In-hospital pulmonary rehabilitation after completion of primary respiratory disease treatment improves physical activity and ADL performance: A prospective intervention study.

INTRODUCTION: Pulmonary rehabilitation improves the physical condition of patients with chronic respiratory disease; however, there are patients who cannot leave the hospital because of their low activities of daily living (ADLs), despite the completion of primary respiratory disease treatment and rehabilitation during treatment. Therefore, this study demonstrated that those patients recovered their ADLs through in-hospital pulmonary rehabilitation after treatment completion. METHODS: We prospectively studied 24 hospitalized patients who had some remaining symptoms and showed low ADL scores of 9 points or less on the short physical performance battery after undergoing treatment for respiratory disease in Fukujuji Hospital from October 2018 to October 2019, excluding 2 patients who had re-exacerbation and 1 patient who could not be examined using the incremental shuttle walk test (ISWT). After completion of the primary respiratory disease treatment, patients moved to the regional comprehensive care ward, and they received pulmonary rehabilitation for 2 weeks. In the ward, patients who could not yet leave the hospital could undergo pulmonary rehabilitation for up to 60 days. Data were evaluated three times: upon treatment completion (baseline), postrehabilitation, and 3 months after baseline. The main outcome was an improvement in the incremental shuttle walk test (ISWT) postrehabilitation. RESULTS: The median age of the patients was 80 (interquartile range (IQR): 74.8-84.5), and 14 patients (58.3%) were male. The ISWT distance significantly increased postrehabilitation (median [IQR]: 60 m [18-133] vs 120 m [68-203], P < .001). The Barthel Index (BI) (P < .001), the modified Medical Research Council (P < .001), and other scale scores were also improved. Among patients with acute respiratory diseases such as pneumonia, chronic obstructive pulmonary disease, and interstitial pneumonia, ISWT and other data showed improvement at the postrehabilitation timepoint. Ten patients who could perform examinations at 3 months after baseline were evaluated 3 months after taking baseline data prior to starting rehabilitation. The ISWT showed significant improvement 3 months after baseline compared to baseline (P = .024), and the ISWT distance was maintained after rehabilitation. DISCUSSION AND CONCLUSIONS: Physical activity, symptoms, mental health, and ADL status in patients who had not recovered after primary treatment completion for respiratory diseases could improve through in-hospital pulmonary rehabilitation.

FOLFIRINOX for Recurrent Pancreatic Cancer After Pancreatic Resection: A Secondary Analysis of the Nationwide Multicenter Observational Study Conducted by the Japan Adjuvant Study Group of Pancreatic Cancer 06.

OBJECTIVES: The multidrug regimen with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is widely used for recurrent pancreatic cancer after pancreatic resection. However, there are concerns about severe toxicities and poor tolerability of FOLFIRINOX in these patients because some suffer from surgery-associated malnutrition, weight loss, and diabetes mellitus. We evaluated the toxicity and tolerability of FOLFIRINOX in these patients. METHODS: This study was conducted as a secondary analysis of the Japan Adjuvant Study Group of Pancreatic Cancer 06 study, which was a multicenter observational study of FOLFIRINOX for pancreatic cancer in Japan. The toxicity and tolerability of FOLFIRINOX in recurrent disease correlated with those of both the locally advanced and the metastatic disease group. RESULTS: The major grades 3 and 4 toxicities observed in the recurrent and locally advanced or metastatic disease groups were neutropenia (68% vs 63%), febrile neutropenia (4% vs 15%, P = 0.007), thrombocytopenia (4% vs 3%), diarrhea (4% vs 8%), and sensory neuropathy (0% vs 2%). The dose modification and relative dose intensity did not differ markedly between the groups. CONCLUSIONS: The toxicity and tolerability of FOLFIRINOX for recurrence after pancreatic resection were similar to those for locally advanced or metastatic disease with appropriate patient selection and dose modifications.

Effects of caffeine on fractional flow reserve values measured using intravenous adenosine triphosphate.

