Cisplatin, rather than oxaliplatin, increases paracellular permeability of LLC-PK1 cells via activating protein kinase C

The clinical use of cisplatin is limited by its adverse events, particularly serious nephrotoxicity. It was clarified that cisplatin is transported by a kidney-specific organic cation transporter (OCT2). OCT2 also mediates the uptake of oxaliplatin into renal proximal tubular cells; however, this agent does not lead nephrotoxicity. In the present study, we carried out comparative experiments with cisplatin and oxaliplatin using porcine kidney LLC-PK1 cell monolayers. In the fluorescein-labeled isothiocyanate-dextran flux assay, the basolateral application of cisplatin, but not oxaliplatin, resulted in an increase in the paracellular permeability of cell monolayers. Even though the cellular accumulation of platinum at 50 μM oxaliplatin could reach the same level at 30 μM cisplatin, oxaliplatin did not induce hyper-permeability in cell monolayers. Cisplatin, but not oxaliplatin, significantly activated PKC. In addition, the combination of PKC inhibitors recovered the increase in paracellular permeability. In conclusion, pharmacodynamic mechanisms via PKC could explain the difference in nephrotoxicity between cisplatin and oxaliplatin

Postoperative daily living activities of geriatric patients administered general or spinal anesthesia for hip fracture surgery: A retrospective cohort study

Purpose:Maintaining independence after hip fracture repair is important for geriatric patients and general welfare. We investigated the effects of anesthetic methods on postoperative activities of daily living (ADLs) following hip fracture surgery in elderly patients.Methods:The medical records of 12,342 patients aged ≥65 years who underwent typical surgeries for hip fracture using either general anesthesia or spinal anesthesia were reviewed. To adjust for baseline differences and minimize selection bias for the chosen method of anesthesia, patients were matched by propensity scores. Factors affecting the deterioration in ADLs during hospital stay were also investigated in all subjects using a multivariate logistic regression analysis. Eating, grooming, toileting, bathing, and walking were selected as the ADL parameters, as they are considered important for an independent life.Results:Of the 12,342 patients, 6918 (56.1%) received general anesthesia and 5424 (43.9%) received spinal anesthesia. After the propensity score matching, the anesthesia types were not associated with ADL scores except toileting at discharge. Results from the multivariate logistic regression analysis showed that the types of anesthesia were not associated with deterioration in ADL scores. Advanced age, male sex, high Charlson Comorbidity Index scores, psychiatric disease, no administration of nonsteroidal anti-inflammatory drugs, and short length of hospital stay were associated with deterioration in ADL scores.Conclusion:The anesthesia types were not associated with ADL dependency except toileting at discharge. Spinal anesthesia adversely affected toilet use at hospital discharge. However, anesthesia types were not factors that affected deterioration in ADL during hospital stay in elderly patients who underwent hip fracture surgery

Design guidelines for the SPICE parameters of waveform-selective metasurfaces varying with the incident pulse width at a constant oscillation frequency

In this study, we numerically demonstrate how the response of recently reported circuit-based metasurfaces is characterized by their circuit parameters. These metasurfaces, which include a set of four diodes as a full wave rectifier, are capable of sensing different waves even at the same frequency in response to the incident waveform, or more specifically the pulse width. This study reveals the relationship between the electromagnetic response of such waveform-selective metasurfaces and the SPICE parameters of the diodes used. First, we show that reducing a parasitic capacitive component of the diodes is important for realization of waveform-selective metasurfaces in a higher frequency regime. Second, we report that the operating power level is closely related to the saturation current and the breakdown voltage of the diodes. Moreover, the operating power range is found to be broadened by introducing an additional resistor into the inside of the diode bridge. Our study is expected to provide design guidelines for circuit-based waveform-selective metasurfaces to select/fabricate optimal diodes and enhance the waveform-selective performance at the target frequency and power level.Comment: 9 pages, 9 figure

Best Thermoelectric Efficiency of Ever-Explored Materials

A thermoelectric device is a heat engine that directly converts heat into electricity. Many materials with a high figure of merit ZT have been discovered in anticipation of a high thermoelectric efficiency. However, there has been a lack of investigations on efficiency-based material evaluation, and little is known about the achievable limit of thermoelectric efficiency. Here, we report the highest thermoelectric efficiency using 13,353 published materials. The thermoelectric device efficiencies of 808,610 configurations are calculated under various heat-source temperatures (T_h) when the cold-side temperature is 300 K, solving one-dimensional thermoelectric integral equations with temperature-dependent thermoelectric properties. For infinite-cascade devices, a thermoelectric efficiency larger than 33% (~1/3) is achievable when T_h exceeds 1400 K. For single-stage devices, the best efficiency of 17.1% (~1/6) is possible when T_h is 860 K. Leg segmentation can overcome this limit, delivering a very high efficiency of 24% (~1/4) when T_h is 1100 K.Comment: 32 pages (main+table+figure captions+figures), 7 additional pages for 6 high resolution figures, Supporting Data file is not public ye

