Carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone-induced toxicities in rats: comparative study with other mitochondrial uncouplers (2,4-dinitrophenol, OPC-163493 and tolcapone).

Unlabelled: FCCP (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone) is known to inhibit oxidative phosphorylation as a protonophore, dissipating the proton gradient across the inner mitochondrial membrane. To understand the toxicity of FCCP, 3-day, 2- and 4-week repeated oral dose studies were performed in male rats. In the 3-day and 2-week repeated dose toxicity studies, observations included salivation, increased body temperature, and dead and moribund animals.

Perioperative Essential Amino Acid Supplementation Facilitates Quadriceps Muscle Strength and Volume Recovery After TKA: A Double-Blinded Randomized Controlled Trial.

Background: Perioperative essential amino acid (EAA) supplementation suppresses lower-limb muscle atrophy and promotes functional improvement in the first 4 weeks after total knee arthroplasty (TKA). However, its effect on the recovery of muscle volume and strength in the intermediate term is unclear. The aim of this study was to evaluate the effect of perioperative EAA supplementation on the recovery of lower-limb muscle volume and strength in the 2 years after TKA.

Association of a Wider Medial Gap (Medial Laxity) in Flexion with Self-Reported Knee Instability After Medial-Pivot Total Knee Arthroplasty.

Background: Medial-pivot total knee arthroplasty (TKA) is designed with high articular conformity in the medial compartment in order to achieve stability. The subjective outcome of patients has been reported to be good postoperatively; however, the association between the objective and subjective knee stability and the influence of subjective stability on the overall outcomes of TKA remained unknown. Our hypothesis was that postoperative flexion joint-gap imbalance could affect subjective knee instability following TKA in medial-pivot prostheses.

Preclinical safety profile of a liver-localized mitochondrial uncoupler: OPC-163493.

Mitochondrial uncouplers (mUncouplers) are known to exhibit a variety of toxic effects in animals. Here we report a safety profile of an mUncoupler, OPC-163493, recently synthesized at Otsuka Pharmaceutical Co, Ltd, and its development as a therapeutic agent for treating diabetes. To understand the acute and subchronic toxicity of OPC-163493, single and repeated oral dose studies in rats, dogs, and monkeys were performed.

No Difference in Postoperative Knee Flexion and Patient Joint Awareness Between Cruciate-Substituting and Cruciate-Retaining Medial Pivot Total Knee Prostheses: A 10-Year Follow-Up Study.

Background: This study aimed to clarify differences in clinical results, including in patients' joint awareness, between cruciate-substituting (CS) and cruciate-retaining (CR) medial pivot total knee arthroplasty (TKA) over a 10-year follow-up.

Methods: A total of 333 TKAs were included in this study. There were 257 cases of CS and 76 cases of CR TKAs.

Comparison of postoperative knee flexion and patient satisfaction between newly and conventionally designed medial pivot total knee arthroplasty: a 5-year follow-up matched cohort study.

Introduction: The medial pivot total knee arthroplasty (TKA) has good patients' satisfaction; however, there is likely the restriction of postoperative knee flexion. The 2nd generation medial pivot TKA prosthesis was designed to improve postoperative knee flexion. This study aimed to compare the clinical outcomes and patient satisfaction between the 2nd generation and 1st generation medial pivot TKA prostheses.

New Approach to Drug Discovery of a Safe Mitochondrial Uncoupler: OPC-163493.

We serendipitously found a mitochondrial uncoupler (mUncoupler), compound , in the process of screening for inhibitors of a gene product related to calorie restriction (CR) and longevity. Compound has a unique 4-cyano-1,2,3-triazole structure which is different from any known mUncoupler and ameliorated HbA1c in Zucker diabetic fatty (ZDF) rats. However, its administration at high doses was not tolerated in an acute toxicity test in rats.

Long-term clinical outcomes of medial pivot total knee arthroplasty for Asian patients: A mean 10-year follow-up study.

Background: Many Asian populations have a unique floor-based lifestyle that might cause mechanical stress of the knees. It is important to clarify the longevity of a medial pivot total knee arthroplasty, as its prosthetic design could cause mechanical stress onto the insert. The purpose of this study was to clarify the clinical results of medial pivot total knee arthroplasty for Asian patients in a 10-year follow-up study.

