Early electrocardiographic indices for predicting chronic doxorubicin-induced cardiotoxicity

BackgroundDealing with chemotherapy-related cardiac dysfunction (CTRCD) remains a significant problem complicated by the difficulty in early detection of cardiotoxicity. Electrocardiogram (ECG) is expected to be the most realistic methodology due to lower cost-performance and non-invasiveness. We investigated the long-term visual fluctuations in the ECG waveforms in patients with chronic doxorubicin (DOX)-induced cardiotoxicity to identify ECG indices for the early detection of cardiotoxicity.MethodsWe conducted a retrospective case series study by reviewing the medical records of 470 consecutive patients with malignant lymphoma who were treated with DOX at our institute between January 2010 and December 2017. Of them, 23 (4.9%) patients developed left ventricular dysfunction and were diagnosed with CTRCD using echocardiography. We assessed the ECG indices on 12-lead ECG recordings before and after treatment in 15 patients; eight patients were excluded due to conduction disturbances or atrial fibrillation.ResultsCTRCD was detected at a median of 475 (interquartile range, IQR: 341–1333) days after initiating chemotherapy. The evaluation of ECG indices preceding CTRCD development was performed 93 (IQR: 52–232) days before the detection of CTRCD. In the stage of CTRCD, the most significant ECG change was T-wave flattening in leads V3–V6 (12 patients, 80%). Additionally, QTa prolongation was observed in leads I and aVL (n = 10, 66%), leads II, III, and aVF (n = 9, 60%), and leads V3–V6 (n = 10, 73%). These ECG changes were not observed before the treatment but were detected mildly in the pre-CTRCD stage, which subsequently worsened in the CTRCD stage.ConclusionsThis study indicated that T-wave changes and QTa prolongation may be useful as an early indicator before the onset of CTRCD in patients with DOX-induced cardiotoxicity.     

Left trisegmentectomy and combined resection of the inferior vena cava, without reconstruction, for giant cystadenocarcinoma of the liver

A 54-year-old woman with giant liver cystadenocarcinoma underwent left trisegmentectomy with combined resection of the inferior vena cava (IVC) and the right hepatic vein. As a result, only the right inferior hepatic vein was preserved as a drainage vein. Because the perivertebral plexus and the azygos vein were both well developed, neither veno-venous bypass nor IVC reconstruction was performed. The developed collateral veins acted as the venous drainage pathway to maintain a stable systemic circulation. On the seventh postoperative day, portal vein flow dramatically decreased and the patient tended to liver failure. Prostaglandin E₁ (PGE₁) was administrated via the superior mesenteric artery. The portal flow then gradually increased and liver failure was avoided. Six months after the operation, she was re-admitted due to obstructive jaundice and presented with complete stenosis of the common bile duct (CBD). The jaundice persisted and liver dysfunction progressed. The patient died seven months after the operation. The confluence of the right inferior vein and the IVC could have been deformed, causing outflow blockade. The intrinsic shunt was not good enough to act as the drainage pathway, and IVC reconstruction may have been needed.     

Somatic mutations of the PIG-A gene found in Japanese patients with paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic disorder caused by deficient biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. PIG-A, an X-linked gene that participates in the first step of GPI-anchor synthesis, is responsible for PNH. Abnormalities of the PIG-A gene have been demonstrated in all patients with PNH that have been studied to date. In this study, we analyzed 14 Japanese patients with PNH and identified 15 somatic mutations of PIG-A. The mutations included eight single-base changes and seven frame shift mutations. The single-base changes were two nonsense, three missense, and three splice site mutations. The frame shift mutations were four single-base deletions, two single-base insertions, and a replacement of two bases with one. They were all different, except for the same missense mutation being found in two patients. Moreover, these mutations were distributed in various regions of the gene. These results indicated that the mutations occurred at random sites and that there is no mutation hot spot in the PIG-A gene. All the mutations resulted in complete loss of function. Interestingly, the granulocytes in these patients contained variable proportions of mutant cells, suggesting that clonal expansion is not determined solely by mutations but is influenced by another factor(s).     

