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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. Increased liver weight was observed in conjunction with hydropic degeneration and centrilobular necrosis of hepatocytes. In addition, pathological changes were observed in the pancreas, testis, epididymal duct, stomach and parotid gland. Electron microscopic examination revealed mitochondrial pleomorphism in the hepatocytes. Swelling of mitochondria was observed in the alpha cells and beta cells of the pancreas. Dilatation of rough endoplasmic reticulum, Golgi bodies and loss of secretory granules were also noted in the beta cells of the pancreas. FCCP was also compared with three other mUncouplers (DNP, OPC-163493 and tolcapone) with regard to in vitro mitochondrial uncoupling (mUncoupling) activities. FCCP produced the peak ΔOCR (oxygen consumption rate) at the lowest concentration (0.4 μM), followed by OPC-163493, tolcapone, and DNP, based on peak values in ascending order of concentration (2.5, 10, and 50 μM, respectively). Considering the relationship between the mUncoupling activity and toxicity profile of the four mUncouplers, there is no parallel relationship between the in vitro mUncoupling activity and the degree of in vivo toxicity. These findings may contribute to the efficient development of new mitochondrial uncoupler candidates., Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00189-x., Competing Interests: Conflict of interestAll authors are employees of Otsuka Pharmaceutical Co., Ltd., (© The Author(s) under exclusive licence to Korean Society of Toxicology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

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., Methods: Sixty patients who underwent unilateral TKA for primary knee osteoarthritis were included in this double-blinded randomized controlled trial. After excluding dropouts, 26 patients assigned to the EAA group (9 g/day) and 26 assigned to the placebo group (powdered lactose, 9 g/day) were available for analysis. Patients received EAA supplementation or a placebo from 1 week prior to surgery to 2 weeks after it. The rectus femoris muscle area was measured using ultrasonography and quadriceps muscle strength was measured isometrically with a handheld dynamometer, preoperatively and periodically up to 2 years postoperatively. Knee pain, knee range of motion, functional mobility, and Knee Society Score 2011 subjective scores were measured at each time point. Perioperative management, except for supplementation, was identical in the 2 groups., Results: Taking the baseline as 100%, the mean values in the EAA and placebo groups were 134% ± 31% and 114% ± 27%, respectively, for the rectus femoris muscle area and 159% ± 54% and 125% ± 40% for the quadriceps muscle strength, respectively, at 2 years after surgery. The differences were significant (p < 0.05). Clinical outcomes were not significantly different between the 2 groups., Conclusions: Perioperative EAA supplementation contributes to the recovery of rectus femoris muscle volume and quadriceps muscle strength in the 2 years after TKA. The EAA supplementation did not impact clinical outcomes., Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/H362)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

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., Materials and Methods: We conducted a retrospective study of 472 consecutive TKAs, performed using either the 2nd generation (EVOLUTION ™ ), having smaller posterior femoral condyle and asymmetrical tibial tray, or 1st generation (ADVANCE ™ ) prosthesis. The use of each system was historically determined. Patient age, sex and body mass index were matched between the two groups, with 157 cases ultimately included in each group. Measured clinical outcomes included: knee range of motion, the Knee Society Score, the rate of re-operation, and radiological parameters. Patient satisfaction was evaluated using the 12-item Forgotten Joint Score (FJS-12)., Results: The average follow-up period was 5.0 (3.7-6.3) years for the 2nd generation group and 8.7 (6.1-12.8) years for the 1st generation group (p < 0.01). The postoperative knee flexion range was 127° (80°-140°) for the 2nd generation and 118° (90°-135°) for the 1st generation at final follow-up (p < 0.01). On multivariate regression analysis, use of the 2nd generation prosthesis predicted greater postoperative knee flexion. The average FJS-12 score was 64 (0-100) for the 2nd generation and mean 57 (0-100) for the 1st generation (p < 0.01). Other clinical outcomes were similar between the two groups., Conclusions: Compared to the 1st generation, the 2nd generation medial pivot prosthesis provides greater postoperative knee flexion and patient satisfaction., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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. The purpose of this study was to analyze the association between the joint gap in flexion and subjective knee instability and between subjective knee instability and outcomes following medial-pivot TKA., Methods: A total of 769 patients who underwent primary TKA with use of medial-pivot prostheses were enrolled. Clinical outcomes included knee range of motion, Knee Society Score-2011 (KSS-2011), Forgotten Joint Score-12 (FJS-12), patient-reported subjective knee instability, and axial knee radiography to assess flexion joint-gap balance measured at the final follow-up. Clinical outcomes were compared between patients with and without subjective knee instability. Moreover, associated factors were analyzed for postoperative subjective knee instability., Results: Overall, 177 patients (23%) reported experiencing postoperative subjective knee instability. Knee flexion (p = 0.04); KSS-2011 symptom (p<0.001), satisfaction (p<0.001), expectation (p=0.008), and activity (p<0.001) subscales; and FJS-12 (p < 0.001) were significantly worse in patients with subjective knee instability. The KSS-2011 subjective score differences were greater than the minimal clinically important difference. Older age at the time of surgery (odds ratio, 1.04; p = 0.04) and a wider postoperative joint gap in flexion on the medial side (odds ratio, 1.21; p = 0.001) were significant risk factors for subjective knee instability. A gap angle of -2.9° (i.e., medial laxity) was the threshold to predict postoperative knee instability (sensitivity, 0.29; specificity, 0.91)., Conclusions: Postoperative flexion joint-gap laxity on the medial side following medial-pivot TKA affected the patient-reported subjective knee instability scores. Postoperative KSS-2011 subjective scores following medial-pivot TKA were poorer in patients with subjective knee instability., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G976)., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

