Mechanical actions of dendritic-spine enlargement on presynaptic exocytosis.

Synaptic transmission involves cell-to-cell communication at the synaptic junction between two neurons, and chemical and electrical forms of this process have been extensively studied. In the brain, excitatory glutamatergic synapses are often made on dendritic spines that enlarge during learning1-5. As dendritic spines and the presynaptic terminals are tightly connected with the synaptic cleft6, the enlargement may have mechanical effects on presynaptic functions7. Here we show that fine and transient pushing of the presynaptic boutons with a glass pipette markedly promotes both the evoked release of glutamate and the assembly of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins8-12-as measured by Förster resonance transfer (FRET) and fluorescence lifetime imaging-in rat slice culture preparations13. Both of these effects persisted for more than 20 minutes. The increased presynaptic FRET was independent of cytosolic calcium (Ca2+), but dependent on the assembly of SNARE proteins and actin polymerization in the boutons. Notably, a low hypertonic solution of sucrose (20 mM) had facilitatory effects on both the FRET and the evoked release without inducing spontaneous release, in striking contrast with a high hypertonic sucrose solution (300 mM), which induced exocytosis by itself14. Finally, spine enlargement induced by two-photon glutamate uncaging enhanced the evoked release and the FRET only when the spines pushed the boutons by their elongation. Thus, we have identified a mechanosensory and transduction mechanism15 in the presynaptic boutons, in which the evoked release of glutamate is enhanced for more than 20 min.

Renoprotective Effects of Daprodustat in Patients with Chronic Kidney Disease and Renal Anemia.

Many large-scale studies revealed that exogenous erythropoietin, erythropoiesis-stimulating agents, have no renoprotective effects. We reported the renoprotective effects of endogenous erythropoietin production on renal function in ischemic reperfusion injury (IRI) of the kidney using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat. The purpose of this study was to investigate the effects of daprodustat on the progression of chronic renal failure. We retrospectively investigated the effects of daprodustat on the progression of chronic renal failure and renal anemia in patients with stages 3a-5 chronic kidney diseases (estimated glomerular filtration rate, eGFR < 60 mL/min/1.73 m2). The results show that daprodustat largely slowed the reduction in eGFR. The recovery of renal function was observed in some patients. Daprodustat is useful not only for renal anemia but also for the preservation of renal function. The renoprotective effect of daprodustat was small in patients with serum creatinine larger than 3-4 mg/dL because of low residual renal function. The appearance of renal anemia would be a sign of the time to start using daprodustat.

Tubular Endogenous Erythropoietin Protects Renal Function against Ischemic Reperfusion Injury.

Many large-scale studies show that exogenous erythropoietin, erythropoiesis-stimulating agents, lack any renoprotective effects. We investigated the effects of endogenous erythropoietin on renal function in kidney ischemic reperfusion injury (IRI) using the prolyl hydroxylase domain (PHD) inhibitor, Roxadustat (ROX). Four h of hypoxia (7% O2) and 4 h treatment by ROX prior to IRI did not improve renal function. In contrast, 24-72 h pretreatment by ROX significantly improved the decline of renal function caused by IRI. Hypoxia and 4 h ROX increased interstitial cells-derived Epo production by 75- and 6-fold, respectively, before IRI, and worked similarly to exogenous Epo. ROX treatment for 24-72 h increased Epo production during IRI by 9-fold. Immunohistochemistry revealed that 24 h ROX treatment induced Epo production in proximal and distal tubules and worked similarly to endogenous Epo. Our data show that tubular endogenous Epo production induced by 24-72 h ROX treatment results in renoprotection but peritubular exogenous Epo production by interstitial cells induced by hypoxia and 4 h ROX treatment did not. Stimulation of tubular, but not peritubular, Epo production may link to renoprotection.

Examination of aminophenol-containing compounds designed as antiproliferative agents and potential atypical retinoids.