Interleukin-18 overproduction exacerbates the development of colitis with markedly infiltrated macrophages in interleukin-18 transgenic mice

BACKGROUND AND AIM: The authors have previously shown that production of interleukin (IL)-18 was increased in the inflamed mucosa of patients with Crohn's disease (CD) and blockade of IL-18 ameliorated the murine model of CD. This demonstrated that IL-18 plays a significant role during intestinal inflammation. However, the initial role of IL-18 during intestinal inflammation was unclear; therefore the susceptibility of IL-18 transgenic (Tg) mice to acute dextran sulfate sodium (DSS)-induced colitis was examined. METHODS: Interleukin-18 Tg and wild-type (WT) mice were fed 2.0% of DSS for 8 days. The total clinical scores (bodyweight loss, stool consistency, and rectal bleeding), colon length and histological scores were assessed. The expressions of surface markers and IL-18 on infiltrating lamina propria mononuclear cells were analyzed immunohistochemistrically. Mesenteric lymph node (MLN) cells were isolated and the expressions of CD4+ T-cell activation markers (CD69, CD25 and IL18R) were analyzed by flow cytometry. RESULTS: The IL-18 Tg mice exhibited an increased susceptibility to DSS-induced colitis, as shown by significantly increased clinical, histological scores, and more severe colonic shortening compared with WT mice. Immunohistochemical analysis revealed a significant increase of IL-18 production and CD11b+ macrophages but not CD4+ T cells in the inflamed mucosa in DSS-fed IL-18 Tg compared with DSS-fed WT mice. Furthermore, MLN cells revealed no evidence of increased CD4+ T-cell activation in DSS-fed IL-18 Tg. CONCLUSIONS: These findings suggest that IL-18 overproduction in the mucosa plays an important role in the marked infiltration of macrophages and exacerbates colitis in IL-18 Tg mice.     

Influence of surgical stress under general anesthesia on serum gonadotropin levels in male and female patients.

Effects of surgical stress under the same general anesthesia (nitrous oxide, oxygen and halothane following induction with thiopental and succinylcholine chloride) on serum LH levels were studied in 18 postmenopausal females, 15 menstruating females and 17 males. In addition, serum FSH levels in female patients and testosterone levels in male patients were estimated. As controls without surgery and anesthesia, serum levels of LH, FSH and testosterone were estimated at identical time intervals to the experimental group in 15 normal postmenopausal females, 15 normal menstruating females and 10 normal males. In male patients, serum LH levels at 30 min and 1 hr after onset of anesthesia increased significantly over those of pre-anesthesia, while no significant intra-operative increase in LH levels was found in female patients. In male and female patients, the LH levels decreased slightly 5-6h and 2 days after onset of anesthesia, though the decreases were not statistically significant except in postmenopausal females. On the 7th postoperative day, the LH levels returned toward the baseline. In female patients, no significant intra-operative changes in FSH levels were found. In male patients, there were significant intra- and post-operative decreases in testosterone levels. In control subjects, no significant changes in serum levels of LH, FSH and testosterone were demonstrated. These observations suggest that significant intraoperative increases in serum LH levels occur in males but not in females.     

Conduction performance of collateral vessels induced by vascular endothelial growth factor or basic fibroblast growth factor

OBJECTIVE: In the present study, we delivered vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) gene to a rabbit model of hind limb ischemia utilizing an ex vivo method of gene transfer, and evaluated the functional performance of the developed collateral vessels. METHOD: The left femoral artery of a male Japanese White rabbit was excised to induce limb ischemia, and a section of skin was resected for culture of auto-fibroblasts. Twenty days later, the VEGF gene, bFGF gene or beta-galactosidase gene (LacZ) was adenovirally transferred to the cultured auto-fibroblasts (5x10(6) cells), and the next day, a pair of specifically infected fibroblasts (total 1x10(7) cells) was injected via the left internal iliac artery of the same rabbit. Pairs of transferred genes into the fibroblasts were as follows: LacZ/LacZ (control group), VEGF/LacZ (VEGF group), bFGF/LacZ (FGF group) and VEGF/bFGF (combination group). Twenty-eight days after cell administration, collateral development and its function were evaluated. RESULTS: Calf blood pressure ratio, resting blood flow of the left iliac artery and capillary density of ischemic muscle showed similar degrees of angiogenic effects in the VEGF and FGF groups, which were significantly greater than those in the control group. On the contrary, angiographic score, collateral conductance and smooth muscle cell (SMC)-positive vessel density in the FGF group were significantly greater than those in the VEGF group. In the combination group, collateral conductance showed synergistic effects, and in vivo blood flow and smooth muscle cell-positive vessel density revealed additive effects of VEGF and bFGF. CONCLUSION: These findings suggested that bFGF-induced collateral development exceeded VEGF-induced collateral development in the induction of arteriogenesis, and that combined gene delivery of VEGF and bFGF produced additive or synergistic effects of collateral development as compared with the effects induced by transfer of each gene alone.     

