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Rehabilitation based on guided walking is effective to recover activity of daily living (ADL) in frail older adults, even octogenarians. However, muscle dysfunction obviously reflects disability, and few studies have focused on ADL recovery by rehabilitation. We employed the state of muscle dysfunctions proposed by the Asian Working Group for Sarcopenia (AWGS) in 2019 and attempted to clarify the relation between the overlapping dysfunctions and the feasibility of ADL recovery after rehabilitation. In total, 297 frail older patients (the mean age: 82.8 years, 46.1% of patients were male) participated in a walking-guided rehabilitation program to achieve the goal of ambulatory discharge. Muscle dysfunction was categorized by four standardized methods at the start of rehabilitation (grip strength, gait speed, time of five sit-to-stand, and short physical performance battery: SPPB), according to the AWGS proposal. ADLs were monitored by Barthel index before admission, at the start of rehabilitation, and at discharge. At least one dysfunction was present in 95.3% of patients. If a single patient had three or more muscle dysfunction, the ADLs recovery was significantly limited (interaction: p < 0.05). The overlapped counts of AWGS muscle dysfunction helps to predict inverse feasibility of ADL recovery in frail older patients through rehabilitation. [ABSTRACT FROM AUTHOR]

Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 µg·kg-1 µmin-1)or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-α and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-α and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Myocarditis is an acute inflammatory disease of the myocardium for which there is currently no specific therapy. We investigated the therapeutic potential of C-type natriuretic peptide (CNP) in acute experimental autoimmune myocarditis. One week after injection of porcine myosin into male Lewis rats, CNP (0.05μg/kg/min) was continuously administered for 2 weeks. CNP infusion significantly increased maximum dP/dt, decreased left ventricular end-diastolic pressure, and improved fractional shortening compared with vehicle administration. In vehicle-treated hearts, severe necrosis and marked infiltration of CD68-positive inflammatory cells were observed. Myocardial and serum levels of monocyte chemoattractant protein-1 were elevated in myocarditis. However, these changes were attenuated by CNP infusion. In addition, treatment with CNP significantly increased myocardial capillary density. Guanylyl cyclase-B, a receptor for CNP, was expressed in myocarditic heart, and cyclic guanosine monophosphate was elevated by CNP infusion. In conclusion, CNP infusion attenuated cardiac function in acute myocarditis through anti-inflammatory and angiogenic effects. [Copyright &y& Elsevier]

An ethyl-substituted diamidine, 1,8-bis( N , N' -diethylamidino)anthracene ( 1 ), for the recognition of dicarboxylic acids has been designed and synthesized. The complexation of diamidine 1 with dicarboxylic acids 3 , 4 and α , ω −dicarboxylic acids 6 (C 6 -C 11 ), showed the formation of 1:1 complexes in CH 3 CN. On the other hand, for the complexation with a monocarboxylic acid and α , ω −dicarboxylic acids 6 (C 3 -C 5 ), formation of the amidinium 1 ·2H + was observed. The crystal structures of the 1:1 complexes of the diamidine 1 and the α , ω −dicarboxylic acids 6 were obtained, and an unusual “U-shaped conformation” of 6 was observed. Furthermore, fluorescence spectra of the diamidine 1 showed “structural vibrational bands” derived from the anthracene unit after recognition of the α , ω −dicarboxylic acids (C 6 -C 11 ). However, for the formation of the dissociated amidinium 1 ·2H + , broad fluorescence bands were observed (without a vibrational structure). Consequently, the stability of the formed complexes can be analyzed by the patterns (vibrational structures) of the fluorescence spectra. [ABSTRACT FROM AUTHOR]