Retinoic acid (RA, 1), an oxidized form of vitamin A, binds to retinoic acid receptors (RAR) and retinoid X receptors (RXR) to regulate gene expression and has important functions such as cell proliferation and differentiation. Synthetic ligands regarding RAR and RXR have been devised for the treatment of various diseases, particularly promyelocytic leukemia, but their side effects have led to the development of new, less toxic therapeutic agents. Fenretinide (4-HPR, 2), an aminophenol derivative of RA, exhibits potent antiproliferative activity without binding to RAR/RXR, but its clinical trial was discontinued due to side effects of impaired dark adaptation. Assuming that the cyclohexene ring of 4-HPR is the cause of the side effects, methylaminophenol was discovered through structure-activity relationship research, and p-dodecylaminophenol (p-DDAP, 3), which has no side effects or toxicity and is effective against a wide range of cancers, was developed. Therefore, we thought that introducing the motif carboxylic acid found in retinoids, could potentially enhance the anti-proliferative effects. Introducing chain terminal carboxylic functionality into potent p-alkylaminophenols significantly attenuated antiproliferative potencies, while a similar structural modification of weakly potent p-acylaminophenols enhanced growth inhibitory potencies. However, conversion of the carboxylic acid moieties to their methyl esters completely abolished the cell growth inhibitory effects of both series. Insertion of a carboxylic acid moiety, which is important for binding to RA receptors, abolishes the action of p-alkylaminophenols, but enhances the action of p-acylaminophenols. This suggests that the amido functionality may be important for the growth inhibitory effects of the carboxylic acids.

Cognitive behavior therapy for autistic adolescents, awareness and care for my autistic traits program: a multicenter randomized controlled trial.

BACKGROUND: Autistic people demonstrate focused interests, sensitivity to sensory stimulation, and, compared with the general population, differences in social communication and interaction. We examined whether a combination of the Awareness and Care for My Autistic Traits (ACAT) program and treatment-as-usual is more effective than only treatment-as-usual in increasing the understanding of autistic attributes, reducing treatment stigma, and improving mental health and social adaptation among autistic adolescents and their parents/guardians. METHODS: Forty-nine adolescents and their parents/guardians were randomly assigned to either a combination of ACAT and treatment-as-usual or only treatment-as-usual. The combined group received six weekly 100-minute ACAT sessions, while the treatment-as-usual group received no additional intervention. The primary outcome was the change in understanding of autistic attributes (Autism Knowledge Quiz-Child), administered from pre- to post-intervention. The secondary outcomes included the change in Autism Knowledge Quiz-Parent, reduced treatment stigma, and improved mental health and social adaptation among autistic adolescents and their parents/guardians. A primary outcome measure scale was scored by assessors who were blind to the group assignment. RESULTS: The combined group (both autistic adolescents and their parents/guardians) showed an increase in Autism Knowledge Quiz scores compared to those in the treatment-as-usual group. Autistic adolescents in the combined group also demonstrated a decrease in treatment-related stigma and an improvement in general mental health compared to those in the treatment-as-usual group, while there were no group differences in the change in social adaptation. For parents/guardians, there were no group differences in the change in treatment-related stigma, general mental health, adaptive skills, or attitudes toward their children. CONCLUSIONS: The ACAT program could be an effective treatment modality to increase the understanding of autistic attributes among both autistic adolescents and their parents/guardians. The ACAT program positively affects self-understanding, reduces treatment stigma, and stabilizes behavioral issues for autistic adolescents as a part of mental health measures, but it does not effectively reduce treatment barriers or improve mental health for parents/guardians. Further research should consider whether additional support for parents/guardians could be beneficial. TRIAL REGISTRATION: The study was registered in UMIN (UMIN000029851, 06/01/2018).

Effects of Antibacterial Agents on Cancerous Cell Proliferation.

