TXB-001, a newly-developed polymer-conjugated anthracycline: Significantly lower adverse effects in animal models of alopecia and hand-foot syndrome.

Anthracycline anti-cancer drugs have been widely used in the treatment of several cancers; however, their use is limited by adverse effects (AEs). Alopecia is a common AE that is minimally invasive, but adversely affects mental health and reduces quality of life (QoL). Hand-foot syndrome (HFS) is a dose-limiting AE of DOXIL, a liposomal formulation of doxorubicin (DOX). Although it is not a life-threatening condition, HFS affects function and reduces QoL. TXB-001 is a new candidate polymer-conjugated anthracycline anti-cancer drug, and modified and optimized polymerized pirarubicin (THP), known as P-THP, is expected to have low toxicity and high efficacy. The anti-cancer effects of TXB-001 were examined using the 4T1 mouse model. An alopecia mouse model and HFS rat model were used to evaluate the alopecia- and HFS-inducing effects of TXB-001 and compare their severity with existing anthracycline anti-cancer drugs. A pharmacokinetic analysis of plasma as well as chest, palmar, and plantar skin samples after the single intravenous administration of DOXIL and TXB-001 to rats was also performed. The results obtained revealed that TXB-001 exerted similar anti-cancer effects to those of DOXIL in mice, weaker alopecia-inducing effects than DOX, DOXIL, and THP in mice, and no or markedly weaker HFS-like changes than DOXIL, which induced significant histopathological changes. The results of the pharmacokinetic analysis showed the accumulation of DOXIL, but not TXB-001, in skin, particularly palmar and plantar skin samples, and these differences were considered to contribute to their HFS-inducing effects.

A search for acrolein scavengers among food components.

Brain stroke is a major cause of being bedridden for elderly people, and preventing stroke is important for maintaining quality of life (QOL). Acrolein is a highly reactive aldehyde and causes tissue damage during stroke. Decreasing acrolein toxicity ameliorates tissue injury during brain stroke. In this study, we tried to identify food components which decrease acrolein toxicity. We found that 2-furanmethanethiol, cysteine methyl and ethyl esters, alliin, lysine and taurine decreased acrolein toxicity. These compounds neutralized acrolein by direct interaction. However, the interaction between acrolein and taurine was not so strong. Approximately 30 mM taurine was necessary to interact with 10 µM acrolein, and 2 g/kg taurine was necessary to decrease the size of mouse brain infarction. Taurine also slightly increased polyamine contents, which are involved in decrease in the acrolein toxicity. Mitochondrial potential damage by acrolein was also protected by taurine. Our results indicate that daily intake of foods containing 2-furanmethanethiol, cysteine methyl and ethyl esters, alliin, lysine and taurine may prevent severe injury in brain stroke and improve the quality of life for elderly people.

Relationship between elevated bilirubin levels and enhanced warfarin effects during biliary obstruction.

OBJECTIVES: A marked prolongation of the prothrombin time-international normalized ratio (PT-INR) is frequently observed during biliary obstruction in patients using warfarin. The objective of this study was to identify factors associated with PT-INR prolongation during biliary obstruction in patients using warfarin. METHODS: Among 44 patients using warfarin who had biliary obstruction, we retrospectively investigated warfarin doses and laboratory data before and during biliary obstruction. The primary outcome was the association between changes in PT-INR (ΔPT-INR) and changes in laboratory data before and during biliary obstruction. RESULTS: Median PT-INR was 1.59 (IQR 1.38-1.95) before biliary obstruction and 2.27 (IQR 1.60-3.49) during biliary obstruction, indicating significant prolongation during the obstruction (P < 0.001). ΔPT-INR showed strong positive correlations with change in total bilirubin (ΔT-Bil; ρ = 0.692, P < 0.001) and change in conjugated bilirubin (ΔC-Bil; ρ = 0.731, P < 0.001). ΔPT-INR showed a weak negative correlation with the change in albumin (ΔAlb; ρ = -0.371, P < 0.05). When ΔPT-INR was used as the dependent variable in multiple linear regression analysis, ΔT-Bil, ΔC-Bil, and ΔAlb were significantly associated with ΔPT-INR. CONCLUSIONS: PT-INR was prolonged during biliary obstruction in patients using warfarin, and changes in bilirubin levels were associated with ΔPT-INR. If biliary obstruction with markedly elevated bilirubin levels occurs, measuring PT-INR could lead to safer warfarin therapy.