Abstract: Stem cell transplantation is one of the attractive therapeutic strategies for the treatment of hindlimb ischemia. However, few studies have quantitatively assessed perfusion noninvasively in deep tissues after cell transplantation. In this study, we examined the feasibility of contrast sonography for the assessment of perfusion after bone marrow–derived mesenchymal stem cell (MSC) transplantation by using a rat unilateral hindlimb ischemia model. The quantitative parameters derived from contrast sonography were compared with the colored microspheres–derived blood flow and the capillary density. Nine rats were assigned each to a control (saline injection) or a treated (MSC transplantation) group. Video intensity vs. pulsing interval plots were acquired with ultraharmonic imaging of SONOS5500 during IV infusion of Levovist. The left-to-right ratio of hindlimb blood volume (A-ratio), microbubble velocity (β-ratio) and hindlimb blood flow (Aβ-ratio) were calculated. The MS-ratio, the ratio of the left to the right hindlimb blood flow determined using colored microspheres, was also calculated. Although A-ratio did not change, β- and Aβ-ratio in the treated group were significantly higher than those in the control group. In addition, MS-ratio and capillary density in the treated group were significantly higher than those in the control group. Compared with A- and Aβ-ratio, β-ratio had the highest correlation with MS-ratio and capillary density (vs. MS-ratio: r = 0.66, p < 0.01; vs. capillary density: r = 0.52, p < 0.05). The results of our study imply that the contrast sonography–derived β-ratio is a useful parameter that reflects the perfusion after cell transplantation in ischemic hindlimb. (E-mail: nnagaya@ri.ncvc.go.jp) [Copyright &y& Elsevier]

Abstract: Beraprost sodium, an orally active prostacyclin analogue, has vasoprotective effects such as vasodilation and antiplatelet activities. We investigated the therapeutic potential of beraprost for myocardial ischemia. Immediately after coronary ligation of Sprague–Dawley rats, beraprost (200μg/kg/day) or saline was subcutaneously administered for 28 days. Four weeks after coronary ligation, administration of beraprost increased capillary density in ischemic myocardium, decreased infarct size, and improved cardiac function in rats with myocardial infarction. Beraprost markedly increased the number of CD34-positive cells and c-kit-positive cells in plasma. Also, four weeks after coronary ligation of chimeric rats with GFP-expressing bone marrow, bone marrow-derived cells were incorporated into the infarcted region and its border zone. Treatment with beraprost increased the number of GFP/von Willebrand factor-double-positive cells in the ischemic myocardium. These results suggest that beraprost has beneficial effects on ischemic myocardium partly by its ability to enhance neovascularization in ischemic myocardium by mobilizing bone marrow cells. [Copyright &y& Elsevier]

The novel and efficient synthesis of type 2 Lewis antigens is reported in this study. The rationally designed lactosamine-3,2′-diol derivative with an orthogonal set of protecting groups is efficiently glycosylated with a benzyl protected 1-thio- l -fucoside donor in a unique regioselective manner to produce Lewis x (Le x ) and Lewis y (Le y ) derivatives in good yields. These derivatives can be prepared not only exclusively but also synchronously by choosing the appropriate reaction temperature and donor–acceptor molar ratio. The Le x derivatives are easily converted into sulfated or non-sulfated Le x bearing a terminal azido functionalized oligo-(ethyleneoxide) linker; the Le y derivative having the same linker can also be prepared, all of which can be further used for the chemical modification of other compounds and materials. [ABSTRACT FROM AUTHOR]

Tissue macrophages can be activated by endogenous danger signals released from cells that are stressed or injured, leading to infiltration of inflammatory macrophages and neutrophils. We postulated that macrophage-related markers might be closely associated with the existence of endogenous danger signals, reflecting ongoing tissue injury in the absence of foreign substances. This study was designed to assess the ability of macrophage-related markers in endomyocardial biopsies to predict ongoing cardiac injury in non-inflammatory myocardial diseases. We examined levels of macrophage-related markers (CD68, CD163, CD45) in endomyocardial biopsies from patients ( n = 86) with various myocardial diseases by quantitative reverse transcription-polymerase chain reaction ( n = 78) and immunohistochemistry ( n = 56). Thirty-three patients without inflammatory cardiac disease such as myocarditis and sarcoidosis were classified as 'improved' or 'non-improved' defined as a 10 % increase in left ventricular ejection fraction by echocardiograph and a value greater than 30 % at the time of follow-up. All macrophage-related (MacR) markers levels were not higher in non-improved dilated cardiomyopathy (DCM) patients than improved patients. However, patients with cardiac amyloidosis, cardiac Fabry disease, mitochondrial cardiomyopathy, and biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC), which were categorized as 'non-improvement diseases,' had elevated macrophage-related markers compared to improved patients. Macrophage-related markers levels were increased in endomyocardial biopsy samples of patients with intractable myocardial diseases such as amyloidosis, mitochondrial disease, Fabry disease, and biventricular ARVC. [ABSTRACT FROM AUTHOR]

