Novel Opioid Analgesics for the Development of Transdermal Opioid Patches That Possess Morphine-Like Pharmacological Profiles Rather Than Fentanyl: Possible Opioid Switching Alternatives Among Patch Formula.

BACKGROUND: Transdermal fentanyl is widely used in the treatment of severe pain because of convenience, safety, and stable blood concentrations. Nevertheless, patients often develop tolerance to fentanyl, necessitating the use of other opioids; transdermal buprenorphine patch is widely used as an analgesic agent, though available formulation does not provide comparable analgesic effect as transdermal fentanyl patch. Opioids bind to the opioid receptor (OR) to activate both G protein-mediated and ß-arrestin-mediated pathways. We synthesized morphine-related compounds with high transdermal absorbability (N1 and N2) and evaluated their OR activities pharmacologically in comparison with fentanyl and morphine. METHODS: In cells stably expressing µ-opioid receptor (MOR), δ-opioid receptor (DOR), and κ-opioid receptor (KOR), G protein-mediated pathways were assessed using the CellKey and an intracellular cyclic adenosine monophosphate (cAMP) assay, while ß-arrestin-mediated pathways were analyzed with ß-arrestin recruitment and receptor internalization assays. Furthermore, analgesic effects were evaluated using a tail-flick test in mice, and the analgesic effect on fentanyl-tolerant mice was evaluated. RESULTS: In the CellKey and cAMP assays, both N1 and N2 showed the highest affinity for MOR and acted as full agonists as well as partial agonists for DOR and KOR. In the ß-arrestin and internalization assays, only fentanyl acted as a full agonist; N1 and N2 acted as partial agonists of MOR. In the mouse tail-flick test, N1 and N2 showed analgesic effects equivalent to those of fentanyl and morphine. In fentanyl-tolerant mice, fentanyl showed a diminished analgesic effect, whereas N1 and N2 as well as morphine retained their analgesic effects. CONCLUSIONS: While N1 and N2 have higher transdermal absorbability than fentanyl, they also have analgesic effects comparable to those of morphine, suggesting that they may be attractive compounds for the development of novel opioid patches for transitioning from fentanyl patches.

Metronidazole-induced encephalopathy in a patient with pyogenic spondylitis: a case report.

BACKGROUND: Metronidazole is an antimicrobial agent commonly used in the treatment of several protozoal and anaerobic infections. Neurotoxicity associated with metronidazole has been rarely reported, and the incidence of metronidazole-induced encephalopathy is unknown. Therefore, the accurate diagnosis of metronidazole-induced encephalopathy is often difficult because of the rarity of the disease. CASE PRESENTATION: An 86-year-old woman suffered from pyogenic spondylitis of the lumbar spine. Parvimonas micra, a gram-positive anaerobic bacterial species and a resident of the flora of the oral cavity, was identified in the biopsy specimens. Oral administration of metronidazole (1500 mg/day) was initiated. Forty-four days after initiating metronidazole (total intake of 66 g), she complained of tingling sensations in the upper limbs. After 4 days, she complained of additional symptoms including sensory disturbance of the tongue, dysarthria, and deglutition disorder. Characteristic brain magnetic resonance imaging findings on T2-weighted fluid-attenuated inversion recovery and diffusion-weighted imaging led to the diagnosis of metronidazole-induced encephalopathy. Metronidazole was discontinued, and her neurological symptoms improved 10 days after discontinuation. At 14 days after discontinuation of oral metronidazole, abnormal findings on diffusion-weighted imaging almost disappeared. CONCLUSIONS: With the possibility of needing to prescribe metronidazole in the orthopedic field for the treatment of various infections, orthopedic surgeons are likely to encounter cases of metronidazole-induced encephalopathy. Thus, they should be able to recognize the condition and its potential complications. With increased awareness, early diagnosis with magnetic resonance imaging and discontinuation of metronidazole may become feasible when such patients are referred. Our report presents a detailed account of such a case, which may help in the early diagnosis and treatment of patients with metronidazole-induced encephalopathy. Furthermore, we recommend that patients treated with metronidazole should undergo careful and constant surveillance after starting antibiotic therapy.

