Direct hemoperfusion using a polymyxin B-immobilized fiber column (DHP-PMX; Toray Industries Inc., Tokyo, Japan) was first developed in 1994 and has since been used for the treatment of septic shock.
The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them.We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as 'pathogenic' by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that two variants in KCNH2 and SCN5A, four variants in SCN10A, and one variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from 'Uncertain significance' to 'Likely pathogenic' in six probands.Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD.
Recently, the existence of a relationship was reported between the severity of lung injury and the serum level of F2-isoprostane, a known oxidative stress marker. Recent reports have suggested that direct hemoperfusion with a polymyxin B-immobilized fiber column (DHP-PMX) may improve the oxygenation in patients with acute lung injury and acute respiratory distress syndrome. Because cases of septic shock associated with respiratory diseases have poor outcomes, we selected cases of septic shock associated with respiratory disease to review the characteristics of the treatment-resistant cases. We treated 13 septic shock cases due to respiratory disease using DHP-PMX. The patients were separated into 2 groups for analysis from oxygenation effect immediately after DHP-PMX: A group (7 cases) PaO2/FiO2 ratio increased more than 20%; B group (6 cases) PaO2/FiO2 ratio did not increase more than 20%. Factors were measured before DHP-PMX. The average Acute Physiology and Chronic Health Evaluation II score was 31.2 ± 9.4, and the average sequential organ failure assessment score was 15.1 ± 5.3 before DHP-PMX. Four patients survived and 9 died. Only the F2-Isoprostane level was significantly high in B group (p = 0.0228). A relationship between F2-Isoplostane and rebellious cases by DHP-PMX in severe respiratory disease patients became clear.
Lithium, which is used for bipolar disorder, can cause toxicity. There are two categories of lithium toxicity, namely, overdose-related and not overdose-related. However, the treatment and prognosis of each type of toxicity are not clearly understood. We, therefore, compared the clinical characteristics of patients with overdose-related and not overdose-related lithium toxicity. Relevant data were obtained from the medical records of 16 patients with lithium toxicity, and renal function and concomitant medications were retrospectively compared between the two groups. We also compared the treatment for, manifestations of, and duration of hospitalization between the two types of lithium toxicity. The not overdose-related group more frequently had a low creatinine clearance (<50 mL/min) than did the overdose-related group (P = 0.01). Multivariable regression analysis demonstrated that creatinine clearance <50 mL/min was a significant predictor of lithium toxicity in the not overdose-related group (P = 0.01). Tremor and dysarthria occurred only in the not overdose-related group, and duration of hospitalization was significantly longer in the not overdose-related than overdose-related group (P = 0.01). Clinicians must monitor the renal function of patients taking lithium, even when in compliance with the prescribed dosage, because they are at long-term risk of lithium toxicity.
Metastasis of a primary osteosarcoma to the muscles is extremely rare. As there have been few reported cases, the necessity of surgical treatment for such metastatic lesions remains controversial. We present the case of a primary osteosarcoma with development of a solitary metastasis to the trapezius muscle during chemotherapy for pulmonary metastasis. The patient was a 51-year-old man diagnosed with osteosarcoma of the right tibia. After undergoing chemotherapy and femoral amputation, he developed pulmonary metastasis. Chemotherapy was reinitiated, however, after approximately 1 year a palpable tumor was identified in the patient’s right shoulder. This tumor grew and was associated with pain in the right shoulder. It was surgically removed 3 years after the re-initiation of chemotherapy. The pathological diagnosis was osteosarcoma with metastasis to the trapezius muscle. Although the patient died of respiratory failure due to pulmonary metastasis 14 months after resection of the metastatic lesion in the trapezius muscle, no new extrapulmonary metastasis was observed after the resection.
