Polypharmacy at admission prolongs length of hospitalization in gastrointestinal surgery patients.

AIM: Polypharmacy in elderly people is a social issue and has been reported to cause not only drug adverse events, but also falls, dysfunction and cognitive decline. Those events may trigger prolonged length of hospitalization. Therefore, the aim of this study was to investigate whether polypharmacy has a prolonging effect on hospitalization. METHODS: The study subjects were 584 patients in a university hospital in Japan who had been admitted for hepatectomy, pancreaticoduodenectomy, gastrectomy or colectomy, and to whom clinical pathways had been applied. In this study, polypharmacy was defined as taking five or more regular oral medications, and prolonged hospitalization was defined as hospitalization longer than that determined by the clinical pathway. Multiple logistic regression analysis was performed to investigate whether polypharmacy affects the length of hospitalization. RESULTS: The subjects were 348 males and 236 females, mean ± SD age of 65.8 ± 12.9 years. Among all subjects, 228 (39.0%) were receiving polypharmacy at admission, and the number of patients with prolonged hospitalization was 262 (44.9%). Multiple logistic regression analysis revealed that the following variables were significantly associated with prolonged hospitalization; polypharmacy (odds ratio = 1.532; 95% confidence interval = 1.010-2.327), age 50-59; 2.971 (1.216-7.7758), age 60-69; 2.405 (1.059-5.909), organ pancreas; 0.298 (0.122-0.708), operation time ≥386 min; 2.050 (1.233-3.432), intraoperative bleeding volume ≥401 mL; 2.440 (1.489-4.038), postoperative delirium; 2.395 (1.240-4.734), postoperative infection; 10.715 (4.270-33.059). CONCLUSION: The current study revealed that polypharmacy at admission was an independent factor for prolonged hospitalization. In future, measures against polypharmacy are required, collaborating with outpatient clinics, family doctors and dispensing pharmacies. Geriatr Gerontol Int 2020; 20: 1085-1090..

The repeating dislodgement of an Amplatzer Septal Occluder device during recovery from general anesthesia in an adult undergoing transcatheter closure of atrial septal defect : a case report.

Transcatheter closure with an Amplatzer Septal Occluder (ASO) has become the standard treatment for secundum atrial septal defect (ASD). However, this procedure is associated with complications, such as device dislodgement. A 52-year-old woman was admitted with exertional dyspnea. Transesophageal echocardiography showed an ASD involving a 29 mm defect. Calculated Qp/Qs was 5.6 and all the rims were ?5 mm, with the exception of the posterior rim, which was 3 mm. Transcatheter ASD closure with an ASO was performed under general anesthesia. During emergence from anesthesia, tachycardia developed and the ASO device became dislodged. Hemodynamic changes associated with the end of anesthetic administration were believed to have led to device dislodgement. In a second transcatheter ASD closure, a low dose of propofol and remifentanil was maintained during emergence from anesthesia to reduce hemodynamic changes. However, device dislodgement occurred with nonsustained ventricular tachycardia. Finally, surgical ASD closure was performed. The large defect size, high Qp/Qs, and rim deficiency may have predisposed to device dislodgement after transcatheter ASD closure with ASO. The risk of device dislodgement should be considered in advance of surgery and, in high-risk cases, the patient's cardiovascular status should be closely monitored. J. Med. Invest. 66 : 194-198, February, 2019.

Novel TPO receptor agonist TA-316 contributes to platelet biogenesis from human iPS cells.

Signaling by thrombopoietin (TPO) in complex with its receptor, c-MPL, is critical for hematopoietic stem cell (HSC) homeostasis and platelet generation. Here we show that TA-316, a novel chemically synthesized c-MPL agonist (CMA), is useful for ex vivo platelet generation from human-induced pluripotent stem (iPS) cell-derived immortalized megakaryocyte progenitor cell lines (imMKCLs). Moreover, the generation is clinically applicable, because self-renewal expansion and platelet release is tightly controllable. TA-316 but not eltrombopag, another CMA, promoted both the self-renewal and maturation of imMKCLs, leading to more than a twofold higher platelet production than that achieved with recombinant human TPO (rhTPO). Interestingly, TA-316 seemed to favor MK-biased differentiation from bone marrow CD34+ HSC/progenitors and imMKCLs through the upregulation of vascular endothelial growth factor A and fibroblast growth factor 2. This result suggests TA-316 could facilitate the development of an efficient and useful system to expand platelets from imMKCLs.