Associations of hypertension and its complications with variations in the xanthine dehydrogenase gene

Hyperuricemia and oxidative stress participate in the pathophysiology of hypertension and its complications. Xanthine dehydrogenase (XDH) produces urate and, in its oxidase isoform, reactive oxygen species. Here we have studied whether or not the genetic variations in XDH could be implicated in hypertension and its complications. By sequencing the promoter region and all exons of XDH in 48 subjects, we identified three missense mutations (G172R, A932T, N1109T) in a heterozygous state in addition to 34 variations, including 15 common single nucleotide polymorphisms (SNPs). The three missense mutations and eight common SNPs (11488C>G, 37387A>G, 44408A>G, 46774G>A, 47686C>T, 49245A>T, 66292C>G, and 69901A>C) were genotyped in 953 hypertensive Japanese subjects and in 1,818 subjects from a general Japanese population. Four hypertensive patients with rare missense mutations (G172R or N1109T) in homozygous form had severe hypertension. Multivariate logistic regression analysis showed a significant association of three SNPs with hypertension in men: 47686C>T (exon 22, odds ratio [OR]: 1.52, p = 0.047) and 69901A>C (intron 31, OR: 3.14, p = 0.039) in the recessive model, and 67873A>C (N1109T) (exon 31, OR: 1.84, p = 0.018) in the dominant model. After full adjustment for all confounding factors, only one polymorphism (69901A>C) was found to be associated with carotid atherosclerosis in the dominant model (p = 0.028). Multiple logistic regression analysis showed that one SNP (66292C>G) was significantly associated with chronic kidney disease (CKD: estimated creatinine clearance < 60 ml/min) in the recessive model (p = 0.0006). Our results suggest that genetic variations in XDH contribute partly to hypertension and its complications, including atherosclerosis and CKD.     

Antibodies to 65Kd heat-shock protein were elevated in rheumatoid arthritis

Summary Antibodies to 65Kd heat-shock protein (hsp) of mycobacterium leprae were measured by enzyme-linked immunosorbent assay (ELISA) in the three immunoglobulin classes in paired sera and synovial fluids of patients with rheumatoid arthritis (RA). Titers of anti-hsp antibody were expressed by optical density (OD) values for sera or indexes (OD values divided by amounts of immunoglobulin in each class) for synovial fluids and for their paired sera. Indexes of anti-hsp antibody were higher in synovial fluids than those in sera at 15/18 for IgG, 17/18 for IgA and 16/18 for IgM class. These results suggest the participation of anti-hsp antibodies to synovitis in RA.National Institute for Leprosy Research Higashimurayama, Tokyo, 189, Japan.     

Neurally mediated syncope and arrhythmias: a study of syncopal patients using the head-up tilt test

Understanding the causes of syncope in patients with arrhythmia is important in determining the therapeutic interventions. Neurally mediated syncope (NMS) was evaluated in 55 patients with various arrhythmias. The head-up tilt test with or without isoproterenol infusion induced NMS in 41 (74%) patients. When these patients was categorized into 3 types, depending on the development of syncope, vasodilatation was significant in a majority of patients. In 46% of patients with tachyarrythmias, NMS was accompanied by an increase in extrasystole. It was concluded that the evaluation of vasodilatation is important for the preventive strategy of NMS in patients with arrhythmias and that NMS may induce arrhythmias.