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. Knee range of motion, Knee Society Score, and radiological outcomes were assessed. The patients' joint awareness was evaluated using the Forgotten Joint Score-12 at the final follow-up. The survival rate with respect to reoperation or revision was analyzed., Results: The mean follow-up period was 10 ± 1.7 years, and the loss to follow-up was 5.4%. All clinical outcomes improved significantly after surgery in both groups (P < .001). Postoperative knee flexion was 118° ± 13° in the CS group and 116° ± 10° in the CR group (P = .10). The mean Forgotten Joint Score-12 scores were 57 ± 27 points in the CS group and 56 ± 28 points in the CR group (P = .59). Ten years after the operation, the survival rates for reoperation were 96.3% in the CS group and 94.2% in the CR group (P = .61), and those for revision were 98.4% and 98.7% in the CS and CR groups, respectively (P = .87). Other postoperative clinical results did not differ between the 2 groups., Conclusion: In this 10-year follow-up study, medial pivot TKA, regardless of polyethylene insert type, showed a high survival rate and good patient awareness of the prosthetic joint., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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. In the rat studies, rigor mortis and increased body temperatures were observed in the high dose group. Focal necrosis, fatty change, and granular eosinophilic cytoplasm of the hepatocytes were also observed in the high dose group. In the dog studies, gastrointestinal manifestations were observed with decreased body weight and decreased food consumption in the high dose group. Necrotizing arteritis was observed in multiple organs as well as meningitis with hemorrhage in the brain. In the monkey studies, vomiting, decreased food consumption, and decreased locomotor activity were observed in the high dose group. Degeneration of the proximal convoluted tubules and the straight tubular epithelium, regeneration of the proximal tubular epithelium, and degeneration of the collecting tubular epithelium were observed. The target organs of OPC-163493 were liver, blood vessels, and kidney in rats, dogs, and monkeys, respectively. In rats, dogs, and monkeys, safety ratios were 100:1, 13:1, and 20:1, respectively, in terms of total exposure (AUC 24h ). These safety ratios showed clear separation between exposure to OPC-163493 in animals at NOAEL and the exposure at the effective dose in ZDF rats. This information should contribute to the drug development of new and effective mUncoupler candidates., (Copyright © 2022 Inoue et al.)

We serendipitously found a mitochondrial uncoupler (mUncoupler), compound 1 , in the process of screening for inhibitors of a gene product related to calorie restriction (CR) and longevity. Compound 1 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. We therefore tried to optimize cyanotriazole compound 1 and convert it into an agent that could be safely administered to patients with diabetes mellitus (DM) or metabolic disorders. Considering pharmacokinetic (PK) profiles, especially organ distribution targeting the liver and avoiding the brain, as well as acute toxicities and pharmacological effects of the derivatives, various conversions and substitutions at the 5-position on the cyanotriazole ring were carried out. These optimizing processes improved PK profiles and effectiveness, and acute toxicities became negligible even at high doses. We finally succeeded in developing an optimized compound, OPC-163493, as a liver-localized/targeted mUncoupler., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