Background Mechanical alternans (MA) and electrical alternans (EA) are predictors of cardiac events. Experimental studies have suggested that refractoriness of calcium cycling underlies these cardiac alternans. However, refractoriness of left ventricular contraction has not been examined in patients with cardiac alternans. Methods In 51 patients with miscellaneous heart diseases, incremental right atrial pacing was performed to induce MA and EA. MA was quantified by alternans amplitude (AA: the difference between left ventricular dP/dt of a strong beat and that of a weak beat), and AA at 100/min (AA100) and maximal AA (AAmax) were measured. EA was defined as alternation of T wave morphology in 12-lead electrocardiogram. Relative refractoriness of left ventricular contraction was examined by drawing the mechanical restitution curve under a basal coupling interval (BCL) of 600 ms (100/min) and was assessed by the slope at BCL (Δmechanical restitution). Postextrasystolic potentiation (PESP) was also examined and the slope of PESP curve (ΔPESP) was assessed as a property to alternate strong and weak beats. Results MA and EA were induced in 19 patients and in none at 100/min or less, and at any heart rate in 32 and in 10, respectively. AA100 and AAmax correlated positively with Δmechanical restitution and negatively with ΔPESP. Patients with EA had a significantly larger Δmechanical restitution and a significantly larger absolute value of ΔPESP than those without. Conclusions In patients with MA and EA, the left ventricular contractile force during tachycardia is under relative refractoriness and prone to cause large fluctuation of contractile force. [ABSTRACT FROM AUTHOR]

Mechanical alternans (MA) is frequently observed in patients with heart failure, and is a predictor of cardiac events. However, there have been controversies regarding the conditions and mechanisms of MA. To clarify heart rate-dependent contractile properties related to MA, we performed incremental right atrial pacing in 17 idiopathic dilated cardiomyopathy (DCM) patients and in six control patients. The maximal increase in left ventricular d P/d t during pacing-induced tachycardia was assessed as the force gain in the force-frequency relationship (FG-FFR), and the maximal increase in left ventricular d P/d t of the first post-pacing beats was examined as the force gain in poststimulation potentiation (FG-PSP). As a result, MA was induced in 9 DCM patients (DCM MA(+)) but not in the other 8 DCM patients (DCM MA(−)), and not in any of the control patients. DCM MA(+) had significantly lower FG-FFR (34.7 ± 40.9 vs 159.4 ± 103.9 mmHg/s, P = 0.0091) and higher FG-PSP (500.0 ± 96.8 vs 321.9 ± 94.9 mmHg/s, P = 0.0017), and accordingly a wider gap between FG-PSP and FG-FFR (465.3 ± 119.4 vs 162.5 ± 123.6 mmHg/s, P = 0.0001) than DCM MA(−) patients. These characteristics of DCM MA(+) showed clear contrasts to those of the control patients. In conclusion, MA is caused with an impaired force-frequency relationship despite significant poststimulation potentiation, suggesting that MA reflects ineffective utilization of the potentiated intrinsic force during tachycardia. [ABSTRACT FROM AUTHOR]

Abstract: We investigated whether correlations between mRNA levels of cytokines versus other proteins from patchy lesion could estimate cytokine paracrine signaling in vivo. Experiments with rat experimental autoimmune myocarditis (EAM), a patchy myocarditis model, indicated IL-1 and other protein levels were correlated, indicating paracrine signaling pathways in vivo. [Copyright &y& Elsevier]