Environmental Surveillance of Norovirus Genogroups I and II for Sensitive Detection of Epidemic Variants.

Sewage samples have been investigated to study the norovirus concentrations in sewage or the genotypes of noroviruses circulating in human populations. However, the statistical relationship between the concentration of the virus and the number of infected individuals and the clinical importance of genotypes or strains detected in sewage are unclear. In this study, we carried out both environmental and clinical surveillance of noroviruses for 3 years, 2013 to 2016. We performed cross-correlation analysis of the concentrations of norovirus GI or GII in sewage samples collected weekly and the reported number of gastroenteritis cases. Norovirus genotypes in sewage were also analyzed by pyrosequencing and compared with those identified in stool samples. The cross-correlation analysis found the peak coefficient (R = 0.51) at a lag of zero, indicating that the variation in the GII concentration, expressed as the log10 number of copies per milliliter, was coincident with that in the gastroenteritis cases. A total of 15 norovirus genotypes and up to 8 genotypes per sample were detected in sewage, which included all of the 13 genotypes identified in the stool samples except 2. GII.4 was most frequently detected in both sample types, followed by GII.17. Phylogenetic analysis revealed that a strain belonging to the GII.17 Kawasaki 2014 lineage had been introduced into the study area in the 2012-2013 season. An increase in GI.3 cases was observed in the 2015-2016 season, and sewage monitoring identified the presence of GI.3 in the previous season (2014-2015). Our results demonstrated that monitoring of noroviruses in sewage is useful for sensitive detection of epidemic variants in human populations.IMPORTANCE We obtained statistical evidence of the relationship between the variation in the norovirus GII concentration in sewage and that of gastroenteritis cases during the 3-year study period. Sewage sample analysis by a pyrosequencing approach enabled us to understand the temporal variation in the norovirus genotypes circulating in human populations. We found that a strain closely related to the GII.17 Kawasaki 2014 lineage had been introduced into the study area at least 1 year before its appearance and identification in clinical cases. A similar pattern was observed for GI.3; cases were reported in the 2015-2016 season, and closely related strains were found in sewage in the previous season. Our observation indicates that monitoring of noroviruses in sewage is useful for the rapid detection of an epidemic and is also sensitive enough to study the molecular epidemiology of noroviruses. Applying this approach to other enteric pathogens in sewage will enhance our understanding of their ecology.

Palladium bionanoparticles production from acidic Pd(II) solutions and spent catalyst leachate using acidophilic Fe(III)-reducing bacteria.

The acidophilic, Fe(III)-reducing heterotrophic bacteria Acidocella aromatica PFBCT and Acidiphilium cryptum SJH were utilized to produce palladium (Pd) bionanoparticles via a simple 1-step microbiological reaction. Monosaccharide (or intracellular NADH)-dependent reactions lead to visualization of intra/extra-cellular enzymatic Pd(0) nucleation. Formic acid-dependent reactions proceeded via the first slow Pd(0) nucleation phase and the following autocatalytic Pd(II) reduction phase regardless of the presence or viability of the cells. However, use of active cells (with full enzymatic and membrane protein activities) at low formic acid concentration (5 mM) was critical to allow sufficient time for Pd(II) biosorption and the following enzymatic Pd(0) nucleation, which consequently enabled production of fine, dense and well-dispersed Pd(0) bionanoparticles. Differences of the resultant Pd(0) nanoparticles in size, density and localization between the two bacteria under each condition tested suggested different activity and location of enzymes and membrane "Pd(II) trafficking" proteins responsible for Pd(0) nucleation. Despite the inhibitory effect of leaching lixiviant and dissolved metal ions, Pd(0) bionanoparticles were effectively formed by active Ac. aromatica cells from both acidic synthetic Pd(II) solutions and from the actual spent catalyst leachates at equivalent 18-19 nm median size with comparable catalytic activity.