In vitro analysis of factors affecting the continuous hemodiafiltration clearance of teicoplanin.

BACKGROUND: In the treatment of sepsis, continuous hemodiafiltration (CHDF) and the administration of antibiotics such as teicoplanin (TEIC) are frequently performed in parallel. We aimed to clarify the factors influencing the CHDF clearance (CLCHDF ) of TEIC using a polymethylmethacrylate (PMMA) membrane or a polyacrylonitrile and sodium methallyl sulfonate copolymer membrane coated with polyethylenimine (AN69ST). We also investigated whether the adsorption of TEIC onto the hemofilters inhibits the adsorption of interleukin (IL)-6 onto the membranes. METHODS: TEIC, human serum albumin (HSA), and IL-6 were incubated with pieces of hemofilter membranes and adsorption rates were calculated. The CLCHDF , diafiltration rate, and adsorption rate of TEIC were calculated using an in vitro CHDF circuit model. RESULTS: The adsorption rates of TEIC onto the pieces of PMMA and AN69ST membranes ranged from 15.0% to 100% and from -10% to 5%, respectively. The adsorption rate of IL-6 was similar with or without TEIC. The CLCHDF and adsorption rate of TEIC under PMMA-CHDF depended on HSA, but not on effluent flow rate (Qe). The CLCHDF under AN69ST-CHDF depended on HSA and Qe. The observed CLCHDF under AN69ST-CHDF was similar to the predicted value (the product of Qe and the plasma unbound fraction). The observed CLCHDF under PMMA-CHDF was 2.0-7.8 times greater than the predicted value. CONCLUSIONS: Adsorption mainly contributes to the CLCHDF of TEIC using PMMA membranes, whereas diafiltration mainly contributes to the CLCHDF of TEIC using AN69ST membranes. TEIC adsorption might not affect the adsorption of IL-6 onto PMMA membrane.

Contribution of diafiltration and adsorption to vancomycin clearance in a continuous hemodiafiltration circuit model in vitro.

BACKGROUND: Vancomycin (VCM) is eliminated mainly by diafiltration under continuous hemodiafiltration (CHDF), but the contribution of adsorption to CHDF clearance (CLCHDF ) of VCM using a polyacrylonitrile and sodium methallyl sulfonate copolymer membrane coated with polyethylenimine (AN69ST) or a polymethylmethacrylate (PMMA) membrane is unknown. This study sought to investigate the contribution of diafiltration and adsorption to the CLCHDF of VCM using AN69ST and PMMA membranes in vitro. METHODS: An in vitro CHDF circuit model was developed. The initial concentration of VCM was 50 µg/mL and human serum albumin (HSA) was prepared at a concentration of 0, 2.5, or 5.0 g/dL. The effluent flow rate (Qe) was set at 800, 1500, or 3000 mL/h. The CLCHDF , diafiltration rate, and adsorption rate of VCM were calculated. RESULTS: Total CLCHDF of VCM using the AN69ST membrane increased and decreased with increasing Qe and HSA concentration, respectively. Diafiltration and adsorption rates were 82.1 ± 9.8% and 12.1 ± 6.1% under all conditions, respectively. Total CLCHDF using the PMMA membrane increased with increasing Qe. Diafiltration and adsorption rates were 89.2 ± 20.4% and 4.6 ± 17.0% under all conditions, respectively. The observed CLCHDF values significantly correlated with the predicted CLCHDF , calculated according to a previous study as the product of Qe and the plasma unbound fraction. CONCLUSIONS: Diafiltration predominantly contributed to CLCHDF of VCM using AN69ST and PMMA membranes. When diafiltration rather than adsorption mainly contributes to the CLCHDF of VCM, the CLCHDF could be predicted from the Qe and HSA concentration, at least in vitro.