We investigated the effects of caffeine intake on fractional flow reserve (FFR) values measured using intravenous adenosine triphosphate (ATP) before cardiac catheterization. Caffeine is a competitive antagonist for adenosine receptors; however, it is unclear whether this antagonism affects FFR values. Patients were evenly randomized into 2 groups preceding the FFR study. In the caffeine group (n = 15), participants were given coffee containing 222 mg of caffeine 2 h before the catheterization. In the non-caffeine group (n = 15), participants were instructed not to take any caffeine-containing drinks or foods for at least 12 h before the catheterization. FFR was performed in patients with more than intermediate coronary stenosis using the intravenous infusion of ATP at 140 µg/kg/min (normal dose) and 170 µg/kg/min (high dose), and the intracoronary infusion of papaverine. FFR was followed for 30 s after maximal hyperemia. In the non-caffeine group, the FFR values measured with ATP infusion were not significantly different from those measured with papaverine infusion. However, in the caffeine group, the FFR values were significantly higher after ATP infusion than after papaverine infusion (P = 0.002 and P = 0.007, at normal and high dose ATP vs. papaverine, respectively). FFR values with ATP infusion were significantly increased 30 s after maximal hyperemia (P = 0.001 and P < 0.001 for normal and high dose ATP, respectively). The stability of the FFR values using papaverine showed no significant difference between the 2 groups. Caffeine intake before the FFR study affected FFR values and their stability. These effects could not be reversed by an increased ATP dose.

Sequential biatrial linear defragmentation approach for persistent atrial fibrillation.

BACKGROUND: The strategy for catheter ablation of persistent atrial fibrillation (AF) and the procedural end point remain controversial. OBJECTIVE: To evaluate the feasibility of a sequential defragmentation approach. METHODS: One hundred thirty-five patients (aged 62.4 ± 9 years; 76 long-standing persistent AF) underwent first ablation procedure for persistent AF. With an end point of AF termination, the ablation procedure was performed sequentially in the following order: pulmonary vein antrum isolation, linear defragmentation of complex fractionated electrograms at left atrial (LA) roof, bottom, septum, inferior LA, base of LA appendage, anterior LA, right atrial septum, crista terminalis, and base of right atrial appendage. Ensuing atrial tachycardias (ATs) were mapped and ablated. RESULTS: AF termination was achieved in 69 (51%) patients (59 in the left atrium and 10 in the right atrium). The total procedure and fluoroscopic times were 145.4 ± 36.1 and 35.1 ± 14.3 minutes, respectively. At median 19.0 months, 105 (78%) patients demonstrated recurrent atrial tachyarrhythmia necessitating repeat ablation procedure(s). With mean 1.7 ± 0.7 procedures per patient, 100 (74%) patients were free from atrial tachyarrhythmia at median 15.0-month follow-up. Among 73 mappable ATs, 49 were macroreentrant ATs. On multivariate Cox regression analysis, greater LA diameter (hazard ratio 1.10; 95% confidence interval 1.04-1.17; P = .0004) and non-AF termination (hazard ratio 1.50; 95% confidence interval 1.01-2.36; P = .036) were independent predictors of AF recurrence after single and multiple ablation procedures, respectively. CONCLUSIONS: Pulmonary vein antrum isolation followed by biatrial substrate modification in a predetermined order of linear ablation of specific anatomical regions with predilection for complex fractionated atrial electrograms is a feasible alternative persistent AF ablation strategy.

Conduction recovery after electrical isolation of superior vena cava--prevalence and electrophysiological properties.

BACKGROUND: Superior vena cava (SVC) is an infrequent yet an important source of atrial fibrillation (AF). The data on SVC reconnection are limited. METHODS AND RESULTS: Following pulmonary vein (PV) antrum isolation for AF, SVC isolation was systemically performed under angiographic and mapping guidance using 4-mm non-irrigated tip catheter. SVC reconnection could be evaluated in 76 consecutive patients (65 ± 9 years, 59 male) who underwent repeat AF ablation after 16 ± 16 months. SVC was isolated at the 1(st), 2(nd), 3(rd) and 4(th) AF ablation procedure in 63, 7, 5 and 1 patient by 7.3 ± 3.1 radiofrequency applications. SVC reconnection was observed in 56 patients (74%). In the majority, the conduction gap was located at the anterolateral SVC-right atrium (RA) junction. After re-isolation of SVC, 2/7 patients (29%) had reconnection at the following procedure. Among 63 patients who underwent PV and SVC isolation at the initial procedure, the prevalence of reconnection for PV and that for SVC were similar (53/63, 84% vs. 46/63, 73%; P=0.129). Dissociated activity, however, was more frequently observed in the PVs than in the SVC (47/63, 73% vs. 10/63, 16%; P<0.0001). During the procedure, AF initiation from a thoracic vein was identified in 19/63 patients (30%). CONCLUSIONS: SVC reconnection is common after 1 or more previous isolation procedures undertaken for AF ablation. Its prevalence is similar to that of PV reconnection. The location of the conduction gap varies widely but is most frequently found at the anterolateral SVC-RA junction.

Clinical implication of adenosine test at repeat atrial fibrillation ablation procedure: the importance of detecting dormant thoracic vein conduction.