Long-delayed expression of the immediate early gene Arc/Arg3.1 refines neuronal circuits to perpetuate fear memory.

Fear memories typically persist for long time periods, and persistent fear memories contribute to post-traumatic stress disorder. However, little is known about the cellular and synaptic mechanisms that perpetuate long-term memories. Here, we find that mouse hippocampal CA1 neurons exhibit biphasic Arc (also known as Arg3.1) elevations after fear experience and that the late Arc expression regulates the perpetuation of fear memoires. An early Arc increase returned to the baseline after 6 h, followed by a second Arc increase after 12 h in the same neuronal subpopulation; these elevations occurred via distinct mechanisms. Antisense-induced blockade of late Arc expression disrupted memory persistence but not formation. Moreover, prolonged fear memories were associated with the delayed, specific elimination of dendritic spines and the reactivation of neuronal ensembles formed during fear experience, both of which required late Arc expression. We propose that late Arc expression refines functional circuits in a delayed fashion to prolong fear memory.

Microbial recovery of vanadium by the acidophilic bacterium, Acidocella aromatica.

OBJECTIVE: To investigate the bioreduction of toxic pentavalent vanadium [vanadate; V(V)] in the acidophilic, Fe(III)-reducing obligately heterotrophic bacterium, Acidocella aromatica PFBC. RESULTS: Although the initial lag-phase of growth became extended with increasing initial V(V) concentrations, the final cell density during aerobic growth of A. aromatica PFBC was unaffected by up to 2 mM V(V). While strain PFBC is an aerobe, growth-decoupled PFBC cell suspensions directly reduced V(V) using fructose, both micro-aerobically and anaerobically, under highly acidic (pH 2) and moderately acidic (pH 4.5) conditions. Bio reduced V(IV) was subsequently precipitated even under micro-aerobic conditions, mostly by encrusting the cell surface. An anaerobic condition at pH 4.5 was optimal for forming and maintaining stable V(IV)-precipitates. Recovery of approx. 70 % of V(V) from the solution phase was made possible with V(V) at 1 mM. CONCLUSIONS: The first case of direct V(V) reducing ability and its subsequent V recovery from the solution phase was shown in acidophilic prokaryotes. Possible utilities of V(V) bioreduction in acidic conditions, are discussed.

Outcome of conservative laparoscopic surgery for adnexal torsion through one-stage or two-stage operation.

AIM: We investigated the outcome on ovarian appearance and occurrence of adhesion after conservative laparoscopic surgery for adnexal torsion during reproductive age. MATERIAL AND METHODS: From April 2009 to September 2012, we treated patients with clinically suspected adnexal torsion who desired future pregnancy. We performed conservative surgery, such as cystectomy or detorsion at one-stage operation, but switched to salpingo-oophorectomy in complicated cases. We evaluated adnexal condition and pattern of adhesion by careful assessment with two-stage laparoscopy or second-look laparoscopy after first surgery. RESULTS: Mean age of patients was 25 ± 8 years. Among 37 patients with suspected adnexal torsion, 18 (49%) had adnexal torsion at first surgery. Conservative treatment was carried out in 14 of 18 cases. We obtained informed consent for second-look laparoscopy or two-stage operation in six of these 14 cases. Among these six patients, two cases were treated with only detorsion by one-stage operation and cystectomy was performed in the other four cases at first operation. At subsequent surgery, the ovary appeared normal in six cases with occurrence of mild to moderate adhesion around the adnexal lesion. Of note, two cases with para-ovarian cyst had torsion that showed complete tubal occlusions and associated severe adhesions. No major complications (peritonitis, thrombotic emboli) were observed after conservative laparoscopic surgery. CONCLUSION: Conservative laparoscopic surgery is a safe procedure to preserve ovarian function in women with adnexal torsion. Careful attention and measures should be considered during follow-up management with the fact in mind that adhesion is a common occurrence and even tubal occlusion may occur in some cases.

Blockade of stimulus convergence in amygdala neurons disrupts taste associative learning.