Identification of factors affecting meropenem pharmacokinetics in critically ill patients: Impact of inflammation on clearance.

INTRODUCTION: The purpose of this study was to explore factors influencing meropenem pharmacokinetics (PKs) in critically ill patients by developing a population PK model and to determine the optimal dosing strategy. METHODS: This prospective observational study involved 12 critically ill patients admitted to the intensive care unit and treated with meropenem 1 g infused over 1 h every 8 h. Blood samples were collected on days 1, 2, and 5 immediately prior to dosing, and at 1, 2, 4, and 6 h after the start of infusion. Population PK parameters were estimated using nonlinear mixed-effects model software. RESULTS: Meropenem PK was adequately described using a two-compartment model. Typical values of total and inter-compartmental clearance were 9.30 L/h and 9.70 L/h, respectively, and the central and peripheral compartment volumes of distribution were 12.61 L and 7.80 L, respectively. C-reactive protein (CRP) was identified as significant covariate affecting total meropenem clearance. The probability of target attainment (PTA) predicted by Monte Carlo simulations varied according to the patients' CRP. The PTA of 100% time above the minimum inhibitory concentration ≤2 mg/L for bacteria was achieved after a dose of 1 and 2 g infused over 4 h every 8 h in patients with CRP of 30 and 5 mg/dL, respectively. CONCLUSION: The findings of this study suggest that CRP might be helpful in managing meropenem dosing in critically ill patients. Higher doses and extended infusion may be required to achieve optimal pharmacodynamic targets.

Oral antibiotics and a low-residue diet reduce the incidence of anastomotic leakage after left-sided colorectal surgery: a retrospective cohort study.

PURPOSE: Anastomotic leakage is a potential complication after colorectal surgery. We investigated the effects of oral antibiotics and a low-residue diet on the incidence of anastomotic leakage after left-sided colorectal surgery. METHODS: Outcomes were retrospectively compared between 64 patients who underwent mechanical bowel preparation alone (group A) and 183 patients who underwent mechanical bowel preparation with addition of oral kanamycin and metronidazole (group B) on the day before left-sided colorectal surgery. After surgery, patients in group A received a normal diet containing dietary fiber and those in group B received a low-residue diet. The primary outcome was the incidence of anastomotic leakage. Secondary outcomes were rates of other postoperative complications, length of postoperative hospital stay, and laboratory data. RESULTS: Anastomotic leakage, surgical site infection, and diarrhea were less common in group B than in group A (4.9% vs 18.8%, 6.6% vs 23.4%, and 25.7% vs 43.8%, respectively). Postoperative C-reactive protein levels were significantly lower in group B. The median postoperative hospital stay was significantly shorter in group B than in group A (8 days vs 9 days, P = 0.010). Adaptive double least absolute shrinkage and selection operator regression revealed that use of preoperative oral antibiotics and a postoperative low-residue diet were associated with lower incidence of anastomotic leakage (odds ratio 0.163, 95% confidence interval 0.062-0.430; P < 0.001). CONCLUSION: Oral antibiotics and a low-residue diet reduced the incidence of anastomotic leakage and shortened the postoperative hospital stay by 1 day.

Initial Experience with Left Transradial Neurointerventions for Cerebral Aneurysms Using the 6-French Simmons Guiding Sheath.