Growth arrest of vascular smooth muscle cells in suspension culture using low-acyl gellan gum.

The proliferation of vascular smooth muscle cells (SMCs) causes restenosis in biomaterial vascular grafts. The purposes of this study were to establish a suspension culture system for SMCs by using a novel substrate, low-acyl gellan gum (GG) and to maintain SMCs in a state of growth inhibition. When SMCs were cultured in suspension with GG, their proliferation was inhibited. Their viability was 70% at day 2, which was maintained at more than 50% until day 5. In contrast, the viability of cells cultured in suspension without GG was 5.6% at day 2. By cell cycle analysis, the ratio of SMCs in the S phase when cultured in suspension with GG was lower than when cultured on plastic plates. In SMCs cultured in suspension with GG, the ratio of phosphorylated retinoblastoma (Rb) protein to Rb protein was decreased and p27Kip1 expression was unchanged in comparison with SMCs cultured on plastic plates. In addition, SMCs could be induced to proliferate again by changing the culture condition from suspension with GG to plastic plates. These results suggest that our established culturing method for SMCs is useful to maintain SMCs in a state of growth inhibition with high viability.

Novel 3-D cell culture system for in vitro evaluation of anticancer drugs under anchorage-independent conditions.

Anticancer drug discovery efforts have used 2-D cell-based assay models, which fail to forecast in vivo efficacy and result in a lower success rate of clinical approval. Recent 3-D cell culture models are expected to bridge the gap between 2-D and in vivo models. However, 3-D cell culture methods that are available for practical anticancer drug screening have not yet been fully attained. In this study, we screened several polymers for their ability to suspend cells or cell spheroids homogeneously in a liquid medium without changing the viscosity behavior, and identified gellan gum (FP001), as the most potent polymer. FP001 promoted cell dispersion in the medium and improved the proliferation of a wide range of cancer cell lines under low attachment conditions by inhibiting the formation of large-sized spheroids. In addition, cancer cells cultured with FP001-containing medium were more susceptible to inhibitors of epidermal growth factor (EGF) signaling than those cultured under attachment conditions. We also showed that ligands of the EGF receptor family clearly enhance proliferation of SKOV3 ovarian carcinoma cells under anchorage-independent conditions with FP001. Consistent with this result, the cells grown with FP001 showed higher EGF receptor content compared with cells cultured under attachment conditions. In conclusion, we developed a novel 3-D cell culture system that is available for high throughput screening of anticancer agents, and is suitable for evaluation of molecular-targeted anticancer drugs. Three-dimensional cell culture using FP001 will be of value in the development of useful technologies for anticancer drug discovery.

Subcritical hydrothermal treatment for the recovery of liquid fertilizer from scallop entrails.

Scallop entrails are organic wastes containing abundant proteins and minerals but are considered difficult to recycle because of high cadmium concentrations. In this work, the current problem of scallop entrails recycling was investigated and a subcritical hydrothermal treatment (SCHT) was examined for the recovery of liquid fertilizer from scallop entrails. Scallop entrails are mainly recycled for composting and feedstuff production. However, the dilution by mixing scallop entrails with other feed waste was the sole countermeasure to reduce the cadmium concentration of compost. For feedstuff production, whole product derived from scallop entrails was exported to other countries instead of domestic utilization. Temperature, retention time (RT) at given temperature, and liquid-to-solid (LS) ratio were examined as SCHT conditions for scallop entrails processing. The extraction ratio of each constituent mainly depends on the temperature rather than the RT or the LS ratio. Upon the SCHT of scallop entrails at 200°C, an RT of 20 min, and an LS ratio of 10, the extraction of fertilizer constituents such as nitrogen, phosphorus, and potassium from the liquid product was optimum, whereas the release of cadmium was suppressed. The concentrations of heavy metals in the liquid product obtained using the above-mentioned SCHT conditions were below the maximum permissible concentration stipulated by the Fertilizer Control Law. SCHT is considered to be a feasible recycling method for scallop entrails to recover fertilizer components with a concomitant separation of cadmium from the product.

