Efficacy of thromboelastography in the management of anticoagulation for veno-venous extracorporeal membrane oxygenation in a coronavirus disease 2019 patient: A case report

Rationale:In coronavirus disease 2019 (COVID-19) patients with acute respiratory distress syndrome refractory to optimal conventional management, we should consider the indication for veno-venous extracorporeal membrane oxygenation (V-V ECMO). Growing evidence indicates that COVID-19 frequently causes coagulopathy, presenting as hypercoagulation and incidental thrombosis. For these reasons, a multifactorial approach with several anticoagulant markers should be considered in the management of anticoagulation using heparin in COVID-19 patients on V-V ECMO.Patient concerns:A 48-year-old man was infected with COVID-19 with a worsening condition manifesting as acute respiratory distress syndrome.Diagnoses:He was refractory to conventional therapy, thus we decided to introduce V-V ECMO. We used heparin as an anticoagulant therapy for V-V ECMO and adjusted the doses of heparin by careful monitoring of the activated clotting time (ACT) and activated partial thromboplastin time (APTT) to avoid both hemorrhagic and thrombotic complications. We controlled the doses of heparin in the therapeutic ranges of ACT and APTT, but clinical hemorrhaging and profound elevation of coagulant marker became apparent.Interventions:Using thromboelastography (TEG; Haemonetics) in addition to ACT and APTT, we were able to clearly detect not only sufficient coagulability of COVID19 on V-V ECMO (citrated rapid thromboelastography-R 0.5 min, angle 75.5°, MA 64.0 mm, citrated functional fibrinogen-MA 20.7 mm) but also an excessive effect of heparin (citrated kaolin -R 42.7 min, citrated kaolin with heparinase 11.7 min).Outcomes:Given the TEG findings indicating an excessive heparin effect, the early withdrawal of ECMO was considered. After an evaluation of the patient''s respiratory capacity, withdrawal from V-V ECMO was achieved and then anticoagulation was stopped. The hemorrhagic complications and elevated thrombotic marker levels dramatically decreased.Lessons:TEG monitoring might be a useful option for managing anticoagulation in COVID-19 patients on V-V ECMO frequently showing a hypercoagulative state and requiring massive doses of heparin, to reduce both hemorrhagic and thrombotic complications.     

Humic acid induces the endothelial nitric oxide synthase phosphorylation at Ser1177 and Thr495 Via Hsp90α and Hsp90β upregulation in human umbilical vein endothelial cells

Humic acid (HA) has been implicated as a contributory factor for blackfoot disease, which is an endemic peripheral vascular disease. We investigated the effect of HA on the regulation of endothelial nitric oxide (NO) synthase (eNOS) in human umbilical vein endothelial cells (HUVECs) to evaluate the involvement of eNOS and related factors in peripheral vascular impairment with HA exposure. Treatment of HUVECs with HA induced upregulation of eNOS. This result coincides with those of previous studies. Furthermore this is the first study to report that HA induces upregulation of heat shock protein (Hsp)90α, Hsp90β, eNOS phosphorylation at Ser1177, and eNOS phosphorylation at Thr495, as compared to that in the control. In contrast, treatment with BAPTA, an intracellular Ca²⁺ chelator, inhibited upregulation of these proteins induced by HA. This study demonstrates that HA treatment leads to increases in both Hsp90α and Hsp90β proteins and indicates that Hsp90α leads to eNOS phosphorylation at Ser1177 and that Hsp90β leads to eNOS phosphorylation at Thr495, respectively. Upregulation of eNOS, Hsp90α, and Hsp90β in HUVECs is regulated by intracellular Ca²⁺ accumulation induced by HA. These results suggest that upregulation of eNOS phosphorylation at Ser1177 and eNOS phosphorylation at Thr495 produce NO and superoxide anions, respectively, resulting in generation of peroxynitrite, which causes impairment of vascular endothelial cells. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 223–231, 2015.     

Interleukin‐8‐producing primary cardiac undifferentiated sarcoma in a child with sustained fever

We report the case of a 12‐year‐old boy with primary undifferentiated sarcoma of the left atrium. He had sustained fever during the clinical course and multiple lung and brain metastases. Chemotherapy and irradiation were ineffective; he died 41 days after hospitalization. On retrospective analysis, interleukin‐8 (IL‐8) was elevated; this was supported by immunohistochemistry and gene expression analysis of tumor samples. IL‐8 continued to increase with tumor progression accompanied by elevated neutrophil count and C‐reactive protein. IL‐8 is involved in malignant tumor proliferation, migration, and angiogenesis and may have been related to the clinical condition and prognosis in the present case.     