OBJECTIVE: The use of a transradial approach utilizing a Simmons-shaped catheter for neurointervention has been steadily increasing. Although the right radial artery is commonly used, in interventional cardiology, the left transradial approach offers clear clinical benefits for right-handed patients. To the best of our knowledge, no previous studies have examined intracranial aneurysm embolization with the routine use of the left transradial approach. The aim of this study was to evaluate the technical feasibility of left transradial intracranial aneurysm embolization. METHODS: We conducted a retrospective review of a prospective database of consecutive patients who had undergone left transradial intracranial aneurysm coiling using a 6-French Simmons guiding sheath between January and August 2021. The following outcome variables were then analyzed: whether the catheterization was successful, the angiographical results, and the presence of any procedure-related complications. RESULTS: In total, 25 patients underwent left transradial coiling for 15 anterior and 10 posterior circulation aneurysms. The Simmons guiding sheath could be successfully shaped and cannulated into the targeted vessel in all patients. All aneurysms were completely embolized without any complications. Immediate postoperative angiograms showed Raymond 1 in 10 aneurysms (40.0%), Raymond 2 in 12 (48.0%), and Raymond 3a in 3 (12.0%). None of the patients required crossover to the right radial or femoral arteries, and no radial artery spasms or occlusions were observed. CONCLUSION: The results of this study suggest that the left transradial approach for intracranial aneurysm coiling is not only safe, effective, and technically feasible, but also provides improved comfort to right-handed patients.

Population Pharmacokinetics of Vancomycin Under Continuous Renal Replacement Therapy Using a Polymethylmethacrylate Hemofilter.

BACKGROUND: Although continuous hemodiafiltration (CHDF) is often performed in critically ill patients during sepsis treatment, the pharmacokinetics of vancomycin (VCM) during CHDF with a polymethylmethacrylate hemofilter (PMMA-CHDF) have not been revealed. In this study, the authors aimed to describe the population pharmacokinetics of VCM in critically ill patients undergoing PMMA-CHDF and clarify its hemofilter clearance (CLhemofilter). METHODS: This single-center, retrospective study enrolled patients who underwent intravenous VCM therapy during PMMA-CHDF at the intensive care unit of Chiba University Hospital between 2008 and 2016. A population analysis was performed, and CLhemofilter was assessed. RESULTS: Twenty-five patients were enrolled. Median body weight (BW) and Sequential Organ Failure Assessment (SOFA) score were 63 kg and 15, respectively. Mean conditions for CHDF were 107.5 ± 18.3 mL/min for blood flow rate and 26.3 ± 6.3 mL/kg/h for effluent flow rate. The mean parameter estimates were distribution volume of the central compartment (V1), 59.1 L; clearance of the central compartment (CL1), 1.35 L/h; distribution volume of the peripheral compartment (V2), 56.1 L; and clearance of the peripheral compartment (CL2), 3.65 L/h. BW and SOFA score were significantly associated with V1 (P < 0.05) and CL1 (P < 0.05), respectively, and were thus selected as covariates in the final model. The estimated dosage of VCM to achieve a target area under the concentration-time curve/minimum inhibitory concentration ≥400 was 27.1 mg/kg for loading and 9.7 mg/kg every 24 hours for maintenance; these dosages were affected by BW and SOFA score. Mean CLhemofilter obtained from 8 patients was 1.35 L/h, which was similar to CL1. CONCLUSIONS: The authors clarified the pharmacokinetics and CLhemofilter of VCM in PMMA-CHDF patients. The PK of VCM in patients undergoing CHDF appeared to vary not only with the CHDF setting and BW but also with SOFA score.

Association of marked prolongation of prothrombin time-international normalized ratio with warfarin and endoscopic nasobiliary drainage for biliary fistula after left hemihepatectomy.

WHAT IS KNOWN AND OBJECTIVE: Vitamin K deficiency is known to cause impaired coagulation. We report a case of marked prolongation of the prothrombin time-international normalized ratio (PT-INR) associated with warfarin and vitamin K deficiency caused by endoscopic nasobiliary drainage (ENBD). CASE PRESENTATION: Oral administration of warfarin was initiated in a 67-year-old man after left hemihepatectomy. He developed a biliary fistula after surgery that was treated by ENBD, which resulted in significant prolongation of the PT-INR. WHAT IS NEW AND CONCLUSION: The effect of warfarin was enhanced in this patient due to reduced absorption of vitamin K as a result of external biliary drainage.