Epalrestat increases glutathione, thioredoxin, and heme oxygenase-1 by stimulating Nrf2 pathway in endothelial cells.

Epalrestat (EPS) is the only aldose reductase inhibitor that is currently available for the treatment of diabetic neuropathy. Recently, we found that EPS at near-plasma concentration increases the intracellular levels of glutathione (GSH) in rat Schwann cells. GSH plays a crucial role in protecting endothelial cells from oxidative stress, thereby preventing vascular diseases. Here we show that EPS increases GSH levels in not only Schwann cells but also endothelial cells. Treatment of bovine aortic endothelial cells (BAECs), an in vitro model of the vascular endothelium, with EPS caused a dramatic increase in intracellular GSH levels. This was concomitant with the up-regulation of glutamate cysteine ligase, an enzyme catalyzing the first and rate-limiting step in de novo GSH synthesis. Moreover, EPS stimulated the expression of thioredoxin and heme oxygenase-1, which have important redox regulatory functions in endothelial cells. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of antioxidant genes. EPS increased nuclear Nrf2 levels in BAECs. Nrf2 knockdown by siRNA suppressed the EPS-induced glutamate cysteine ligase, thioredoxin-1, and heme oxygenase-1 expression. Interestingly, LY294002, an inhibitor of phosphatidylinositol 3-kinase, abolished the EPS-stimulated GSH synthesis, suggesting that the kinase is associated with Nrf2 activation induced by EPS. Furthermore, EPS reduced the cytotoxicity induced by H2O2 and tert-butylhydroperoxide, indicating that EPS plays a role in protecting cells from oxidative stress. Taken together, the results provide evidence that EPS exerts new beneficial effects on endothelial cells by increasing GSH, thioredoxin, and heme oxygenase-1 levels through the activation of Nrf2. We suggest that EPS has the potential to prevent several vascular diseases caused by oxidative stress.

Concentration-dependent effects of spermine on apoptosis and consequent generation of multilayer myotube sheets from mouse embryoid bodies in vitro.

The concentration-dependent effect of spermine was investigated on the spermine-induced generation of multilayer myotube sheets (MMTS) from mouse embryoid bodies (EBs). During spermine treatment for 24 h, a monolayer cell sheet that had already grown radially from the periphery of an EB was exfoliated. The exfoliation was inhibited by z-VAD.fmk, indicating the occurrence of apoptosis, and inhibited also by aminoguanidine, indicating the involvement of amine oxidase. Following the exfoliation, the cell growth restarted from the fresh periphery of EB in a spermine-free medium and finally formed MMTS. To analyze the contribution of apoptosis to the cell death causing exfoliation, the numbers of apoptotic, necrotic, and 2nd apoptotic cells were counted by staining with Annexin V-Cyanine-3 (AVC3) and 7-aminoactinomycin (7AAC). AVC3-positive, 7AAC-positive, and AVC3/7AAC doubly positive cells were assigned as apoptotic, necrotic, and 2nd necrotic cells, respectively. The relative number of apoptotic and 2nd necrotic cells (N A + N A/7) to the total number of dying cells (N T) was 84 ∼ 94%, which was independent of spermine concentration in the range from 0.1 to 2.0 mM. The MMTS generation rate at the final stage, however, was dependent on the spermine concentration. It was 60 ∼ 80% in the range from 0.1 to 1.5 mM, while it decreased sharply to 1% at 2 mM. This suggests another role of spermine in the MMTS generation in addition to the induction of apoptosis. This 2nd role seems to be inhibited at a spermine concentration higher than a critical limit between 1.5 and 2.0 mM.

Elevation of muscle temperature stimulates muscle glucose uptake in vivo and in vitro.