Humans and non-human animals learn associations of temporally contingent stimuli to better cope with the changing environment. In animal models of classical conditioning, a neutral conditioned stimulus (CS) predicts an aversive unconditioned stimulus (US). Several lines of indirect evidence indicate that this learning may rely on stimulus convergence in a subset of neurons, but this hypothesis has not been directly tested. In the current study, we tested this hypothesis using a pharmacogenetic approach, the cAMP response element-binding protein (CREB)/Allatostatin Receptor system, to target a subset of amygdala neurons receiving convergent stimuli in mice during conditioned taste aversion. Virally infected basolateral amygdala neurons with higher CREB levels were predominantly active during CS presentation. Blocking stimulus convergence in infected neurons by silencing them during US disrupted taste associative memory. Moreover, silencing infected neurons only during CS also disrupted associative memory formation. These results provide support for the notion that convergent inputs of CS and US in a subpopulation of neurons are critical for associative memory formation.

Post-retrieval late process contributes to persistence of reactivated fear memory.

Several studies have demonstrated the mechanisms involved in memory persistence after learning. However, little is known about memory persistence after retrieval. In this study, a protein synthesis inhibitor, anisomycin, was infused into the basolateral amygdala of mice 9.5 h after retrieval of contextual conditioned fear. Anisomycin attenuated fear memory after 7 d, but not after 2 d. In contrast, infusion of anisomycin 5- or 24-h post-retrieval was ineffective. These findings indicate that anisomycin attenuates the persistence of reactivated fear memory in a time-dependent manner. We propose that late protein synthesis is required for memory persistence after retrieval.

Adhesive performance of silver-palladium-copper-gold alloy and component metals bonded with organic sulfur-based priming agents and a tri-n-butylborane initiated luting material.

OBJECTIVE: The purpose of the current study was to evaluate the effect of thione-based metal priming agents on the adhesive behavior of a Ag-Pd-Cu-Au alloy and component metals bonded with an acrylic resin. MATERIALS AND METHODS: Disk specimens (10 mm in diameter by 3 mm thick) were prepared from a silver-palladium-copper-gold (Ag-Pd-Cu-Au) alloy (Castwell M.C.12), high-purity silver, palladium, copper and gold. Four single-liquid priming agents containing organic sulfur compound (Alloy Primer, Metaltite, M.L. Primer and V-Primer) and three acidic priming agents (All Bond II Primer B, Estenia Opaque Primer and Super-Bond Liquid) were assessed. The metal specimens were flat-ground with abrasive papers, primed with one of the agents and bonded with a tri-n-butylborane initiated resin. The shear bond strengths were determined both before and after repeated thermocycling (5°C and 55°C, 1 min each, 20,000 cycles). The results were statistically analyzed with a non-parametric procedure (p = 0.05 level). RESULTS: The post-thermocycling bond strengths in MPa (median; n = 11) associated with the Alloy Primer, Metaltite, M.L. Primer and V-Primer materials were, respectively, 20.8, 22.8, 17.8 and 18.4 for the Ag-Pd-Cu-Au alloy; 19.6, 21.9, 14.4 and 20.1 for silver; 5.4, 4.5, 12.8 and 5.3 for palladium; 17.1, 19.2, 0.7 and 6.6 for copper; and 18.5, 17.7, 22.8 and 15.4 for gold. CONCLUSIONS: It can be concluded that the use of the four priming agents, which are based on organic sulfur compounds, effectively enhanced bonding to the Ag-Pd-Cu-Au alloy and the component metals, although the bonding performance varied among the priming agents and metal elements. The priming agents appeared to have more of an effect on the alloy, silver and gold than on the palladium and copper.

Idarucizumab for Emergency Reversal of the Anticoagulant Effects of Dabigatran: Final Results of a Japanese Postmarketing Surveillance Study.