[Unilateral Transcranial Endoscopic Surgical Removal for Large Intraventricular Tumor Assisted by Contralateral Neuroendoscope].

We report a case of a patient with large intraventricular tumor treated with craniotomy assisted by a neuroendoscope. A 25-year-old man, who had headache and nausea for several months, was transferred to our hospital with the diagnosis of an intraventricular tumor. Because of intracranial hypertension and hydrocephalus, we first performed a biopsy and bilateral intraventricular drainage using a neuroendoscope. Since the pathological finding indicated central neurocytoma, we secondarily attempted tumor removal. The main location of the tumor was the left lateral ventricle, protruding into the third ventricle and contralateral lateral ventricle. The operation was performed mainly under microscopic visualization through left-sided craniotomy, and the total excision was accomplished using a neuroendoscope through the right lateral ventricle. In order to accomplish the optimal removal of an intraventricular tumor, endoscope-assisted microsurgery should be considered a surgical strategy.

[Carotid Artery Stenting for Non-bifurcating Cervical Carotid Artery Stenosis:A Case Report].

INTRODUCTION: Non-bifurcating cervical carotid artery(NBCCA)is a rare carotid artery anomaly, occurring at a rate of only 0.2%. We report a case in which carotid artery stenting(CAS)was performed for NBCCA stenosis. CASE REPORT: In a 69-year-old man had noted bilateral carotid artery stenosis was noted by chance during treatment for myocardial infarction. Carotid angiography revealed stenosis in both cervical carotid arteries, and the right side did not bifurcate(i.e. it was an NBCCA). Silent ischemia was observed in the left cerebral hemispheres in an MRI, and CAS was performed. A subsequent ultrasound examination revealed an increase in the peak systolic velocity in the right carotid artery, and CAS was planned for the right side. As it was not possible to use a guide-wire to guide into the external carotid artery, we planned to introduce it directly, approaching from the right brachial artery using a 6Fr Simmons guiding sheath. Angiography during distal balloon occlusion revealed significant retrograde flow from the facial and maxillary arteries to the internal carotid artery via the ophthalmic artery. Considering this finding, we decided to perform CAS with a femoral artery approach and flow reversal using distal and proximal balloon occlusion. Intraoperative embolism was prevented, and a successful treatment outcome was obtained. CONCLUSION: There are few reports of NBCCA stenosis treated with carotid endarterectomy or CAS. As CAS to treat NBCCA stenosis has several drawbacks, such as the impossibility of anchoring the wire in the external carotid artery. It is important to take appropriate steps to prevent distal embolism.

Correlation between vancomycin penetration into cerebrospinal fluid and protein concentration in cerebrospinal fluid/serum albumin ratio.

Bacterial meningitis is a life-threatening condition. Vancomycin (VCM) is one of the antibiotics used as empirical therapy for bacterial meningitis. It is essential to maintain an adequate concentration of VCM in cerebrospinal fluid (CSF) to treat bacterial meningitis effectively. VCM administered intravenously must pass the blood-brain barrier (BBB) to enter the CSF and the extent of VCM penetration into CSF varies widely among patients. Previous report indicated that CSF albumin level is useful for estimation of VCM CSF penetration. However, CSF albumin level is not measured in routine practice. We focused on CSF protein concentration that is generally examined at the beginning of diagnosis and treatment of bacterial meningitis. We examined the relationship between CSF protein concentration/serum albumin ratio and the extent of VCM penetration into CSF. This retrospective study involved 7 patients admitted to our hospital who were treated with VCM for suspected bacterial meningitis. The VCM concentrations in serum and CSF were 17.6 ± 7.2 µg/mL and 3.31 ± 3.14 µg/mL, respectively. The serum VCM concentrations showed no significant correlation with CSF VCM concentrations. On the other hand, the protein concentration in CSF/serum albumin ratio showed a strong positive correlation with the VCM CSF/serum ratio (r = 0.877, p < 0.005). Our study indicates that the ratio of CSF protein concentration/serum albumin is likely useful for estimating the approximate VCM CSF/serum ratio. This could contribute to an improvement in the treatment of bacterial meningitis.