Myelosuppression, a side effect of anticancer drugs, makes people more susceptible to infectious diseases by compromising the immune system. When a cancer patient develops a contagious disease, treatment with an anticancer drug is suspended or postponed to treat the infectious disease. If there was a drug that suppresses the growth of cancer cells among antibacterial agents, it would be possible to treat both infectious diseases and cancer. Therefore, this study investigated the effect of antibacterial agents on cancer cell development. Vancomycin (VAN) had little effect on cell proliferation against the breast cancer cell, MCF-7, prostate cancer cell, PC-3, and gallbladder cancer cell, NOZ C-1. Alternatively, Teicoplanin (TEIC) and Daptomycin (DAP) promoted the growth of some cancer cells. In contrast, Linezolid (LZD) suppressed the proliferation of MCF-7, PC-3, and NOZ C-1 cells. Therefore, we found a drug that affects the growth of cancer cells among antibacterial agents. Next, when we examined the effects of the combined use of existing anticancer and antibacterial agents, we found VAN did not affect the growth suppression by anticancer agents. However, TEIC and DAP attenuated the growth suppression of anticancer agents. In contrast, LZD additively enhanced the growth suppression by Docetaxel in PC-3 cells. Furthermore, we showed that LZD inhibits cancer cell growth by mechanisms that involve phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway suppression. Therefore, LZD might simultaneously treat cancer and infectious diseases.

Inhibitory Effects of Vitamin A and Its Derivatives on Cancer Cell Growth Not Mediated by Retinoic Acid Receptors.

Vitamin A is an important trace essential nutrient. Vitamin A is present as a retinyl ester in animal foods and as ß-carotene (provitamin A), which is a precursor of vitamin A, in plant foods such as green and yellow vegetables. After ingestion and absorption in the body, these are converted into retinol and stored as retinyl esters in stellate cells in the liver. The stored retinyl esters are decomposed into retinol as needed, and converted into the aldehyde retinal, which plays an important role in vision. Retinoic acid (RA) has a variety of effects. In particular, RA is used as a therapeutic agent for acute promyelocytic leukemia. This review will cover (1) elucidation of anti-refractory cancer effects of retinol (vitamin A) not mediated by RA receptors, (2) elucidation of anti-cancer effects of RA not mediated by RA receptors and (3) the development of candidate new anti-cancer agents that combine the actions of RA and retinol. Lessons learned from these findings are that vitamin A has anti-cancer activity not mediated by RA receptors; that nutritional management of vitamin A leads to prevention and treatment of cancer, and that new compounds developed from RA derivatives represent good anti-cancer drug candidates that are in various stages of clinical trials.

Effects of Roxadustat on Erythropoietin Production in the Rat Body.

Anemia is a major complication of chronic renal failure. To treat this anemia, prolylhydroxylase domain enzyme (PHD) inhibitors as well as erythropoiesis-stimulating agents (ESAs) have been used. Although PHD inhibitors rapidly stimulate erythropoietin (Epo) production, the precise sites of Epo production following the administration of these drugs have not been identified. We developed a novel method for the detection of the Epo protein that employs deglycosylation-coupled Western blotting. With protein deglycosylation, tissue Epo contents can be quantified over an extremely wide range. Using this method, we examined the effects of the PHD inhibitor, Roxadustat (ROX), and severe hypoxia on Epo production in various tissues in rats. We observed that ROX increased Epo mRNA expression in both the kidneys and liver. However, Epo protein was detected in the kidneys but not in the liver. Epo protein was also detected in the salivary glands, spleen, epididymis and ovaries. However, both PHD inhibitors (ROX) and severe hypoxia increased the Epo protein abundance only in the kidneys. These data show that, while Epo is produced in many tissues, PHD inhibitors as well as severe hypoxia regulate Epo production only in the kidneys.

Early and midterm outcomes of celiac artery coverage during thoracic endovascular aortic repair.