INTRODUCTION: Idarucizumab, a monoclonal antibody fragment that rapidly reverses the anticoagulant effects of dabigatran, was approved in Japan in September 2016, at which time an all-case, postmarketing surveillance (PMS) study was initiated to collect data on idarucizumab in Japanese patients. Interim results were published previously, and the final results are reported herein. METHODS: This multicenter, open-label, uncontrolled, non-interventional PMS study was conducted in Japanese patients who received idarucizumab at the approved dose (2 × 2.5 g/50 ml) and had uncontrolled bleeding (group A) or required an emergency procedure (group B). The primary endpoint was the frequency of adverse drug reactions (ADRs). The secondary endpoint was the maximum extent of reversal of the anticoagulant effects of dabigatran, within 4 h of idarucizumab administration, based on activated partial thromboplastin time (aPTT). RESULTS: The final analysis included 804 patients. ADRs during the idarucizumab treatment and post-treatment periods were reported in 17 of 542 patients (3.1%) in group A and 12 of 240 patients (5.0%) in group B. Thrombotic events were reported in 22 patients (4.1%) in group A and 15 patients (6.3%) in group B, and hypersensitivity occurred in four (0.7%) and five patients (2.1%), respectively. Among 793 patients evaluated for effectiveness, 78 in group A and 26 in group B had aPTT data at baseline (immediately before idarucizumab administration) and within 4 h of idarucizumab administration; in these patients, median maximum percentage reversal within 4 h of idarucizumab administration was 100%. CONCLUSIONS: The final analysis from the PMS study confirms previous findings suggesting that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients in clinical practice. The results support the continued use of idarucizumab in Japan. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov (NCT02946931).

Atrial fibrillation is an irregular heart rhythm (arrhythmia), and the type of atrial fibrillation not caused by a heart valve problem is known as "non-valvular atrial fibrillation" or NVAF. People with NVAF have an increased risk of ischemic stroke, in which a blood clot (thrombus) blocks an artery in the brain. Drugs that inhibit blood clots, known as anticoagulants, are prescribed to people with NVAF to prevent ischemic stroke. Historically, warfarin has been one of the most prescribed anticoagulant drugs. However, a novel anticoagulant drug, known as dabigatran, has clinical advantages over warfarin and is approved in many countries for people with NVAF. People who take anticoagulants may experience life-threatening bleeding or need urgent surgery, and thus rapid and effective reversal of the anticoagulant effects is critical. The drug idarucizumab specifically binds to dabigatran to reverse its anticoagulant effects in people with uncontrolled bleeding or who require an urgent procedure. Idarucizumab was approved for use in Japan in September 2016. In Japan, drug companies are obligated to collect data after a new drug is launched as an approval condition, which is done through a postmarketing surveillance study. Here, we report the final results of a postmarketing surveillance study conducted between September 2016 and November 2020 to evaluate the safety and effectiveness of idarucizumab in Japanese patients receiving dabigatran. The results of our study show that idarucizumab can safely and effectively reverse the anticoagulant effects of dabigatran in Japanese patients, and support the continued use of idarucizumab in Japan in clinical practice.

Ethynyl-linked push-pull porphyrin hetero-dimers for near-IR dye-sensitized solar cells: photovoltaic performances versus excited-state dynamics.

Ethynyl-linked porphyrin hetero-dimers substituted by a series of electron donors, namely, bis(4-methoxyphenyl)amino (BMPA), bis(4-tert-butylphenyl)amino (BTBPA) and 3,6-di-tert-butylcarbazol-9-yl (DTBC) as well as a reference dimer with a non-donor moiety (3,5-di-tert-butylphenyl, DTBP) have been synthesized to systematically investigate the influence of donor introduction on the photovoltaic performances of near-IR dye-sensitized solar cells (DSCs) with these sensitizers incorporated. Despite the expected bathochromic shift and intensification of long-wavelength absorption bands as well as elevated LUMO levels and thus increased electron injection driving forces, the substitution of diphenylamino groups (BMPA and BTBPA) with stronger electron-donating abilities gave rise to surprising mediocrity in the short-circuit photocurrent densities (J(sc)), leading to overall energy conversion efficiencies in the order BMPA (3.94%) < DTBP (4.57%) < BTBPA (4.83%) < DTBC (5.21%). A study of the in situ fluorescent behavior of these sensitizers revealed that for all the sensitizers, excited-state lifetimes were significantly shortened in the simulated DSC environment compared to those in a free solution. BMPA showed the shortest intrinsic in situ lifetime while DTBC showed the longest one. These results were correlated with the photovoltaic performances, which is required for a better understanding and further design of porphyrin array sensitizers.