The clinical implications of mechanical alternans in patients with pulmonary arterial hypertension (PAH) remain unknown. In this study, the prevalence, characteristics, and prognostic implications of mechanical alternans in patients with PAH were investigated. Thirty-two consecutive patients with PAH confirmed by cardiac catheterization from 2000 to 2010 were included in this cohort study. During cardiac catheterization, 8 patients (25%) showed mechanical alternans at rest. All alternans were detected in the right ventricle and pulmonary trunk. Serum level of brain natriuretic peptide (584 ± 177 vs 238 ± 252 pg/ml, p = 0.001), World Health Organization functional class (3.5 ± 0.5 vs 2.9 ± 0.4, p = 0.02), mean pulmonary arterial pressure (59 ± 10 vs 47 ± 18 mm Hg, p = 0.03), mean right atrial pressure (10 ± 4 vs 5 ± 4 mm Hg, p = 0.01), right ventricular end-diastolic pressure (15 ± 5 vs 9 ± 5 mm Hg, p = 0.01), and heart rate at catheterization (96 ± 17 vs 70 ± 11 beats/min, p = 0.003) were significantly higher in patients with alternans than in those without. Twelve-month mortality of patients with alternans was higher than in patients without alternans (p = 0.03): the 12-month survival rate after cardiac catheterization was 37% for the alternans group and 75% for the group without alternans. In conclusion, isolated right-sided mechanical alternans is not an uncommon event in patients with PAH. The existence of alternans is associated with the severity of PAH and right ventricular dysfunction and implies a poor prognosis in the short term. [Copyright &y& Elsevier]

Abstract: Cell therapy is a promising therapeutic strategy for regenerative medicine. However, its current efficacy is insufficient, because of the short lifetime and low engraftment of transplanted cells. Transplantation of genetically modified stem cells has been reported to improve the efficacy of cell therapy. The aim of this study was to elucidate the feasibility of a combination of ultrasound and microbubbles (US-MB) for delivery of small interfering RNA (siRNA) into mesenchymal stem cells (MSC). Although cell damage was observed after US-MB treatment, the transfection efficiency determined using fluorescent-labeled siRNA was significantly increased after US-MB. Furthermore, the intracellular delivery of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) siRNA by US-MB resulted in significant knockdown of PTEN mRNA expression and activation of Akt, a mediator of a survival signaling pathway. Our results indicate that US-MB could serve as a nonviral delivery method of siRNA into MSC. The transplantation of genetically modified MSC by US-MB could be a useful strategy for regenerative medicine in the future. [Copyright &y& Elsevier]

The role of endostatin in coronary heart disease (CHD) is not well known. This study aimed to investigate the dynamics of endostatin, an antiangiogenic growth factor, within the coronary circulation and to elucidate its relation to coronary collateral formation in patients with CHD. We recruited 72 subjects with suspected or previously diagnosed CHD. Blood samples from the left ventricular (LV) cavity and coronary sinus (CS) were obtained during coronary angiography, and the serum concentration of endostatin was measured by enzyme-linked immunosorbent assay kits. Patients were then divided into 2 groups: the normal group (n = 15) defined as patients with atypical chest pain and no evidence of organic cardiac diseases and the CHD group (n = 57) defined as patients with ≥75% coronary stenosis at coronary angiography and chest pain on exertion. Endostatin in CS sera was significantly elevated in patients with CHD compared with normal subjects (median 79.7 [interquartile range 46.2 to 130.3] vs median 49.6 [interquartile range 29.1 to 84.5] ng/ml, p = 0.02). Spillover of endostatin (CS − LV value) from the coronary circulation in patients with CHD with severe stenosis was higher than in those with moderate stenosis (28.2 [4.8 to 48.6] vs 7.3 [−37.0 to 25.6] ng/ml, p = 0.01). In addition, endostatin production within the coronary circulation was higher in patients with poorly developed collaterals than in those with well-developed collaterals. In conclusion, endostatin is suggested to be produced from the coronary circulation in patients with CHD and may play an important role in the regulation of the growth of coronary collateral vessels. [Copyright &y& Elsevier]

Abstract: Acute myocarditis is a non-ischemic inflammatory disease of the myocardium for which there is currently no specific treatment. We have previously shown that mesenchymal stem cells (MSC) can ameliorate heart injury during acute ischemia and in dilated cardiomyopathy; however, the therapeutic potential in acute myocarditis is unclear. In this study, we investigated the ability of MSC to attenuate myocardial injury and dysfunction during the acute phase of experimental myocarditis. Ten-week-old male Lewis rats were injected with porcine myosin to induce myocarditis. Cultured MSC (3×106 cells/rat) were injected intravenously 7 days after myosin injection. At 3 weeks, myosin injection resulted in severe inflammation and significant deterioration of cardiac function. MSC transplantation attenuated increases in CD68-positive inflammatory cells and monocyte chemoattractant protein-1 (MCP-1) expression in myocardium, and improved cardiac function in this model. Furthermore, myocardial capillary density was higher in myocarditis tissue, and was further increased by MSC transplantation. In vitro, cultured adult rat cardiomyocytes were injured in response to MCP-1, whereas this effect was attenuated by MSC-derived conditioned medium, suggesting cardioprotective effects of MSC acting in a paracrine manner. MSC transplantation attenuated myocardial injury and dysfunction in a rat model of acute myocarditis, at least in part through paracrine effects of MSC. [Copyright &y& Elsevier]

