the FS practice guideline was updated in Japan. METHOD: In this single-center, retrospective study, children (6-60 months of age) with FS who were transported to our center by ambulance from January 2011 through December 2018 were included. Rectal administration of diazepam (0.3-0.5 mg/kg) after the first seizure and seizure recurrence within 24 h were compared between 2011-2015 (pre-guideline revision) and 2016-2018 (post-guideline revision). RESULTS: Among the total of 509 children, 297 were transported to our hospital in 2011-2015 and 212 in 2016-2018. Rectal diazepam administration was decreased in 2016-2018 (17 %) compared to 2011-2015 (53 %, P < 0.0001), while seizure recurrence was increased in 2016-2018 (20 %) compared to 2011-2015 (12 %, P = 0.0087). Similarly, hospital revisits (23 %) and hospital admissions (26 %) were increased in 2016-2018 compared to 2011-2015 (15 %, P = 0.031 and 18 %, P = 0.026, respectively). Multiple logistic regression analyses showed that prophylactic diazepam administration was the only factor related to preventing seizure recurrence. FS recurrence after the initial seizure was significantly less frequent with diazepam use (6 %) than without diazepam use (21 %, P < 0.0001; relative risk reduction, 70 %; number needed to treat, 6.8 children). CONCLUSION: The FS practice guideline revision was associated with reduced prophylactic diazepam usage and increased FS recurrence within 24 h in Japan. Prophylactic diazepam use should be determined based on clinical safety, local health infrastructure, and parental anxiety.

Trajectory of instantaneous axis of rotation in fixed lumbar spine with instrumentation.

BACKGROUND: Several studies showed instantaneous axis of rotation (IAR) in the intact spine. However, there has been no report on the trajectory of the IAR of a damaged spine or that of a fixed spine with instrumentation. It is the aim of this study to investigate the trajectory of the IAR of the lumbar spine using the vertebra of deer. METHODS: Functional spinal units (L5-6) from five deer were evaluated with six-axis material testing machine. As specimen models, we prepared a normal model, a damaged model, and a pedicle screw (PS) model. We measured the IAR during bending in the coronal and sagittal planes and axial rotation. In the bending test, four directions were measured: anterior, posterior, right, and left. In the rotation test, two directions were measured: right and left. RESULTS: The IAR of the normal model during bending moved in the bending direction. The IAR of the damaged model during bending moved in the bending direction, but the magnitude of displacement was bigger compared to that of the normal model. In the PS model, the IAR during bending test hardly moved. During rotation test, the IAR of the normal model and PS model located in the spinal canal, but the IAR of the damaged model located in the posterior part of the vertebral body. CONCLUSIONS: In this study, the IAR of damaged model was scattering and that of PS model was concentrating. This suggests that higher mechanical load applied to the dura tube and nerve roots in the damaged model and less mechanical load applied to that in the PS model.

Sujiaonori-Derived Algal Biomaterials Inhibit Allergic Reaction in Allergen-Sensitized RBL-2H3 Cell Line and Improve Skin Health in Humans.

Sujiaonori, a river alga growing in the Kochi prefecture, Japan, contains several bioactive compounds such as sulfated polysaccharides (ulvans), ω-3 fatty acids, and vitamins. Dietary intake of this alga-based supplement has been reported to increase circulatory adiponectin, a salutary hormone that is reported to be associated with healthy longevity and prevents a number of cardiovascular and metabolic disorders. This report highlights the anti-allergic and skin health enhancing effects of Sujiaonori-derived ulvan (Tosalvan) and supplement, respectively. RBL-2H3 cell line was used to investigate the anti-allergic effect of algal SP through the evaluation of ß-hexosaminidase activity. Algal sulfated polysaccharides or SP (Tosalvan, Yoshino SP) were extracted from powders of dried alga samples provided by local food manufacturers. Report on the effect of daily dietary intake of Sujiaonori-based supplement on skin health is part of a four-week clinical investigation that, in comparison with a supplement made of 70% corn starch powder and 30% spinach powder mixture (twice 3 g daily), explore the beneficial effects of Sujiaonori algal biomaterial (SBM; 3 g taken twice daily) on cardiovascular, gastrointestinal and skin health in a sample of Japanese women. Transepidermal water loss (TEWL) was the skin health marker used in this study and was measured with the use of a corneometer. Significant reduction of ß-hexosaminidase activity was observed in Tosalvan and Yoshino SP-treated cells (vs. control; p < 0.05), whereas dietary intake of SBM markedly reduced TEWL level after four weeks of supplementation, as compared to baseline TEWL (p < 0.001). Additionally, SBM improved TEWL better than the control product (p < 0.001). Findings contained in this report suggest that Sujiaonori-derived Tosalvan and Yoshino SP have anti-allergic potential and that the dietary intake of SBM has a beneficial effect on skin health.

Laxative Effects of Dietary Supplementation with Sujiaonori Algal Biomaterial in Japanese Adult Women with Functional Constipation: A Case Study.

Constipation is a gastrointestinal motility disorder that represents a major health problem in Japan. Approximately 26% of young Japanese adult women are reported to have this complaint. We report on the health effects of daily intake of Sujiaonori algal biomaterial (SBM) on constipation on 12 Japanese adult women. Data are from a four-week dietary intervention study on the health effects of daily Sujiaonori supplementation on cardiovascular, skin, and gastrointestinal health in which 32 adult Japanese volunteers (age range: 20-54 years) participated. They underwent clinical and laboratory investigations, and completed two study questionnaires (the brief diet history questionnaire (BDHQ) and the current health questionnaire) before and after dietary intervention. Of the 12 women volunteers with functional constipation, there were six SBM-supplemented subjects who received 3 g of Sujiaonori powder twice daily during meal, whereas the six others (controls) were from the group of those who took 3 g of a power made of 70% corn starch and 30% Japanese spinach mixture. The analysis of data on daily nutrient intake showed no significant dietary changes for nutrients (minerals, proteins, fiber, fat) and calorie intake (except alcohol intake that was reduced) in both groups. In SBM group, a significant reduction of the proportion of women with constipation was observed (p < 0.001), whereas no significant change was noted within the control group (p > 0.05). When both groups were compared, SBM was more effective than the control product; 66.7% (4/6) of SBM-supplemented women had their constipation relieved, whereas only one control (16.7%) controls benefited from dietary intervention (p < 0.001). In addition, no adverse effect was reported in the SBM group, whereas two controls reported nausea at post-survey. These results suggest that Sujiaonori contains compounds that can improve gastrointestinal function and relieve constipation.