Usefulness of directly observed therapy (DOT) during hospitalization as DOTS in Japanese style

Many patients with smear positive tuberculosis were hospitalized during the initial phase of chemotherapy but DOT was not applied to patients with tuberculosis in Japan. We tried randomized clinical study to evaluate the usefulness of DOT during admission. 135 culture positive TB patients were administered by DOT and 124 culture positive TB patients were self-administered during admission. There was no significant difference between 2 groups in the clinical background factors, treatment and the incidence of adverse reactions. Treatment completion rate was 94.1% in DOT group and 87.9% in non-DOT group. Default rate was significantly lower in DOT group (4.4%) than in non-DOT group (11.3%). We concluded that "DOT during admission" was useful to improve the outcome of chemotherapy for tuberculosis and it is preferable to apply DOT throughout treatment course for patients with tuberculosis in Japan.     

Serratus Anterior and Lower Trapezius Muscle Activities During Multi-Joint Isotonic Scapular Exercises and Isometric Contractions

Context:Proper scapular function during humeral elevation, such as upward rotation, external rotation, and posterior tilting of the scapula, is necessary to prevent shoulder injury. However, the appropriate intensity of rehabilitation exercise for the periscapular muscles has yet to be clarified.Objective:To identify the serratus anterior, lower trapezius, infraspinatus, and posterior deltoid muscle activities during 2 free-motion exercises using 3 intensities and to compare these muscle activities with isometric contractions during quadruped shoulder flexion and external rotation and abduction of the glenohumeral joint.Design:Cross-sectional study.Setting:Health Science Laboratory.Results:Significant interactions in electromyographic activity were observed between intensities and exercises (P < .05). The quadruped shoulder-flexion exercise activated all 4 muscles compared with other exercises. Also, the modified robbery free-motion exercise activated the serratus anterior, lower trapezius, and infraspinatus compared with the lawn-mower free-motion exercise. However, neither exercise showed a difference in posterior deltoid electromyographic activity.Conclusions:Three intensities exposed the nature of the periscapular muscle activities across the different exercises. The free-motion exercise in periscapular muscle rehabilitation may not modify serratus anterior, lower trapezius, and infraspinatus muscle activities unless knee-joint extension is limited.Key Words: upper extremity, shoulder joint, overhead performance

Key Points

• Modulation of electromyographic activity of the serratus anterior and lower trapezius muscles varied with multi-joint free-motion exercises though exercise intensity was increased.
• No increase in the electromyographic activity of the lower trapezius was found in the lawn-mower exercise despite increasing intensity.
• Isometric shoulder flexion in the quadruped position showed the highest amplitude of electromyographic activity of the serratus anterior and lower trapezius muscles compared with the free-motion exercises.

Periscapular muscles have been intensively studied for the purposes of injury prevention and rehabilitative exercise in patients with asymptomatic and symptomatic shoulders. These include symptomatic patients with shoulder impingement syndrome and rotator cuff injury.^1–13 The scapula acts as the base from which kinetic force and energy are transferred to the distal segments of the upper extremity, especially in overhead athletes.¹⁴ Also, the stability of the scapula enables the rotator cuff muscles to be maximally activated.¹⁵ For instance, the empty-can position at 90° of abduction (ABD) of the glenohumeral (GH) joint in the scapular plane increased ABD resistance when the scapular position was retracted by a clinician with forearm pressure on the medial scapular border.¹⁵The appropriate functional scapular motions of upward rotation, posterior tilt, and external rotation increase the width of the subacromial space during humeral elevation, whereas a lack of proper scapular function, so-called scapular dyskinesis, increases the translation of the humeral head and alters scapular position and motion in both static and dynamic applications.^2,16–18 A shoulder rehabilitation exercise program must emphasize the external rotation, posterior tilting, and upward rotation of the scapula.¹⁹ Moreover, current researchers have advocated that the serratus anterior (SA) and lower trapezius (LT) muscles be reconditioned even before the rotator cuff muscles for symptomatic shoulders of overhead athletes.²⁰ However, the effects of exercise intensity on conditioning these muscles has yet to be investigated. Most, if not all, previous authors used 1 intensity to compare periscapular muscle activities across a variety of scapular exercises.^{1,3,5,12,21–23} Although using 1 level of intensity may allow researchers to compare a certain amount of muscle activity across different exercises, the modulation in muscle activity cannot be fully determined with experimental paradigms using only 1 intensity. Some muscle activation may not increase proportionally as the level of exercise intensity increases, and different compensation from other muscles often occurs during the same movement with different intensities.²⁴Free-motion exercises that simultaneously extend the knee joints, hip joints, and trunk, such as the lawn-mower and robbery exercises, were analyzed for scapular muscle activity to identify the amounts of scapular retraction and depression. Exercises with multi-joint movement such as these activated the SA and LT by approximately 30% of maximum voluntary isometric contraction (MVIC) without providing information about exercise intensity.² The sequential motion inherent in these exercises, which transfer forces from the lower to upper extremities and follow a proximal-to-distal progression, has been of interest to clinicians for shoulder rehabilitation exercise programming.^17,25 However, researchers have not yet identified how different intensities of such multi-joint isotonic exercises affect the activities of the SA and LT muscles. Therefore, the purpose of our study was to identify the muscular activity of the SA and LT at different levels of intensity during the lawn-mower, robbery, and quadruped shoulder-flexion (QSF) exercises.     