Abstract: Objective. : The purpose of this study was to report the results of adjuvant CPT-11 and MMC combination chemotherapy (CPT-M) for ovarian clear cell adenocarcinoma (OCCA). Methods. : Between 1996 and 2002, 20 patients with OCCA underwent primary debulking surgery and received 6 treatments of CPT-11 (140 mg/m2) in combination with MMC (7 mg/m2), 2 weeks apart with a space of 3–4 weeks between the 3rd and 4th treatment in adjuvant setting. Overall survival was compared with our historical control treated between 1983 and 1995, in which 14 patients with OCCA were treated with an initial optimal standard surgery and postoperative adjuvant cyclophosphamide, doxorubicin, and cisplatin (CAP) combination chemotherapy. Results. : Median age was 51 years old (range, 29–74). Twelve patients were in stage Ic, 1 in stage IIa, 5 in stage IIc, 1 in stage IIIc, and 1 in stage IV. Optimal cytoreduction with standard surgery was obtained in all 20 patients. The major toxicity with this regimen was neutropenia, which was reversible. The incidences of grade 3 and 4 neutropenia were 25% and 15%, respectively. The non-hematological toxicities were generally mild and well tolerated. One patient with stage Ic refused chemotherapy after the first cycle of CPT-M, and died of her disease 8 months after initial surgery. Five-year survival rate was 95.0% for CPT-M group, and 63.5% for CAP group (P = 0.042). Survival was significantly better for patients treated with CPT-M. Conclusion. : This preliminary study shows that the combination of CPT-M appears to be safe and useful in patients with OCCA. Prospective randomized trials should be conducted to assess this regimen appropriate for women with OCCA. [Copyright &y& Elsevier]

Objective. This study was performed to define the subgroups of patients who benefit from postoperative adjuvant chemotherapy in stage I and II endometrial carcinoma.Methods. A retrospective review of 170 International Federation of Gynecology and Obstetrics (FIGO) stage I and II endometrial carcinoma patients treated between 1988 and 2000 at Niigata University Hospital was performed. All patients underwent surgery, of which 41 patients underwent adjuvant chemotherapy, consisting of intravenous cisplatin, doxorubicin, and cyclophosphamide. Multivariate analysis was performed for the prognostic factors and actuarial techniques were used for the survival and recurrence rates.Results. The patients were divided into low-risk and high-risk groups based on the number of prognostic factors (tumor grade G3, outer half myometrial invasion, lymph-vascular space involvement (LVSI), and cervical invasion). The 5-year disease-free survival and the 5-year overall survival for the low-risk group were 97.4%, and 100%, respectively, which were significantly better than 77.4% and 88.1% for the high-risk group (P < 0.0001, P < 0.0001), respectively. Among high-risk group patients, the 5-year disease-free survival and the 5-year overall survival were 88.5% and 95.2% in 26 patients treated with adjuvant chemotherapy, and 50.0% and 62.5% in eight cases who underwent only surgery (P = 0.0150, P = 0.0226). Disease recurrence occurred in 7 (20.6%) of 34 high-risk group patients. Four of seven recurrences occurred in patients who did not receive postoperative chemotherapy, in which all four were distant failure. In the remaining three patients who were in the CAP group, two had vaginal wall recurrence and only one had pulmonary recurrence. Three recurrences were also observed in the 133 low-risk group patients. Only isolated vaginal wall recurrence occurred in three patients without adjuvant chemotherapy after the initial surgery.Conclusions. There is possibility that postoperative adjuvant CAP may be omitted in surgical stage I or II endometrial cancer patients with 0 or 1 prognostic factor. The high-risk group of patients should be treated with postoperative adjuvant CAP to decrease distant failure and improve prognosis. [Copyright &y& Elsevier]

A letter to the editor on correlation between right heart failure due to anemia is presented.