Bonding of resin-based luting cements to zirconia with and without the use of ceramic priming agents.

PURPOSE: This study evaluated and compared bonding characteristics of resin-based luting agents and special ceramic primers to zirconia. MATERIALS AND METHODS: Disk specimens (n = 242) were fabricated from zirconium dioxide ceramics (Katana) and bonded with four resin-based luting agents without priming. In addition, zirconia was bonded with 7 bondingsystem combinations of three priming agents and three resin-based luting agents. Two of the resin-based luting agents and two ceramic priming agents contain an identical adhesive monomer, 10-methacryloyloxydecyl dihydrogen phosphate (MDP), either in the material itself or in the priming agent. Shear bond strength was determined after 20,000 cycles of thermocycling. The Kruskal-Wallis test was performed for both pre- and post-thermocycling groups to evaluate the difference among primer and luting agent variations. On the basis of the Kruskal-Wallis test, Steel-Dwass multiple comparisons were further performed to compare the difference among four luting agents and seven conbinations of three primers and three luting agents for both pre- and post-thermocycling conditions. RESULTS: Within the four unprimed groups, Clearfil SA Cement (5.8 MPa) and Panavia F 2.0 (6.7 MPa) showed statistically higher post-thermocycling bond strength than the other materials (0.1 MPa) (p < 0.05). Among the seven primer/cement combinations, Clearfil Ceramic Primer combined with Clearfil Esthetic Cement exhibited the highest post-thermocycling bond strength (7.5 MPa), followed by two groups primed with Monobond Plus (4.0-4.6 MPa) (p < 0.05). CONCLUSION: Application of resin-based luting and priming agents containing the adhesive monomer MDP provide better bond strength to zirconia than do other systems.

Targeted delivery of immunogen to primate m cells with tetragalloyl lysine dendrimer.

Effective uptake of Ags by specialized M cells of gut-associated lymphoid tissues is an important step in inducing efficient immune responses after oral vaccination. Although stable nontoxic small molecule mimetics of lectins, such as synthetic multivalent polygalloyl derivatives, may have potential in murine M cell targeting, it remains unclear whether synthetic multivalent polygalloyl derivatives effectively target nonhuman and human M cells. In this study, we evaluated the ability of a tetragalloyl derivative, the tetragalloyl-D-lysine dendrimer (TGDK), to target M cells in both in vivo nonhuman primate and in vitro human M-like cell culture models. TGDK was efficiently transported from the lumen of the intestinal tract into rhesus Peyer's patches by M cells and then accumulated in germinal centers. Oral administration of rhesus CCR5-derived cyclopeptide conjugated with TGDK in rhesus macaque resulted in a statistically significant increase in stool IgA response against rhesus CCR5-derived cyclopeptide and induced a neutralizing activity against SIV infection. Furthermore, TGDK was specifically bound to human M-like cells and efficiently transcytosed from the apical side to the basolateral side in the M-like cell model. Thus, the TGDK-mediated vaccine delivery system represents a potential approach for enabling M cell-targeted mucosal vaccines in primates.

Effect of acidic monomers on bonding to SUS XM27 stainless steel, iron, and chromium with a tri-n-butylborane-initiated acrylic resin.