2020 Chitranjan S. Ranawat Award: Perioperative essential amino acid supplementation suppresses rectus femoris muscle atrophy and accelerates early functional recovery following total knee arthroplasty.

Aims: The aim of this study was to assess the effectiveness of perioperative essential amino acid (EAA) supplementation to prevent rectus femoris muscle atrophy and facilitate early recovery of function after total knee arthroplasty (TKA).

Methods: The study involved 60 patients who underwent unilateral TKA for primary knee osteo-arthritis (OA). This was a double-blind, placebo-controlled, randomized control trial with patients randomly allocated to two groups, 30 patients each: the essential amino acid supplementation (9 g daily) and placebo (lactose powder, 9 g daily) groups.

Antidiabetic and cardiovascular beneficial effects of a liver-localized mitochondrial uncoupler.

Inducing mitochondrial uncoupling (mUncoupling) is an attractive therapeutic strategy for treating metabolic diseases because it leads to calorie-wasting by reducing the efficiency of oxidative phosphorylation (OXPHOS) in mitochondria. Here we report a safe mUncoupler, OPC-163493, which has unique pharmacokinetic characteristics. OPC-163493 shows a good bioavailability upon oral administration and primarily distributed to specific organs: the liver and kidneys, avoiding systemic toxicities.

Single-Dose Pharmacokinetics of the CCR9 Receptor Antagonist Vercirnon in Healthy US and Japanese Subjects.

Two randomized, single-dose, crossover studies were carried out to assess different formulations and doses of the CCR9 receptor antagonist vercirnon in healthy subjects. US study (n = 24): a five-period crossover study in healthy US subjects to assess the bioavailability of four new GlaxoSmithKline formulations compared with a "reference" formulation. Each subject received a single 500 mg dose of each of the five vercirnon formulations in a fed state.

Validation of computer-administered clinical rating scale: Hamilton Depression Rating Scale assessment with Interactive Voice Response technology--Japanese version.

Aim: The aim of this study was to examine the reliability and validity of the Interactive Voice Response (IVR) program to rate the 17-item Hamilton Rating Scale for Depression (HAM-D) score in Japanese depressive patients.

Methods: Depression severity was assessed in 60 patients by a clinician and psychologists using HAM-D. Scoring by the IVR program was conducted on the same and the following days.

Multicenter prospective evaluation of a novel rapid immunochromatographic diagnostic kit specifically detecting influenza A H1N1 2009 virus.

Background: Definitive diagnosis is crucial in reducing morbidity and mortality from pandemic influenza A H1N1 2009 (A/H1N1/2009), especially in high-risk populations. We recently developed a rapid diagnosis kit (RDK) capable of specifically detecting A/H1N1/2009.

Objectives: To evaluate the diagnostic capability of the RDK in a multicenter, prospective trial.

Establishment and characterization of a novel method for evaluating gluconeogenesis using hepatic cell lines, H4IIE and HepG2.

The liver gluconeogenic pathway is recognized as a target for treating diabetes mellitus. In this study, we attempted to establish a new method to evaluate gluconeogenesis using rat H4IIE hepatoma cells. High-density preculture and exposure to hypertonic solutions, which are known to upregulate the expression of gluconeogenic genes, enhanced glucose release (GR) promoted by gluconeogenic substrates (GS: 1mM pyruvate and 10mM lactate).

Characterization of STZ-Induced Type 2 Diabetes in Zucker Fatty Rats.

The Zucker fatty (ZF) rat is a disease model of obesity and metabolic syndrome, such as hyperlipidemia and insulin resistance, resulting from hyperphagia owing to the loss of function of the leptin receptor, but it rarely develops hyperglycemia. We examined the effects of different doses of streptozotocin (STZ). A low dosage of STZ (30 mg/kg body weight, i.

A case of Moebius syndrome presenting with congenital bilateral vocal cord paralysis.

We describe a female infant with bilateral facial paralysis and abducens palsy. To the best of our knowledge, this is the first report of Moebius syndrome presenting with congenital bilateral vocal cord paralysis (CBVCP). Although CBVCP can be part of a recognizable syndrome, i.