BACKGROUND: In thoracic endovascular aortic repair (TEVAR), covering the celiac artery (CA) is sometimes necessary to secure the distal seal. We report the outcomes of planned CA coverage in our experience with TEVAR. METHODS: Cases requiring CA coverage during TEVAR from October 2008 to September 2018 were retrospectively reviewed. Patient demographics, indications for CA coverage, communication between the CA and the superior mesenteric artery (SMA), concomitant CA embolization, and perioperative and late results were collected in a prospective database and analyzed. RESULTS: During the study decade, 357 patients underwent TEVAR at our institution. Of these patients, 15 (4.2%) required CA coverage. All 15 patients were male, and the mean age was 72.8 years (range, 44-80 years). The mean aneurysm size was 67.5 mm (range, 50-82 mm). The etiologies included 10 degenerative aneurysms (66.7%; 2 ruptures [13.3%], 4 dissecting aneurysms [26.7%], and 1 case of type IB endoleak [6.7%]) after TEVAR. Communicating collaterals between the CA and the SMA were confirmed by preoperative computed tomography angiography in eight patients (53.3%) and by intraoperative angiography in four patients (26.7%). Seven patients (46.7%) underwent concomitant embolization of the CA. CA coverage offered a mean extension of 20.3 mm (range, 12-22 mm) in the length of the distal seal. Postoperative computed tomography angiography revealed a type IB endoleak that resolved spontaneously in one patient (6.7%). Postoperative complications included splenic infarction/pancreatitis in one patient (6.7%) and spinal cord ischemia in two patients (13.3%). There were no cases of postoperative in-hospital mortality. During the follow-up period (mean, 3.6 years; range, 0.9-8.0 years), two patients developed a new type IB endoleak. One patient underwent distal extension of the stent graft with ilio-SMA bypass, and one patient was observed conservatively in accordance with the patient's decision. There were no cases of type II endoleak via the CA. Most aneurysms (86.7%) were stable or reduced in size at the most recent follow-up. There were no cases of targeted aneurysm-related death during the follow-up period. CONCLUSIONS: Our study demonstrates the safety and efficacy of CA coverage in facilitating adequate distal sealing in selected patients undergoing TEVAR. Because the distal sealing length is not completely sufficient in most cases requiring CA coverage, the long-term efficacy of CA coverage during TEVAR should be determined in a large prospective study.

Suprarenal fixation is associated with worse midterm renal function after endovascular abdominal aortic aneurysm repair compared with infrarenal fixation.

BACKGROUND: Several reports have indicated that suprarenal (SR) fixation may impair renal function after endovascular abdominal aortic aneurysm repair (EVAR). However, most were short-term or at most, 1-year observational studies; therefore, the midterm effects on renal function remain unclear. This study aimed to identify predictors of midterm renal dysfunction after EVAR and compare renal outcomes in patients after EVAR with SR and infrarenal (IR) fixation. METHODS: A total of 467 patients who underwent EVAR of nonruptured IR abdominal aortic aneurysm between 2007 and 2014 were reviewed in a prospectively collected database. Patients on hemodialysis at baseline were excluded. Among the remaining patients, those with 3-year laboratory testing were included in this study. Patients who developed acute kidney injury were excluded from the late renal function estimation. Predictors of 3-year renal function decline were estimated using logistic regression analysis. In addition, patients undergoing EVAR with IR (IR group) and SR fixation devices (SR group) were propensity matched by age, sex, baseline renal function, baseline aneurysm diameter, comorbidities, smoking habits, and regular use of medicines that may act on kidney function. Changes in renal function after surgery were compared between the IR group and the SR group. RESULTS: During the study period, 237 patients (102 IRs and 135 SRs) were followed up with laboratory testing 3 years after surgery. Logistic regression analysis revealed that the use of a SR fixation device was independently predictive of a more than 20% decrease in the estimated glomerular filtration rate at 3 years after EVAR (odds ratio, 2.06; 95% confidence interval, 1.18-3.58; P = .011). Eleven patients who developed acute kidney injury (1 IR and 10 SRs) were excluded from the subsequent analysis. After propensity score matching, 87 pairs were selected (mean age, 77.2 ± 6.3 years; 151 males [86.8%]). The mean follow-up duration was 5.5 ± 1.8 years. In the SR group, estimated glomerular filtration rate at 3 years after surgery decreased significantly more than that in the IR group (mean of 17.8% vs 11.6%, respectively; P = .034). CONCLUSIONS: This study suggests that, compared with EVAR with IR endograft fixation, EVAR with SR endograft fixation is associated with worse outcomes for midterm renal function.

Autofluorescence changes of tomato surface tissues during overripening.

We investigated the autofluorescence of tomato surface tissues during overripening at 25 °C for 13 days. Microscopic images and fluorescence spectra of tissues, including the epidermis and cuticle, were examined (excitation at 360 nm), revealing that the autofluorescence changes were related to the epidermis, particularly the fluorophores in the cuticle.

Increased Vancomycin Clearance in Patients with Solid Malignancies.