BACKGROUND: Pulmonary vein reconnection after electrical isolation is commonly observed in the context of atrial fibrillation ablation and is associated with recurrent atrial tachyarrhythmias. Adenosine test was been performed to identify acute dormant conduction immediately after pulmonary vein isolation at index procedure. However, the utility of adenosine test at repeat procedure has not been reported. METHODS AND RESULTS: We report 5 paroxysmal atrial fibrillation cases without any structural heart disease in which dormant thoracic vein conduction was associated with recurrent atrial tachyarrhythmias. All patients had undergone circumferential ipsilateral pulmonary vein isolation at the index procedure. Superior vena cava isolation was performed if superior vena cava-triggered atrial fibrillation was identified. At the index procedure, adenosine test did not provoke venous reconduction. At the repeat procedure, adenosine provoked clinical arrhythmia in 4 out of 5 cases after transient reconnection between culprit thoracic vein and atrium despite absence of reconnection at the start of the procedure. After the elimination of the dormant conduction gaps, all patients were free from recurrent arrhythmia. CONCLUSIONS: Adenosine provokes dormant thoracic vein conduction associated with the late recurrence of atrial tachyarrhythmias after previous thoracic vein isolation. Thus, adenosine provocation test can specifically help identify and target the cause of recurrent atrial arrhythmia.

Two distinct electrocardiographic forms of idiopathic ventricular arrhythmia originating in the vicinity of the His bundle.

AIM: The objective is to assess electrocardiographic characteristics predicting the precise location of ventricular arrhythmia (VA) origin within the right ventricle (RV) close to the His bundle (HB) region. METHODS AND RESULTS: Twenty-five patients (14 men, age 65 ± 14 years) underwent successful catheter ablation of para-Hisian VA. Ventricular arrhythmias were considered to arise in the vicinity of the HB region based on the criteria that mapping exhibited the earliest RV activation before QRS onset in the HB region. Surface 12-lead electrocardiogram during the para-Hisian VAs was analysed. Of the 25 patients, 8 originated from the RV antero-septum just above the HB region, and 17 arose from the RV mid-septum just below the HB region. There was no significant difference in precedence of the local ventricular electrogram of the HB region from the onset of surface QRS during VAs. Surface electrocardiographic findings were characterized according to R-wave amplitude in lead I (0.43 ± 0.18 vs. 0.67 ± 0.19 mV, P = 0.005), mean R-wave amplitude in inferior leads (1.12 ± 0.32 vs. 0.71 ± 0.24 mV, P = 0.002), R-wave amplitude ratio of leads III/II (0.77 ± 0.10 vs. 0.50 ± 0.23, P = 0.005), incidence of S-wave in lead III [1/8 (13%) vs. 16/17 (94%), P < 0.001], and QS morphology in lead V1 [3/8 (38%) vs. 17/17 (100%), P = 0.001]. CONCLUSIONS: Despite their adjacent locations, para-Hisian VAs could be classified into two subgroups with distinctive electrocardiographic characteristics according to origin either above or below the HB region. The present findings can be helpful for planning catheter ablation of para-Hisian VAs, and can reduce the risk of inadvertent atrioventricular block.

Retrospective nationwide survey of Japanese patients with transfusion-dependent MDS and aplastic anemia highlights the negative impact of iron overload on morbidity/mortality.

OBJECTIVE: Myelodysplastic syndromes (MDS) and aplastic anemia (AA) are the most common anemias that require transfusion therapy in Japan. This retrospective survey investigated relationships between iron overload, chelation practices, and morbidity/mortality in patients with these diseases. METHOD: Medical histories of transfusion-dependent patients were assessed at transfusion onset, chelation onset, and study end. RESULTS: Data were collected from 292 patients with MDS, AA, pure red cell aplasia, myelofibrosis, and other conditions. Patients received a mean of 61.5 red blood cell units during the previous year. Fewer than half (43%) of patients had previously received deferoxamine (DFO) therapy. Only 8.6% received daily/continuous DFO. In all, 75 deaths were reported, with cardiac and liver failure noted in 24.0 and 6.7% of cases. Of these, 97% had ferritin levels >1000 ng/mL. Abnormal cardiac and liver function was observed in 21.9% (14/64) and 84.6% (11/13) of all patients assessed. Effective chelation with DFO resulted in improved serum ferritin, liver enzymes, and fasting blood sugar. CONCLUSIONS: Mortality is higher in heavily iron-overloaded patients, with liver and cardiac dysfunction being the primary cause. Daily/continuous chelation therapy was effective at reducing iron burden and improving organ function. Chelation therapy should be initiated once serum ferritin levels exceed 1000 ng/mL.