Interstitial 1q43-q43 deletion with left ventricular noncompaction myocardium.

We describe a newborn infant with del(1)(q) syndrome, presenting with rare congenital cardiomyopathy and left ventricular noncompaction myocardium (LVNC), as well as typical clinical features such as facial dysmorphism and psychomotor retardation. Although conventional chromosome banding at 850 bands per haploid set indicated a karyotype of 46,XX,add(1)(q42.3), FISH analysis confirmed that the deleted portion was limited to within q43, and q44 was preserved.

Nevo syndrome with an NSD1 deletion: a variant of Sotos syndrome?

A 17-month-old girl with clinical manifestations of Nevo syndrome and NSD1 (nuclear receptor binding SET domain protein 1) deletion is described. Nevo syndrome is a rare overgrowth syndrome showing considerable phenotypic overlap with Sotos syndrome-another, more frequent overgrowth syndrome caused by NSD1 mutations or deletions. About a half of Japanese Sotos syndrome patients carry a 2.

Validation of the care notebook for measuring physical, mental and life well-being of patients with cancer.

To measure patients' QOL in the daily practice of clinical oncology, we developed and tested the Care Notebook. This instrument has 24 questions expressed in single words or short phrases to make it more acceptable to patients. The Care Notebook, EORTC QLQ-C30 and FACIT-Sp-12 were administered to 249 outpatients with cancer.

Mutated G-protein-coupled receptor GPR10 is responsible for the hyperphagia/dyslipidaemia/obesity locus of Dmo1 in the OLETF rat.

1. We have confirmed the Diabetes Mellitus OLETF type I (Dmo1) effect on hyperphagia, dyslipidaemia and obesity in the Otsuka Long-Evans Tokushima Fatty (OLETF) strain. The critical interval was narrowed down to 570 kb between D1Got258 to p162CA1 by segregation analyses using congenic lines.

Synthesis of optically active homocysteine from methionine and its use in preparing four stereoisomers of cystathionine.

In order to synthesize four stereoisomers of cystathionine (CYT), D- and L-homocysteines (D- and L-Hcy) were synthesized from methionine (Met) by a facile procedure. L-Met was reacted with dichloroacetic acid in concentrated hydrochloric acid under reflux to give (4S)-1,3-thiazane-2,4-dicarboxylic acid hydrochloride [(4S)-TDC.HCl].

Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats.

Aim: Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes in the Otsuka Long Evans Tokushima Fatty (OLETF) rat strain. To evaluate possible metabolic and pathological improvements generated by correction of the Dmo1 genetic pathway, we produced congenic lines, in which both OLETF Dmo1 alleles are replaced by the F344-derived genome.

Methods: Congenic animals were produced by introgressing F344-derived Dmo1 alleles into the OLETF rat.

Genetic analysis of pancreatic duct hyperplasia in Otsuka Long-Evans Tokushima Fatty rats: possible association with a region on rat chromosome 14 that includes the disrupted cholecystokinin-A receptor gene.

An Otsuka Long-Evans Tokushima Fatty (OLETF) strain of rat spontaneously developed hyperglycemia, hyperinsulinemia, insulin resistance and mild obesity, which had been studied as animal model for type II diabetes mellitus (T2DM). Recently, we observed that this strain coincidentally developed atypical hyperplasia of the choledocho-pancreatic ductal epithelium with a complete incidence. In an effort to locate genes responsible for this hyperplasia, we prepared 288 backcross progeny from a mating between OLETF rats and BN rats (which do not develop hyperplasia), and performed a genome-wide scan using 207 polymorphic genetic markers.

Expression of TMEFF1 mRNA in the mouse central nervous system: precise examination and comparative studies of TMEFF1 and TMEFF2.

TMEFF1 and TMEFF2 are putative transmembrane proteins comprised of one epidermal growth factor (EGF)-like domain and two follistatin-like domains. Both TMEFF1 and TMEFF2 are predominantly expressed in the brain. We previously demonstrated that recombinant TMEFF2 protein can promote survival of neurons in primary culture and determined expression sites of TMEFF2 mRNA in the mouse central nervous system.