Vancomycin (VAN) is an anti-microbial agent used to treat a number of bacterial infections, which has a high incidence of nephrotoxicity. We examined the pharmacokinetics of VAN retrospectively based on trough concentrations at large scale and identified pharmacokinetic differences between Japanese patients having solid malignancy and non-malignancy patients. Data were analyzed from 162 solid malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN. We failed to detect differences in values for VAN clearance or shorter elimination half-lives between these two groups. In contrast, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to solid malignancies in each stage. We conclude that VAN clearance in solid malignancy patients is increased and that the blood concentration of VAN becomes lower than expected. These results suggest that early monitoring of VAN levels in solid malignancy patients might be essential for maintaining desired effects without side-effects.

Risk Associated with Severe Hematological Toxicity in Patients with Urothelial Cancer Receiving Combination Chemotherapy of Gemcitabine and Cisplatin.

INTRODUCTION: Combination chemotherapy of gemcitabine and cisplatin (GC) is the standard treatment for patients with urothelial cancer (UC). However, hematological toxicity is a major side effect of GC therapy in patients with UC. In particular, discontinuation of the GC therapy is associated to adverse events such as hematological toxicity. Some studies have reported general risk factors of hematological toxicity such as age. However, little is known about risk factors for GC therapy-associated hematological toxicity in patients with UC. OBJECTIVE: We aimed to identify risk factors for hematological toxicity in patients with UC receiving GC therapy. METHODS: We performed a retrospective evaluation of the data of 128 patients with UC who received GC therapy. The study end point was defined as the occurrence of grade 4 neutropenia and grade ≥3 thrombocytopenia. Logistic regression analysis was used to determine risk factors that were significantly associated with neutropenia and thrombocytopenia. RESULTS: In total, 62 (48.4%) patients experienced grade 4 neutropenia, and 27 (21.1%) patients experienced grade ≥3 thrombocytopenia. In the multivariate analysis, performance status (PS) ≥1 (odds ratio [OR] 3.764, 95% confidence interval [CI] 1.410-10.047, p = 0.008) and neutrophil count (OR 0.648, 95% CI 0.468-0.898, p = 0.009) were significantly associated with grade 4 neutropenia. Platelet count (PLT) (OR 0.896, 95% CI 0.832-0.966, p = 0.004) and potassium (K) level (OR 6.966, 95% CI 1.313-36.989, p = 0.023) were also significantly associated with grade ≥3 thrombocytopenia. CONCLUSIONS: PS ≥ 1, neutrophil count, PLT, and K level were important risk factors for GC therapy-induced hematological toxicity in patients with UC. To continue GC therapy, further management systems by hematological toxicity risk factors for patients with UC will be required.

Lethality of MalE-LacZ hybrid protein shares mechanistic attributes with oxidative component of antibiotic lethality.

Downstream metabolic events can contribute to the lethality of drugs or agents that interact with a primary cellular target. In bacteria, the production of reactive oxygen species (ROS) has been associated with the lethal effects of a variety of stresses including bactericidal antibiotics, but the relative contribution of this oxidative component to cell death depends on a variety of factors. Experimental evidence has suggested that unresolvable DNA problems caused by incorporation of oxidized nucleotides into nascent DNA followed by incomplete base excision repair contribute to the ROS-dependent component of antibiotic lethality. Expression of the chimeric periplasmic-cytoplasmic MalE-LacZ72-47 protein is an historically important lethal stress originally identified during seminal genetic experiments that defined the SecY-dependent protein translocation system. Multiple, independent lines of evidence presented here indicate that the predominant mechanism for MalE-LacZ lethality shares attributes with the ROS-dependent component of antibiotic lethality. MalE-LacZ lethality requires molecular oxygen, and its expression induces ROS production. The increased susceptibility of mutants sensitive to oxidative stress to MalE-LacZ lethality indicates that ROS contribute causally to cell death rather than simply being produced by dying cells. Observations that support the proposed mechanism of cell death include MalE-LacZ expression being bacteriostatic rather than bactericidal in cells that overexpress MutT, a nucleotide sanitizer that hydrolyzes 8-oxo-dGTP to the monophosphate, or that lack MutM and MutY, DNA glycosylases that process base pairs involving 8-oxo-dGTP. Our studies suggest stress-induced physiological changes that favor this mode of ROS-dependent death.