The Comparison of the Surgical Outcome for the Full-Thickness Macular Hole with/without Lamellar Hole-Associated Epiretinal Proliferation

Aims. To compare the surgical outcome of pars plana vitrectomy (PPV) for full-thickness macular hole (FTMH) with and without lamellar hole-associated epiretinal proliferation (LHEP). Methods. This retrospective study included 158 eyes of 158 patients with FTMH treated with PPV. The following variables were analyzed: sex, age, preoperative best corrected visual acuity (pre-BCVA), BCVA 6 months after the surgery (6M-BCVA), the axial length of eye, the minimum diameter of FTMH, the diameter of basal side of FTMH, postoperative continuity of subfoveal ellipsoid zone (EZ) and external limiting membrane (ELM), and the preoperative presence of LHEP. Results. Twenty-eight eyes had FTMH with LHEP and 130 without LHEP. The mean ± SD age (years) was 72.6 ± 7.9 and 68.6 ± 8.7, respectively (p=0.02). 6M-BCVA was 0.38 ± 0.30 and 0.26 ± 0.25, respectively (p=0.03). The diameter of basal side of FTMH (μm) was 901.5 ± 404.9 and 658.9 ± 288.1, respectively (p=0.00027). EZ was disrupted in 24 eyes and 63 eyes, respectively (p=0.00071). ELM was disrupted in 15 eyes and 23 eyes, respectively (p=0.00015). The FTMH diameters and the presence of LHEP were inversely correlated with the continuity of EZ and ELM. Conclusion. The preoperative appearance of LHEP could be one of the prognostic factor for the treatment of FTMH

Pyridoxal in the Cerebrospinal Fluid May Be a Better Indicator of Vitamin B6–dependent Epilepsy Than Pyridoxal 5′-Phosphate

Background We aimed to demonstrate the biochemical characteristics of vitamin B6–dependent epilepsy, with a particular focus on pyridoxal 5′-phosphate and pyridoxal in the cerebrospinal fluid. Methods Using our laboratory database, we identified patients with vitamin B6–dependent epilepsy and extracted their data on the concentrations of pyridoxal 5′-phosphate, pyridoxal, pipecolic acid, α-aminoadipic semialdehyde, and monoamine neurotransmitters. We compared the biochemical characteristics of these patients with those of other epilepsy patients with low pyridoxal 5′-phosphate concentrations. Results We identified seven patients with pyridoxine-dependent epilepsy caused by an ALDH7A1 gene abnormality, two patients with pyridoxal 5′-phosphate homeostasis protein deficiency, and 28 patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Cerebrospinal fluid pyridoxal and pyridoxal 5′-phosphate concentrations were low in patients with vitamin B6–dependent epilepsy but cerebrospinal fluid pyridoxal concentrations were not reduced in most patients with other epilepsies with low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. Increase in 3-O-methyldopa and 5-hydroxytryptophan was demonstrated in some patients with vitamin B6–dependent epilepsy, suggestive of pyridoxal 5′-phosphate deficiency in the brain. Conclusions Low cerebrospinal fluid pyridoxal concentrations may be a better indicator of pyridoxal 5′-phosphate deficiency in the brain in vitamin B6–dependent epilepsy than low cerebrospinal fluid pyridoxal 5′-phosphate concentrations. This finding is especially helpful in individuals with suspected pyridoxal 5′-phosphate homeostasis protein deficiency, which does not have known biomarkers

Potential application of measuring serum infliximab levels in rheumatoid arthritis management: A retrospective study based on KURAMA cohort data