PURPOSE: To evaluate the effects of carboxylic and phosphate functional monomers on the bond strength and durability of an acrylic resin joined to a magnetizable stainless steel and its component metals. MATERIALS AND METHODS: Disk specimens (10 and 8 mm in diameter and 2.5 mm thick) were prepared from SUS XM27 stainless steel, high-purity iron, and chromium metals. The specimens were ground with abrasive paper, and divided into an unprimed control group and 4 groups primed with: 1. Alloy Primer (thione and phosphate); 2. Estenia Opaque Primer (phosphate); 3. Mr. Bond (aliphatic carboxylic acid); or 4. Super-Bond C&B Liquid (aromatic carboxylic anhydride). The disks were bonded with tri-n-butylborane (TBB)-initiated resin, and the shear bond strengths were determined both before and after thermocycling (20,000 X, 5°C - 55°C). The debonded surfaces were analyzed using Xray diffraction (XRD). RESULTS: The Alloy Primer and Estenia Opaque Primer materials containing 10-methacryloyloxydecyl dihydrogen phosphate (MDP) effectively bonded the steel (30.3 to 32.4 MPa) and iron (33.6 to 34.8 MPa), whereas the four acidic primers bonded chromium (24.6 to 32.3 MPa). X-ray diffractometry detected corroded iron at the debonded interface. CONCLUSION: Bearing in mind the limitations of the present study, the use of two primers with MDP is recommendable for bonding SUS XM27 steel with TBB-initiated resin. Iron was considered to be a corrosive factor at the adhesive interface, although the associated bonding characteristics were adequate.

Combination Therapy of Pembrolizumab plus Axitinib for a Patient on Hemodialysis with Metastatic Renal Cell Carcinoma: A Case Report.

Here, we discuss the safety and management of adverse events associated with pembrolizumab plus axitinib combination therapy for metastatic renal cell carcinoma in patients on hemodialysis. A 76-year-old man was diagnosed with cT3aN0M0 renal cell carcinoma due to gross hematuria. Stereoscopic radiotherapy for metastatic lesions of the ipsilateral kidney was performed 9 years after right laparoscopic radical nephrectomy. Soon after, the patient started to receive hemodialysis due to end-stage renal disease. Further stereoscopic radiotherapy was needed for metastasis of the ipsilateral kidney and lung. Fifteen years after diagnosis, systemic therapy was necessary to control new metastases, such as in the right scapular bone. We selected pembrolizumab plus axitinib combination therapy as the first-line systemic therapy for any risk as defined by the International Metastatic RCC Database Consortium. Although we needed to pay attention to the adverse events unique to hemodialysis, he underwent this combination therapy without any difficulty for 6 months. Here, we report the practice of combination therapy in patients on hemodialysis in light of the literature.

Injury-induced neural stem/progenitor cells in post-stroke human cerebral cortex.

Increasing evidence points to accelerated neurogenesis after stroke, and support of such endogenous neurogenesis has been shown to improve stroke outcome in experimental animal models. The present study analyses post-stroke cerebral cortex after cardiogenic embolism in autoptic human brain. Induction of nestin- and musashi-1-positive cells, potential neural stem/progenitor cells, was observed at the site of ischemic lesions from day 1 after stroke. These two cell populations were present at distinct locations and displayed different temporal profiles of marker expression. However, no surviving differentiated mature neural cells were observed by 90 days after stroke in the previously ischemic region. Consistent with recent reports of neurogenesis in the cerebral cortex after induction of stroke in rodent models, the present current data indicate the presence of a regional regenerative response in human cerebral cortex. Furthermore, observations underline the potential importance of supporting survival and differentiation of endogenous neural stem/progenitor cells in post-stroke human brain.

Adhesive bonding of zirconia with single-liquid acidic primers and a tri-n-butylborane initiated acrylic resin.