Distinct initial SNARE configurations underlying the diversity of exocytosis.

The dynamics of exocytosis are diverse and have been optimized for the functions of synapses and a wide variety of cell types. For example, the kinetics of exocytosis varies by more than five orders of magnitude between ultrafast exocytosis in synaptic vesicles and slow exocytosis in large dense-core vesicles. However, in all cases, exocytosis is mediated by the same fundamental mechanism, i.e., the assembly of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. It is often assumed that vesicles need to be docked at the plasma membrane and SNARE proteins must be preassembled before exocytosis is triggered. However, this model cannot account for the dynamics of exocytosis recently reported in synapses and other cells. For example, vesicles undergo exocytosis without prestimulus docking during tonic exocytosis of synaptic vesicles in the active zone. In addition, epithelial and hematopoietic cells utilize cAMP and kinases to trigger slow exocytosis of nondocked vesicles. In this review, we summarize the manner in which the diversity of exocytosis reflects the initial configurations of SNARE assembly, including trans-SNARE, binary-SNARE, unitary-SNARE, and cis-SNARE configurations. The initial SNARE configurations depend on the particular SNARE subtype (syntaxin, SNAP25, or VAMP), priming proteins (Munc18, Munc13, CAPS, complexin, or snapin), triggering proteins (synaptotagmins, Doc2, and various protein kinases), and the submembraneous cytomatrix, and they are the key to determining the kinetics of subsequent exocytosis. These distinct initial configurations will help us clarify the common SNARE assembly processes underlying exocytosis and membrane trafficking in eukaryotic cells.

Associations of nutritional status and muscle size with mortality after open aortic aneurysm repair.

OBJECTIVE: Open surgical repair (OSR) for abdominal aortic aneurysms is a more invasive approach than endovascular aneurysm repair but has more enduring results and may lead to a lower reintervention rate. Therefore, strict selection of patients should be based on assessments of both early and late outcomes. The controlling nutritional status (CONUT) score and skeletal muscle mass index (SMI) have been reported as indicators of nutritional status and muscle size, respectively. The aim of this study was to identify prognostic factors, including sarcopenia and nutritional status, for early and late outcomes. METHODS: We reviewed data from 360 consecutive abdominal aortic aneurysm patients who underwent OSR from 2007 to 2014. We collected data on patients' characteristics, nutritional status (CONUT score), and muscle size (SMI). Cox proportional hazards analysis and logistic regression analysis identified independent predictors of midterm mortality and Clavien-Dindo class IV complications as late and early outcomes, respectively. RESULTS: During the study period, 360 patients underwent elective OSR. The following characteristics were associated with midterm mortality: age >71 years (hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.41-17.13; P = .01), low SMI (HR, 4.32; 95% CI, 1.16-16.13; P = .03), CONUT score indicating a moderate risk of malnutrition (vs normal status or mild risk: HR, 4.16; 95% CI, 1.03-16.76; P = .045), and estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR, 3.54; 95% CI, 1.09-11.47; P = .035). Two patients died within 30 days of undergoing OSR (0.6%). A CONUT score indicating moderate risk (HR, 4.42; 95% CI, 1.01-19.28; P = .048), estimated glomerular filtration rate <30 mL/min/1.73 m2 (HR, 7.34; 95% CI, 2.20-24.51; P < .001), and diabetes mellitus (HR, 3.71; 95% CI, 1.25-11.00; P = .02) were independent predictors of Clavien-Dindo class IV complications. CONCLUSIONS: These results may be useful for identifying and optimizing treatment of high-risk patients who will not benefit from OSR so that endovascular aneurysm repair or no intervention can be recommended. Consideration of nutritional status and sarcopenia may therefore support the development of a more personalized, cost-effective treatment strategy.

Effects of ß-carotene on oxazolone-induced atopic dermatitis in hairless mice.