Ethyl pyruvate ameliorates distant organ injury in a murine model of acute necrotizing pancreatitis.

OBJECTIVE: Ethyl pyruvate has been shown to be an effective anti-inflammatory agent in a variety of in vitro and in vivo model systems. Herein, we used a murine model of acute pancreatitis to compare the effects of treatment with either Ringer's lactate solution or ethyl pyruvate solution on several physiologic and biochemical variables related to disease severity. DESIGN: Experimental animal study. SETTING: University laboratory. SUBJECTS: C57Bl/6 mice. INTERVENTIONS: Pancreatitis was induced by feeding the animals a choline-deficient diet supplemented with 0.5% ethionine for 24 hrs and then challenging the animals with seven hourly 50 microg/kg intraperitoneal injections of cerulein and a single intraperitoneal injection of Escherichia coli lipopolysaccharide (4 mg/kg). MEASUREMENTS AND MAIN RESULTS: When mice were treated with ethyl pyruvate (40 mg/kg intraperitoneally every 6 hrs for 48 hrs) instead of Ringer's lactate solution starting 2 hrs after the injection of lipopolysaccharide, long-term survival was improved from one of ten to six of ten (p =.057). When mice were treated with a 40 mg/kg dose of ethyl pyruvate just before the first dose of cerulein and then injected with a second 40 mg/kg dose 6 hrs later, serum concentrations of alanine aminotransferase measured 10 hrs after the first cerulein dose were significantly lower than in mice with pancreatitis treated with Ringer's lactate solution. In this model of acute pancreatitis, the same dosing regimen for ethyl pyruvate also ameliorated bacterial translocation to mesenteric lymph nodes and leakage of fluorescein isothiocyanate-labeled albumin from blood into bronchoalveolar lavage fluid. Treatment with ethyl pyruvate decreased pancreatic expression of tumor necrosis factor and interleukin-6 messenger RNA and nuclear factor-kappaB DNA binding in nuclear extracts prepared from pancreatic tissue. CONCLUSION: Treatment with ethyl pyruvate ameliorated the local inflammatory response and decreased local and distant organ injury in a murine model of necrotizing pancreatitis.

Coexistent rearrangements of c-MYC, BCL2, and BCL6 genes in a diffuse large B-cell lymphoma.

We present a patient with stage III de novo diffuse large B-cell lymphoma. The lymphoma cells showed mature B-cell immunophenotype but lacked surface immunoglobulin (Ig) expression. Long-distance and long-distance inverse polymerase chain reaction assays to detect the oncogene/Ig gene rearrangement revealed that the cells carried 3 independent fusion genes, namely, c-MYC/Ig heavy chain gene (IgH), BCL2/IgH, and Ig lambda light chain gene/BCL6. Thus, the lymphoma cells concurrently carried t(8;14)(q24;q32), t(14;18)(q32;q21), and t(3;22)(q27;q11), which developed in association with class switching, V/D/J recombination, and somatic hypermutation, respectively. The lymphoma responded to chemoradiotherapy, and the patient has been well for 2 years, suggesting that multiple oncogene rearrangements may not necessarily be associated with poor clinical outcome.

Dose-dependent effects of ethyl pyruvate in mice subjected to mesenteric ischemia and reperfusion.

OBJECTIVE: We previously showed that infusing rats with a solution of ethyl pyruvate ameliorates intestinal mucosal injury after mesenteric ischemia and reperfusion. Ethyl pyruvate also has been shown to inhibit the expression of various pro-inflammatory cytokines in several animal models of critical illness, but dose-response relationships have not been investigated. DESIGN: Anesthetized C57BL/6 mice were subjected to 60 min of mesenteric ischemia followed by 60 min of reperfusion. After 55 min of ischemia, groups of mice were treated with normal saline or graded bolus doses of ethyl pyruvate dissolved in a calcium-containing balanced salt solution. Some animals (i.e., those in the sham group) were subjected to the anesthetic, but not mesenteric ischemia/reperfusion. Gut mucosal permeability was assessed using an everted gut sac technique. SETTING: University research laboratory. MEASUREMENTS AND RESULTS: Mesenteric ischemia/reperfusion significantly increased ileal mucosal permeability to the hydrophilic macromolecule, fluorescein isothiocyanate dextran (molecular mass 4,000 Da). Whereas the lowest dose of ethyl pyruvate evaluated (17 mg/kg) had no effect on gut mucosal permeability, the two highest doses tested (50 and 150 mg/kg) significantly ameliorated the development of ischemia/reperfusion-induced mucosal hyperpermeability to about the same extent. The two highest doses of ethyl pyruvate also significantly ameliorated deficits in ileal serosal and mucosal and hepatic surface microvascular perfusion induced by mesenteric ischemia/reperfusion. Ethyl pyruvate inhibited post-ischemia/reperfusion hepatic NF-kappaB activation and TNF mRNA expression in a dose-dependent fashion. CONCLUSION: Doses of ethyl pyruvate equal to or greater than 50 mg/kg ameliorate inflammation, microvascular hypoperfusion and gut mucosal damage induced by mesenteric ischemia/reperfusion in mice.