Organic Anion-Transporting Polypeptide (OATP)-Mediated Drug-Drug Interaction Study between Rosuvastatin and Cyclosporine A in Chimeric Mice with Humanized Liver.

The influence of transporters on the pharmacokinetics of drugs is being increasingly recognized, and DDIs via transporters may be a risk factor for adverse events. Cyclosporine A, a strong OATP inhibitor, has been reported to increase the systemic exposure of rosuvastatin, an OATP substrate, by 7.1-fold in clinical studies. PXB mice are chimeric mice with humanized livers that are highly repopulated with human hepatocytes and have been widely used for drug discovery in drug metabolism and pharmacokinetics studies. In the present study, we examined in vivo and in vitro DDIs between rosuvastatin and cyclosporine A in PXB mice and fresh human hepatocytes (PXB cells) obtained from PXB mice. We initially investigated the active transport of rosuvastatin into PXB cells, and found concentration-dependent uptake with a Michaelis-Menten constant value of 4.0 µmol/l and a Vmax value of 4.63 pmol/min per 106 cells. Cyclosporine A inhibited the uptake of rosuvastatin with an IC50 value of 0.21 µmol/l. We then examined in vivo DDIs, and the exposure of orally administered rosuvastatin increased by 3.3-fold and 11-fold in PXB mice pretreated with 10 and 50 mg/kg cyclosporine A, whereas it increased by 2.5-fold and 6.2-fold when rosuvastatin was administered intravenously, in studies that were conducted for considering gastrointestinal DDIs. The liver-to-blood concentration ratio of rosuvastatin was dose-dependently decreased by pretreatment with cyclosporine A in PXB mice and SCID mice. Observed DDIs in vivo were considered to be reasonable based on the estimated concentrations of cyclosporine A at the inlet to the liver and in the liver tissues of both mice. In conclusion, our results indicate that PXB mice might be a useful tool for predicting human OATP-mediated DDIs in drug discovery, and its limitation due to the differences of gastrointestinal condition from human should also be considered.

The effect of cholesterol overload on mouse kidney and kidney-derived cells.

INTRODUCTION: Dyslipidemia is one of the onset and risk factors of chronic kidney disease and renal function drop is seen in lipoprotein abnormal animal models. However, the detailed molecular mechanism of renal lipotoxicity has not been clarified. Therefore, the present study aimed to investigate the influence of cholesterol overload using mouse kidney tissue and kidney-derived cultured cells. METHODS: C57BL/6 mice were fed normal diet (ND) or 1.25% cholesterol-containing high-cholesterol diet (HCD) for 11 weeks, and we used megalin as a proximal tubule marker for immunohistology. We added beta-very low density lipoprotein (ßVLDL) to kidney-derived cells and examined the effect of cholesterol overload on megalin protein and mRNA expression level, cell proliferation and cholesterol content in cells. RESULTS: In the kidney of HCD mice, the gap between glomerulus and the surrounding Bowman's capsule decreased and the expression level of megalin decreased. After ßVLDL treatment to the cells, the protein expression and mRNA expression level of megalin decreased and cell proliferation was restrained. We also observed an increase in cholesterol accumulation in the cell and free cholesterol/phospholipid ratios increased. CONCLUSIONS: These findings suggest that the increased cholesterol load on kidney contribute to the decrease of megalin and the overloaded cholesterol is taken into the renal tubule epithelial cells, causing suppression on cell proliferation, which may be the cause of kidney damage.