Skin acts as a barrier, which protects internal tissues and promotes moisture retention. Atopic dermatitis (AD) is an inflammatory skin disease associated with a variety of genetic and environmental factors that involve helper T cells. ß-Carotene (provitamin A) exhibits antioxidant activity and activates the immune system. However, it is not clear whether inflammation in AD skin is improved by posttreatment with ß-carotene. In the current study, we investigated the effects of ß-carotene on the skin of hairless mice with oxazolone-induced inflammation/oedema (Ox-AD mice). We found that skin inflammation was significantly reduced by oral administration of ß-carotene. In addition, treatment with ß-carotene suppressed protein levels of TNF-α, IL-1ß and MCP-1, as well as mRNA expression associated with IL-1ß, IL-6, IL-4 and Par-2 in skin tissues. Furthermore, the mRNA and protein levels of filaggrin, a structural protein in the epidermal stratum corneum, were elevated by ß-carotene administration as compared with Ox-AD mice. ß-Carotene significantly reduced the activity of proMMP-9, but not proMMP-2. These results suggest that in Ox-AD mice, ß-carotene improves skin inflammation by suppressing the expression of inflammatory factors, promoting filaggrin expression and reducing MMP-9 activity. ß-Carotene is a potent anti-inflammatory agent that improves the barrier functions of AD skin.

Effect of Intraoperative Division of the Left Renal Vein on the Fate of Renal Function and Left Renal Volume After Open Repair of Para- and Juxtarenal Aortic Aneurysm.

BACKGROUND: The effect of left renal vein division (LRVD) during open surgery (OS) for pararenal and juxtarenal abdominal aortic aneurysm (P/JRAA) on postoperative renal function remains controversial, so we focused on chronic renal decline (CRD) and separately examined renal volume as a surrogate index of split renal function.Methods and Results:The 115 patients with P/JRAA treated with OS from June 2007 to January 2017 were reviewed: 26 patients without LRVD were matched to 27 patients with LRVD according to preoperative chronic kidney disease (CKD) stage and proximal clamp sites. The effect of LRVD on CRD was investigated by a time-to-event analysis. During a median follow-up of 23.5 months, CRD occurred in 5 patients with LRVD and in 4 patients without LRVD. Comparison of freedom from CRD showed no significant difference between the matched groups (P=0.870). The separate renal volumes were evaluated before surgery and at 1 and 2 years of follow-up using CT images from 18 patients with LRVD. At 2 years, the mean renal volume had decreased by 15% in the left kidney and by 9% in the right kidney (P=0.052 and 0.148, respectively), but the left-to-right renal volume ratio showed no significant change (P=0.647). CONCLUSIONS: LRVD had no significant effect on CRD or left renal volume relative to the right renal volume for up to 2 years.

Growth Inhibition of Human Breast and Prostate Cancer Cells by Cinnamic Acid Derivatives and Their Mechanism of Action.

Cancer is the leading cause of death and there is a particularly pressing need to develop effective treatments for breast and prostate cancer. In the current study, we show the inhibitory effects of cinnamic acid derivatives, including caffeic acid phenethyl ester (CAPE, 1), on the growth of breast and prostate cancer cells. Among the compounds examined, 3,4,5-trihydroxycinnamic acid decyl ester (6) showed the most potent inhibition of cancer cell growth by the induction of apoptosis. Compound 6 could be a new anti-cancer agent for use against breast and prostate cancer.

Augmented Renal Clearance of Vancomycin in Hematologic Malignancy Patients.

The pharmacokinetics of vancomycin (VAN) was retrospectively examined based on trough concentrations at large scale to identify pharmacokinetic differences between Japanese hematologic malignancy and non-malignancy patients. Data from 261 hematologic malignancy patients and 261 non-malignancy patients, including the patient's background, VAN dose, and pharmacokinetics of VAN estimated by an empirical Bayesian method, were collected and analyzed. Our results showed significantly higher values for VAN clearance and shorter elimination half-lives in patients with hematologic malignancies than non-malignancy patients. In addition, multiple regression analysis under adjusting for confounding factors by propensity score, showed that VAN clearance significantly increased in relation to hematologic malignancies. In conclusion, since in hematologic cancer patients VAN clearance is increased, the blood concentration of VAN becomes lower than expected and this may contribute to the survival of resistant bacteria when VAN is administered at low doses. These results suggest that early monitoring of VAN levels in hematologic cancer patients might be recommended to maintain desired effects without side-effects.