Comparison of gene expression profiles of lymphoma cell lines from transformed follicular lymphoma, Burkitt's lymphoma and de novo diffuse large B-cell lymphoma.

To determine the specific gene expression in B-cell lymphoma subtypes, we compared expression profiles of cell lines from transformed follicular lymphoma (tFL), Epstein-Barr virus-negative (EBV(-)) Burkitt's lymphoma (BL) and EBV(+)BL. Complementary DNAs were synthesized from these cell lines and hybridized with the Atlas Human 1.2 Array membrane. Hierarchical clustering analysis based upon the levels of 43 genes highlighted characteristic expression patterns of the 3 lymphoma subtypes. Genes expressed at higher levels in tFL than EBV(-)BL and EBV(+)BL included calcium/calmodulin-dependent protein kinase I (CAMK1) and mitogen-activated protein kinase 10 (MAPK10). EBV(-)BL was characterized by high-level expression of amyloid beta precursor protein (APP), heat shock 27 kD protein 1 (HSPB1) and mothers against decapentaplegic homolog 1 (MADH1). Gardner-Rasheed feline sarcoma viral oncogene homolog (FGR) was the most significant gene to delineate EBV(+)BL. A subtype prediction algorithm using 34 genes correctly classified 22 (92%) of 24 lymphomas into FL/tFL, EBV(-)BL or EBV(+)BL. By comparison with normal reference B-cell materials, the expression patterns of the selected genes were characteristic of lymphomas. We extended the clustering analysis to cell lines from de novo diffuse large B-cell lymphoma (DLBCL). The DLBCL cell lines were either separated from the former 3 lymphoma subtypes or segregated with EBV(+)BL, possibly reflecting variable genetic abnormalities. The associations of CAMK1 with tFL, APP and MADH1 with EBV(-)BL, FGR with EBV(+)BL, and BCL2 with tFL and DLBCL were confirmed by real-time quantitative reverse transcriptase-mediated polymerase chain reaction assays. This study has provided new molecular markers, expressions of which are closely associated with B-cell lymphoma subtypes.

Possible role of ceramide as an indicator of chemoresistance: decrease of the ceramide content via activation of glucosylceramide synthase and sphingomyelin synthase in chemoresistant leukemia.

We investigated the possibility of the proapoptotic lipid ceramide as an indicator of chemoresistance in leukemia. Doxorubicin (DOX) increased the ceramide level and apoptosis in drug-sensitive HL-60 cells but not in drug-resistant HL-60/ADR cells, under the condition that the uptake of DOX was not different between the two cell lines. In addition, exogenous N-acetylsphingosine (C2-ceramide) enhanced DOX-induced apoptosis in HL-60/ADR cells without affecting the expression of multidrug resistant-1 protein (MDR 1) and the uptake of DOX. A lower level of ceramide with higher activities of glucosylceramide synthase (GCS) and sphingomyelin synthase (SMS) was detected in HL-60/ADR cells than in HL-60 cells. In contrast, HL-60/GCS cells, overexpressing GCS, significantly inhibited DOX-induced ceramide increase and apoptosis. These observations suggest the involvement of ceramide regulation in drug resistance of leukemia cells. In vivo, the level of ceramide was lower in chemoresistant leukemia patients (6.4 +/- 1.8 pmol/nmol phosphate; n = 14) than in chemosensitive patients (9.5 +/- 2.7 pmol/nmol phosphate; n = 9), and the activities of GCS and SMS were more than 2-fold higher in chemoresistant leukemia cells than in chemosensitive cells. MDR-1 protein was faintly expressed in one of four chemoresistant patients, but Bcl-2 were clearly detected in four patients. Therefore, it is suggested that a decrease of the ceramide level via activation of GCS and SMS is associated with the chemoresistant condition in leukemia, probably in relation to Bcl-2 but not to MDR-1 expression.