The purpose of this study was to examine whether elevation of muscle temperature per se might be a stimulatory factor to increase muscle glucose uptake. Heat stimulation to rat hindlimbs increased glucose uptake measured in vivo in the extensor digitorum longus (EDL) and soleus muscles with a significant increase in muscle temperature. This thermal effect was observed again when glucose uptake was measured in vitro in both isolated muscles immediately after the heat stimulation in vivo. When heat stimulation was imposed on isolated EDL muscles, glucose uptake was facilitated in proportion to the increase in muscle temperature. The heat stimulation led to a significant amplification in the phosphorylation of AMP-activated protein kinase (AMPK) and Akt, and treatment with compound C, wortmannin, or LY294002 partially blocked the thermal effect on muscle glucose uptake. We provide evidence that elevation of muscle temperature per se can directly stimulate muscle glucose uptake and that this thermal effect is compound C-, wortmannin-, and LY294002-inhibitable.

Molecular cloning and characterization of plasma membrane- and vacuolar-type Na⁺/H⁺ antiporters of an alkaline-salt-tolerant monocot, Puccinellia tenuiflora.

A better understanding of salt tolerance in plants might lead to the genetic engineering of crops that can grow in saline soils. Here we cloned and characterized plasma membrane and vacuolar Na⁺/H⁺ antiporters of a monocotyledonous alkaline-tolerant halophyte, Puccinellia tenuiflora. The predicted amino acid sequence of the transporters were very similar to those of orthologs in monocotyledonous crops. Expression analysis showed that (1) NHA was more strongly induced by NaCl in the roots of P. tenuiflora while in rice it was rather induced in the shoots, suggesting that the role of NHA in salt excretion from the roots partly accounts for the difference in the tolerance of the two species, and that (2) NHXs were specifically induced by NaHCO3 but not by NaCl in the roots of both species, suggesting that vacuolar-type Na⁺/H⁺ antiporters play roles in pH regulation under alkaline salt conditions. Overexpression of the antiporters resulted in increased tolerance of shoots to NaCl and roots to NaHCO3. Overexpression lines exhibited a lower Na⁺ content and a higher K⁺ content in shoots under NaCl treatments, leading to a higher Na⁺/H⁺ ratio.

The effect of high-intensity intermittent swimming on post-exercise glycogen supercompensation in rat skeletal muscle.

A single bout of prolonged endurance exercise stimulates glucose transport in skeletal muscles, leading to post-exercise muscle glycogen supercompensation if sufficient carbohydrate is provided after the cessation of exercise. Although we recently found that short-term sprint interval exercise also stimulates muscle glucose transport, the effect of this type of exercise on glycogen supercompensation is uncertain. Therefore, we compared the extent of muscle glycogen accumulation in response to carbohydrate feeding following sprint interval exercise with that following endurance exercise. In this study, 16-h-fasted rats underwent a bout of high-intensity intermittent swimming (HIS) as a model of sprint interval exercise or low-intensity prolonged swimming (LIS) as a model of endurance exercise. During HIS, the rats swam for eight 20-s sessions while burdened with a weight equal to 18% of their body weight. The LIS rats swam with no load for 3 h. The exercised rats were then refed for 4, 8, 12, or 16 h. Glycogen levels were almost depleted in the epitrochlearis muscles of HIS- or LIS-exercised rats immediately after the cessation of exercise. A rapid increase in muscle glycogen levels occurred during 4 h of refeeding, and glycogen levels had peaked at the end of 8 h of refeeding in each group of exercised refed rats. The peak glycogen levels during refeeding were not different between HIS- and LIS-exercised refed rats. Furthermore, although a large accumulation of muscle glycogen in response to carbohydrate refeeding is known to be associated with decreased insulin responsiveness of glucose transport, and despite the fact that muscle glycogen supercompensation was observed in the muscles of our exercised rats at the end of 4 h of refeeding, insulin responsiveness was not decreased in the muscles of either HIS- or LIS-exercised refed rats compared with non-exercised fasted control rats at this time point. These results suggest that sprint interval exercise enhances muscle glycogen supercompensation in response to carbohydrate refeeding as well as prolonged endurance exercise does. Furthermore, in this study, both HIS and LIS exercise prevented insulin resistance of glucose transport in glycogen supercompensated muscle during the early phase of carbohydrate refeeding. This probably led to the enhanced muscle glycogen supercompensation after exercise.