Possible effects of interleukin‐6 ( IL ‐6) on reproductive performance, embryonal development, parturition, and postnatal development have been suggested based on protein/m RNA expression level of IL ‐6 in related organs, but less is known about functions of IL ‐6 signals in these areas. Following two different approaches have been employed to investigate the role of IL ‐6 signals in fertility and pre‐/postnatal development: administration of a rat anti‐mouse IL ‐6 receptor antibody, MR 16‐1, to mice as a neutralizing antibody system, and B 6.129S2‐ I l6 tm1Kopf / J ( IL ‐6 knockout [ KO ]) mice as a KO system. By intravenously dosing 50 mg/kg of MR 16‐1 every 3 days, animals in male and female fertility studies and dams in a pre‐/postnatal development study exhibited plasma MR 16‐1 concentrations much higher than the effective plasma concentration, indicating that MR 16‐1 exposure was sufficient to completely block IL ‐6 signals. The concentration of MR 16‐1 in the plasma of fetuses exceeded that in the plasma of pregnant animals, and MR 16‐1 concentration in milk was about one‐fourth of that in plasma. Both the transient IL ‐6 signal blockade by MR 16‐1, and the constitutive IL ‐6 signal inhibition using IL ‐6 KO mice in a combined fertility and pre‐/postnatal development study, revealed no biologically important effects on fertility, early embryonic development to implantation, or pre‐/postnatal development, including I g G / I g M production by keyhole limpet hemocyanin sensitization. These results indicate that IL ‐6 signals have no unique, noncompensable roles in reproduction and development in the whole body system, although contributions of IL ‐6 in the signaling network appear to exist, as suggested by previously published investigations.
Septic shock is a condition associated with diffuse coagulopathy and multiple organ failure, and frequently ends in death. Direct hemoperfusion using a polymyxin B-immobilized fiber column (DHP-PMX) was first developed in Japan in 1994 and has since been used for the treatment of septic shock. On the other hand, the effectiveness of continuous hemodiafiltration using a polymethylmethacrylate membrane hemofilter (PMMA- CHDF) for critically ill patients has also been reported. We treated 27 septic shock patients by DHP-PMX. The patients, except for the nine in whom CHDF was not performed after DHP-PMX, were divided into two groups: namely, a group in which PMMA-CHDF therapy was added after DHP-PMX (11 cases), and a group in which continuous hemodiafiltration using a polyacrylonitrile membrane hemofilter (PAN-CHDF) therapy was added after DHP-PMX (7 cases). The outcomes in the two groups were compared. The average Acute Physiology and Chronic Health Evaluation (APACHE) II score and the average sepsis-related organ failure assessment (SOFA) score were not significantly different between the two groups. The PMMA-CHDF group showed significantly better outcomes, with significant improvements of the serum PAI-1, protein C, IL-6 and N-arachidonoylethanolamine (AEA) levels. We conclude that PMMA-CHDF may be more effective than PAN-CHDF in the management of septic shock.
LQTS (long QT syndrome) is caused by mutations in cardiac ion channel genes; however, the prevalence of LQTS in the general population is not well known. In the present study, we prospectively estimated the prevalence of LQTS and analysed the associated mutation carriers in Japanese children. ECGs were recorded from 7961 Japanese school children (4044 males; mean age, 9.9+/-3.0 years). ECGs were examined again for children who had prolonged QTc (corrected QT) intervals in the initial ECGs, and their QT intervals were measured manually. An LQTS score was determined according to Schwartz's criteria, and ion channel genes were analysed. In vitro characterization of the identified mutants was performed by heterologous expression experiments. Three subjects were assigned to a high probability of LQTS (3.5< or = LQTS score), and eight subjects to an intermediate probability (1.0< LQTS score < or =3.0). Genetic analysis of these II subjects identified three KCNH2 mutations (M124T, 547-553 del GGCGGCG and 2311-2332 del/ins TC). In contrast, no mutations were identified in the 15 subjects with a low probability of LQTS. Electrophysiological studies showed that both the M124T and the 547-553 del GGCGGCG KCNH2 did not suppress the wild-type KCNH2 channel in a dominant-negative manner. These results demonstrate that, in a random sample of healthy Japanese children, the prevalence of a high probability of LQTS is 0.038% (three in 7961), and that LQTS mutation carriers can be identified in at least 0.038% (one in 2653). Furthermore, large-scale genetic studies will be needed to clarify the real prevalence of LQTS by gene-carrier status, as it may have been underestimated in the present study.