Infliximab (IFX) therapy has considerably improved the treatment of rheumatoid arthritis (RA). However, some patients still do not respond adequately to IFX therapy, or the efficacy of the treatment diminishes over time. Although previous studies have reported a relationship between serum IFX levels and therapeutic efficacy, the potential applications of IFX therapeutic drug monitoring (TDM) in clinical practice remain unclear. The purpose of this study was to investigate the potential applications of IFX TDM by analyzing a Japanese cohort database. Data were collected retrospectively from the Kyoto University Rheumatoid Arthritis Management Alliance cohort between January 1, 2011, and December 31, 2018. Serum IFX levels were measured using a liquid chromatography-tandem mass spectrometer. Out of the 311 RA patients that used IFX, 41 were eligible for the analysis. Serum IFX levels were significantly higher in responders than in non-responders. An optimal cut-off value was determined to be 0.32 μg/mL based on a receiver operating characteristic curve. At the IFX measurement point, a better therapeutic response was observed in the high IFX group (n = 32) than in the low IFX group (n = 9). Conversely, at the maximum effect point, when DAS28-ESR was the lowest between IFX introduction and measurement points, there were no differences in responder proportions between the low and high IFX groups. IFX primary ineffectiveness could be avoided with appropriate dose escalation without blood concentration measurement in clinical practice. In conclusion, IFX TDM could facilitate the identification of secondary non-responders and in turn, proper IFX use

Immunological profile in a family with nephrogenic diabetes insipidus with a novel 11 kb deletion in AVPR2 and ARHGAP4 genes

<p>Abstract</p> <p>Background</p> <p>Congenital nephrogenic diabetes insipidus (NDI) is characterised by an inability to concentrate urine despite normal or elevated plasma levels of the antidiuretic hormone arginine vasopressin. We report a Japanese extended family with NDI caused by an 11.2-kb deletion that includes the entire <it>AVPR2 </it>locus and approximately half of the <it>Rho GTPase-activating protein 4 </it>(<it>ARHGAP4</it>) locus. ARHGAP4 belongs to the RhoGAP family, Rho GTPases are critical regulators of many cellular activities, such as motility and proliferation which enhances intrinsic GTPase activity.</p> <p>ARHGAP4 is expressed at high levels in hematopoietic cells, and it has been reported that an NDI patient lacking <it>AVPR2 </it>and all of <it>ARHGAP4 </it>showed immunodeficiency characterised by a marked reduction in the number of circulating CD3+ cells and almost complete absence of CD8+ cells.</p> <p>Methods</p> <p>PCR and sequencing were performed to identify the deleted region in the Japanese NDI patients. Immunological profiles of the NDI patients were analysed by flow cytometry. We also investigated the gene expression profiles of peripheral blood mononuclear cells (PBMC) from NDI patients and healthy controls in microarray technique.</p> <p>Results</p> <p>We evaluated subjects (one child and two adults) with 11.2-kb deletion that includes the entire <it>AVPR2 </it>locus and approximately half of the <it>ARHGAP4</it>. Hematologic tests showed a reduction of CD4+ cells in one adult patient, a reduction in CD8+ cells in the paediatric patient, and a slight reduction in the serum IgG levels in the adult patients, but none of them showed susceptibility to infection. Gene expression profiling of PBMC lacking <it>ARHGAP4 </it>revealed that expression of RhoGAP family genes was not influenced greatly by the lack of <it>ARHGAP4</it>.</p> <p>Conclusion</p> <p>These results suggest that loss of <it>ARHGAP4 </it>expression is not compensated for by other family members. ARHGAP4 may play some role in lymphocyte differentiation but partial loss of <it>ARHGAP4 </it>does not result in clinical immunodeficiency.</p

Nutraceutical Approach for Preventing Obesity-Related Colorectal and Liver Carcinogenesis

Obesity and its related metabolic abnormalities, including insulin resistance, alterations in the insulin-like growth factor-1 (IGF-1)/IGF-1 receptor (IGF-1R) axis, and the state of chronic inflammation, increase the risk of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). However, these findings also indicate that the metabolic disorders caused by obesity might be effective targets to prevent the development of CRC and HCC in obese individuals. Green tea catechins (GTCs) possess anticancer and chemopreventive properties against cancer in various organs, including the colorectum and liver. GTCs have also been known to exert anti-obesity, antidiabetic, and anti-inflammatory effects, indicating that GTCs might be useful for the prevention of obesity-associated colorectal and liver carcinogenesis. Further, branched-chain amino acids (BCAA), which improve protein malnutrition and prevent progressive hepatic failure in patients with chronic liver diseases, might be also effective for the suppression of obesity-related carcinogenesis because oral supplementation with BCAA reduces the risk of HCC in obese cirrhotic patients. BCAA shows these beneficial effects because they can improve insulin resistance. Here, we review the detailed relationship between metabolic abnormalities and the development of CRC and HCC. We also review evidence, especially that based on our basic and clinical research using GTCs and BCAA, which indicates that targeting metabolic abnormalities by either pharmaceutical or nutritional intervention may be an effective strategy to prevent the development of CRC and HCC in obese individuals