PURPOSE: The purpose of the current study was to evaluate the effect of acidic primers on the bond strength and durability of an acrylic resin luting agent to zirconia. MATERIALS AND METHODS: Disk specimens were fabricated from zirconia partially stabilized with yttrium oxide (Katana, Noritake Dental Supply). The disks were treated with one of the following acidic primers: Acryl Bond (Shofu), All Bond II Primer B (Bisco), Alloy Primer (Kuraray), Estenia Opaque Primer (Kuraray), Eye Sight Opaque Primer (Kanebo), M.L. Primer (Shofu), MR. Bond (Tokuyama Dental), or Super-Bond Liquid (Sun Medical). Unprimed specimens served as the control. The disks were bonded with a tri-n-butylborane (TBB)-initiated acrylic resin. Shear bond strengths were determined both before and after 10,000 thermocycles (5°C and 55°C, 1 min dwell time each). RESULTS: The pre-thermocycling bond strength ranged from 0.7 MPa to 30.8 MPa, whereas post-thermocycling bond strength varied from 0.3 MPa to 17.6 MPa. The significantly highest post-thermocycling bond strength was obtained when using the Alloy Primer and Estenia Opaque Primer agents. CONCLUSION: Within the limitations of the current experiment, it can be concluded that application of either the Alloy Primer or the Estenia Opaque Primer, both of which contain 10-methacryloyloxydecyl dihydrogen phosphate (MDP), is recommended for bonding the Katana zirconia material with TBB-initiated acrylic resin.

Bioequivalence of a Newly Developed Dabigatran Etexilate Tablet Versus the Commercial Capsule and Impact of Rabeprazole-Induced Elevated Gastric pH on Exposure in Healthy Subjects.

BACKGROUND AND OBJECTIVE: Dabigatran etexilate (DE) is an anticoagulant with proven efficacy and tolerability for stroke prevention in patients with non-valvular atrial fibrillation. For the commercial capsule, a complex formulation is used to maintain the acidic microenvironment required for maximal absorption. Consequently, its efficacy and safety are similar with or without concomitant intake of proton-pump inhibitors (PPIs). A simplified DE tablet formulation was developed and tested in two studies. One investigated bioequivalence (BE) of the novel DE tablet versus the commercial DE capsule. The other investigated DE bioavailability (BA) under pretreatment with the PPI rabeprazole and assessed the effect of elevated pH on exposure to dabigatran. METHODS: BE of the novel DE tablet versus the DE capsule was assessed in a randomized two-treatment, four-period, two-sequence crossover study (NCT03070171). The effect of rabeprazole on the BA of the DE tablet was assessed in an open-label, single-arm study (NCT03143166). Both studies were conducted at sites in Japan. Participants were healthy male volunteers, aged ≥ 20-40 years. In the BE study, participants received the DE tablet or capsule (single oral dose, 110 mg); primary endpoints were area under the concentration-time curve from baseline to the last quantifiable data point (AUC0-tz) and maximum plasma concentration (Cmax) of unconjugated dabigatran. In the relative BA study, participants received the DE tablet (single oral dose, 110 mg) with or without rabeprazole pretreatment (once daily for 5 days, 20 mg); primary endpoints were AUC0-tz and Cmax of total dabigatran. RESULTS: In total, 160 participants were randomized in the BE study; 36 participants were enrolled in the BA study. The 90% confidence intervals of geometric mean (gMean) ratios for AUC0-tz (101.4-116.0%) and Cmax (101.8-116.6%) of unconjugated dabigatran were within pre-defined acceptance criteria for BE. In the relative BA study, the gMeans of AUC0-tz (667 to 192 ng h/mL) and Cmax (83.1 to 21.8 ng/mL) were decreased by approximately 70% when the tablet was administered under rabeprazole pretreatment. The reduction in BA was observed at a mean gastric pH of 5.3. Treatment was well tolerated; no deaths, serious adverse events (AEs) or significant AEs were reported in either study. CONCLUSION: The DE tablet demonstrated BE to the capsule; however, at high gastric pH, BA of the tablet was reduced by approximately 70%, which may lead to reduced efficacy. Data indicate the importance of examining not only BE under standard conditions, but relative BA at elevated gastric pH. Such investigations may avoid the reduced BA at elevated pH that is quite common in the target population (the elderly and/or patients treated with gastric-acid modifying co-medications), and therefore reduce treatment failure with DE. Registration: ClinicalTrials.gov identifier numbers: NCT03070171, and NCT03143166.