Laparoscopic surgery with urinary tract reconstruction and bowel endometriosis resection for deep infiltrating endometriosis

Deep infiltrating endometriosis (DIE) is the most severe form of endometriosis. It causes chronic pelvic pain, severe dysmenorrhea, deep dyspareunia, dyschezia, and dysuria, markedly impairing the quality of life of women of reproductive age. A number of randomized controlled trials on surgical and medical treatments to reduce the pain associated with endometriosis have been reported, but few have focused on this in DIE. DIE causes not only pain but also functional invasion to the urinary organs and bowel, such as hydronephrosis and bowel stenosis. In addition to DIE resection, surgical treatment involves adhesion separation as well as resection and reconstruction of the urinary organs and bowel; high‐level skills are required. The severity of DIE should be evaluated preoperatively as accurately as possible. Using ENZIAN in conjunction with the AFS (The revised American Fertility Society classification of endometriosis) classification makes a more detailed assessment of DIE possible. The operative procedures used for laparoscopic resection of urinary DIE and reconstruction of the urinary organs are chosen based on the type of lesion (intrinsic/extrinsic) and length of stenosis. In addition to ureteroneocystostomy, the psoas bladder hitch and Boari bladder flap procedures are applied when necessary to extend the urinary tract. Bowel resection for bowel endometriosis is classified into classic segmental resection and conservative approaches (shaving/discoid). When these procedures are employed, it is advisable to work in consultation with urologists and gastroenterologists and to inform the patients of the associated risks and outcomes. Furthermore, postoperative medication is essential because it is difficult to conduct repeated surgeries.     

Beneficial biological effects and the underlying mechanisms of molecular hydrogen - comprehensive review of 321 original articles -

Molecular hydrogen (H2) is clinically administered; however, in some hospitals, H2 is given to patients without consideration of its safe use. In the present study, we prepared convenient and safe devices for the drinking of super-saturated H2 water, for intravenous drip infusion of H2-rich saline, and for the inhalation of H2 gas. In order to provide useful information for researchers using these devices, the changes in H2 concentration were studied. Our experimental results should contribute to the advance of non-clinical and clinical research in H2 medicine.     

72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised,Double Blind,Placebo-Controlled,Phase III APEX Study and its Open-Label Extension

Introduction

The long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS.

Methods

Safety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded.

Results

Overall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups.

Conclusion

The 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports.

Trial Registration

ClinicalTrials.gov identifier NCT01838668.

Funding

Biogen Japan Ltd.

     

Quantitative evaluation of the pulmonary microdistribution of TiO2 nanoparticles using X‐ray fluorescence microscopy after intratracheal administration with a microsprayer in rats

The unevenness of pulmonary nanoparticle (NP) distribution, which hinders the establishment of an absolute dose–response relationship, has been described as one of the limitations of intratracheal administration techniques for toxicological assessment of inhaled NPs. Quantification of the NP microdistribution would facilitate the establishment of a concentration–response relationship in localized regions of the lung; however, such quantitative methods have not been reported. Here, we established a quantitative method for evaluating pulmonary TiO₂ NP microdistribution in rats using X‐ray fluorescence microscopy. Ti intensity in lung sections from rats intratracheally administered 10 mg kg^–1 TiO₂ NPs with a microsprayer was measured using X‐ray fluorescence with a 100 µm beam size. Ti reference samples were prepared by dropping different concentrations of Ti solutions on glass slide or lung sections of untreated rat. Ti intensity increased linearly with Ti content in the reference samples on both substrates. The detection limit of TiO₂ was estimated to be 6.3 ng mm^–2. The reproducibility was confirmed for measurements done in the short‐ (2 weeks) and long‐term (6 months). The quantitative results of TiO₂ NP microdistribution suggested that more TiO₂ NPs were distributed in the right caudal and accessory lobes, which are located downstream of the administration direction of the NP suspension, and the lower portion of each lobe. The detection rates of TiO₂ NPs were 16.6–25.0%, 5.19–15.6%, 28.6–39.2%, 21.4–38.7% and 10.6–23.2% for lung sections from the right cranial, middle, caudal, accessory and left lobes, respectively. Copyright © 2015 John Wiley & Sons, Ltd.