Novel pegylated interferon-ß as strong suppressor of the malignant ascites in a peritoneal metastasis model of human cancer.

Malignant ascites manifests as an end-stage event during the progression of a number of cancers and lacks a generally accepted standard therapy. Interferon-ß (IFN-ß) has been used to treat several cancer indications; however, little is known about the efficacy of IFN-ß on malignant ascites. In the present study, we report on the development of a novel, engineered form of human and murine IFN-ß, each conjugated with a polyethylene glycol molecule (PEG-hIFN-ß and PEG-mIFN-ß, respectively). We provide evidence that these IFN-ß molecules retain anti-viral potency comparable to unmodified IFN-ß in vitro and manifested improved pharmacokinetics in vivo. Interestingly, PEG-mIFN-ß significantly inhibited the accumulation of ascites fluid and vascular permeability of the peritoneal membrane in models of ovarian cancer and gastric cancer cell xenograft mice. We further show that PEG-hIFN-ß directly suppresses VEGF165 -induced hyperpermeability in a monolayer of human vascular endothelial cells and that PEG-mIFN-ß enhanced gene expression for a number of cell adhesion related molecules in mouse vascular endothelial cells. Taken together, these findings unveil a hitherto unrecognized potential of IFN-ß in maintaining vascular integrity, and provide proof-of-mechanism for a novel and long-acting pegylated hIFN-ß for the therapeutic treatment of malignant ascites.

[De Novo Cavernous Angioma Secondary to a Developmental Venous Anomaly:A Case Report and Review of the Literature].

OBJECTIVE: Previously, cavernous angiomas(CAs)have been thought to be only congenital in origin. Recently, however, a few cases of de novo CAs have been reported in the literature. We present a case of a de novo CA and discuss the etiology of the newly appeared CA. CASE REPORT: A 29-year-old man was presented to a local clinic because of hypersomnia. MRI demonstrated a heterogeneous mass peripherally located, which was in contact with a developmental venous anomaly(DVA)at the left thalamus. Six years before the presentation, he visited the same clinic because of faintness, and MRI results indicated no abnormality except for the DVA. Three weeks later, he suddenly experienced difficulty in speech, and the MRI revealed an increase in the size of the mass. Subsequently, he was admitted at our institution, and neurological examination revealed aphasia and right hemiparesis. A left carotid angiogram on venous phase showed a narrowing of the DVA, which was seen as it entered the internal cerebral vein. The diagnosis of a de novo CA was made. The mass was completely resected through the transcallosal transventricular approach to avoid injuring the DVA. The DVA could not be found during surgery. The pathological diagnosis was in line with the findings of CA. Postoperatively, the patient continued having difficulty in speech and was transferred to another institution for speech rehabilitation. CONCLUSIONS: Although the association of CA and DVA has been described with increasing frequencies recently, the etiology of de novo CA in the case of this association has been a matter of debate. In the present case, it was speculated that a narrowing of the DVA resulted in increased venous pressure and caused the development of de novo CA.

Characterization of methadone as a ß-arrestin-biased µ-opioid receptor agonist.

BACKGROUND: Methadone is a unique µ-opioid receptor agonist. Although several researchers have insisted that the pharmacological effects of methadone are mediated through the blockade of NMDA receptor, the underlying mechanism by which methadone exerts its distinct pharmacological effects compared to those of other µ-opioid receptor agonists is still controversial. In the present study, we further investigated the pharmacological profile of methadone compared to those of fentanyl and morphine as measured mainly by the discriminative stimulus effect and in vitro assays for NMDA receptor binding, µ-opioid receptor-internalization, and µ-opioid receptor-mediated ß-arrestin recruitment. RESULTS: We found that fentanyl substituted for the discriminative stimulus effects of methadone, whereas a relatively high dose of morphine was required to substitute for the discriminative stimulus effects of methadone in rats. Under these conditions, the non-competitive NMDA receptor antagonist MK-801 did not substitute for the discriminative stimulus effects of methadone. In association with its discriminative stimulus effect, methadone failed to displace the receptor binding of MK801 using mouse brain membrane. Methadone and fentanyl, but not morphine, induced potent µ-opioid receptor internalization accompanied by the strong recruitment of ß-arrestin-2 in µ-opioid receptor-overexpressing cells. CONCLUSIONS: These results suggest that methadone may, at least partly, produce its pharmacological effect as a ß-arrestin-biased µ-opioid receptor agonist, similar to fentanyl, and NMDA receptor blockade is not the main contributor to the pharmacological profile of methadone.

p27(Kip1) and p21(Cip1)-independent proliferative inhibition of vascular smooth muscle cells cultured in type-I collagen matrix honeycombs.

The proliferation of vascular smooth muscle cells (SMCs) contributes to atherosclerotic plaque formation and restenosis. Cyclin-dependent kinase inhibitors, such as p27(Kip1) and p21(Cip1), are known to play significant roles in the control of the aberrant proliferation of SMCs. Primary cultured SMCs stop proliferating immediately when cultured in three-dimensional matrices of type-I collagen "honeycombs" structures. To clarify whether p27(Kip1) and p21(Cip1) are involved in the proliferative inhibition of SMCs cultured in honeycombs, the characteristics of SMCs derived from the aorta of both wild-type mice (p27[+/+] SMCs) and p27(Kip1) knockout mice (p27[-/-] SMCs) were investigated. Although the growth of p27(-/-) SMCs cultured on plates was faster than that of p27(+/+) SMCs, the number of both p27(+/+) and p27(-/-) SMCs did not change when they were cultured in honeycombs. p21(Cip1) expression was decreased but maintained in p27(-/-) SMCs cultured on plates and in honeycombs. Knockdown of p21(Cip1) in p27(-/-) SMCs promoted proliferation on plates. On the contrary, p21(Cip1) knockdown had no effect on the proliferation of p27(-/-) SMCs cultured in honeycombs. In conclusion, p27(Kip1) and p21(Cip1) are insufficient for the proliferative inhibition of SMCs cultured in honeycombs.

Analysis of gene expression for microminipig liver transcriptomes using parallel long-read technology and short-read sequencing.

The microminipig is one of the smallest minipigs that has emerged as a possible experimental animal model, because it shares many anatomical and/or physiological similarities with humans, including the coronary artery distribution in the heart, the digestive physiology, the kidney size and its structure, and so on. However, information on gene expression profiles, including those on drug-metabolizing phase I and II enzymes, in the microminipig is limited. Therefore, the aim of the present study was to identify transcripts in microminipig livers and to determine gene expression profiles. De novo assembly and expression analyses of microminipig transcripts were conducted with liver samples from three male and three female microminipigs using parallel long-read and short-read sequencing technologies. After unique sequences had been automatically aligned by assembling software, the mean contig length of 50843 transcripts was 707 bp. The expression profiles of cytochrome P450 (P450) 1A2, 2C, 2E1 and 3A genes in livers in microminipigs were similar to those in humans. Liver carboxylesterase (CES) precursor, liver CES-like, UDP-glucuronosyltransferase (UGT) 2C1-like, amine sulfotransferase (SULT)-like, N-acetyltransferases (NAT8) and glutathione S-transferase (GST) A2 genes, which are relatively unknown genes in pigs and/or humans, were expressed strongly. Furthermore, no significant gender differences were observed in the gene expression profiles of phase I enzymes, whereas UGT2B17, SULT1E1, SULT2A1, amine SULT-like, NAT8 and GSTT4 genes were different between males and females among phase II enzyme genes under the present sample conditions. These results provide a foundation for mechanistic studies and the use of microminipigs as model animals for drug development in the future. Copyright © 2016 John Wiley & Sons, Ltd.