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., Methods: Consecutive, primary total knee arthroplasties (n = 257) were analyzed in the study using the medial pivot knee system. The clinical outcomes were assessed preoperatively and at the final follow-up. The patient-reported Forgotten Joint Score-12 and radiological outcomes were measured at the final follow-up. The survival rate was assessed with reoperation or revision as the end-point., Results: The mean follow-up period was 10.1 ± 1.7 years. The lost to follow-up was 4.5%. All clinical outcomes improved significantly after surgery (p < 0.001). The mean postoperative knee flexion was 118° ± 11° and the mean Forgotten Joint Score-12 was 59.7 ± 27 points. The radiolucent line was observed in 29 patients (11.3%), however there was no aseptic loosening noted. The survival rates with reoperation or revision were 96.3% or 98.4% at 10 years after the operation., Conclusions: Medial pivot total knee arthroplasty used for Asian patients showed good longevity and patient-reported outcome measurement in a mean 10-year follow-up study. Medial pivot total knee arthroplasty has long-term stability among patients who have a floor-based lifestyle., Level of Evidence: III., Competing Interests: Declaration of competing interest There were no direct conflicts of interest to report with regard to this study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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. Supplementation and placebo were provided from one week before to two weeks after surgery. The area of the rectus femoris muscle were measured by ultrasound imaging one month before surgery and one, two, three, and four weeks postoperatively. The serum albumin level, a visual analogue knee pain score, and mobility were also measured at each time point. The time to recovery of activities of daily living (ADLs) was recorded. Postoperative nutrition and physiotherapy were identical in both groups., Results: The mean relative change from baseline was as follows for the amino acid group: 116% in rectus femoris muscle area (71% to 206%); 95% in serum albumin (80% to 115%) and 39% in VAS pain (0% to 100%) at four weeks after surgery. These values in the placebo group were: 97% in muscle area (68 to 155); 89% in serum albumin (71% to 100%) and 56% in VAS pain four weeks after surgery (0% to 100%). All changes were statistically significant (p < 0.05). The mean time to recovery of ADLs was shorter in the amino acid group compared with the placebo group (p = 0.005)., Conclusion: Perioperative essential amino acid supplementation prevents rectus femoris muscle atrophy and accelerates early functional recovery after TKA. Cite this article: Bone Joint J 2020;102-B(6 Supple A):10-18.

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. It exhibits insulin-independent antidiabetic effects in multiple animal models of type I and type II diabetes and antisteatotic effects in fatty liver models. These beneficial effects can be explained by the improvement of glucose metabolism and enhancement of energy expenditure by OPC-163493 in the liver. Moreover, OPC-163493 treatment lowered blood pressure, extended survival, and improved renal function in the rat model of stroke/hypertension, possibly by enhancing NO bioavailability in blood vessels and reducing mitochondrial ROS production. OPC-163493 is a liver-localized/targeted mUncoupler that ameliorates various complications of diabetes.

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. Primary pharmacokinetic (PK) endpoints were maximum plasma concentration, (Cmax ), and exposure as assessed by area under the curve (AUC). There was no significant difference in PK parameters and bioavailability between the formulations tested. Japanese study (n = 30): a four-period crossover study in healthy Japanese male subjects to assess PK and dose proportionality following single, ascending, oral doses of 250, 500, and 1,000 mg vercirnon under fasted and fed conditions. Vercirnon Cmax and AUC parameters in the fasted state increased in a less than dose proportional manner and were on average 20% higher in fed subjects compared with fasted subjects. Overall, these results support the premise that vercirnon has similar PK/safety profiles within US and Japanese populations. There was no evidence to preclude the use of the new vercirnon formulation in future studies., (© 2013, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.)

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. Test-retest reliability, internal consistency, and concurrent validity for total HAM-D scores were examined by calculating intraclass correlation coefficient, Cronbach's alpha, and Pearson's correlation coefficient. Inter-rater consistency for each HAM-D item was examined by Cohen's kappa., Results: Test-retest reliability of the IVR program was high (intraclass correlation coefficient: 0.93). Internal consistency of each total score obtained by the clinician, psychologists, and IVR program was high (Cronbach's alpha: 0.77, 0.79, 0.78, and 0.83). Regarding concurrent validity, correlation coefficients between total scores obtained by the clinician versus IVR and that by the clinician versus psychologists were high (0.81 and 0.93). The HAM-D total score rated by the clinician was 3 points lower than that of IVR. Inter-rater consistency for each HAM-D item evaluated by the clinician versus IVR was estimated to be fair (Cohen's kappa coefficient: 0.02-0.50)., Conclusion: Our results suggest that the Japanese IVR HAM-D program is reliable and valid to assess 17-item HAM-D total score in Japanese depressive patients. However, the current program tends to overestimate depression severity, and the score of each item did not always show high agreement with clinician's rating, which warrants further improvement in the program., (© 2013 The Authors. Psychiatry and Clinical Neurosciences © 2013 Japanese Society of Psychiatry and Neurology.)

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., Study Design: Samples were obtained by nasal swab from patients with suspected influenza. The diagnostic capability of the RDK was compared with that of the standard, real-time reverse transcription-polymerase chain reaction (RT-PCR) method., Results: Of 266 patients who met the criteria, 122 and 92 were positive for A/H1N1/2009 influenza by PCR and by the newly developed RDK, respectively. The sensitivity, specificity and positive and negative predictive values of the RDK were 73.0%, 97.9%, 96.7% and 81.0%, respectively. A/H1N1/2009 detection rates by the RDK were significantly lower in samples obtained from patients more than 3 days after onset than in samples obtained between 1 and 2 days., Conclusions: The A/H1N1/2009-specific RDK is a reliable test that can be used easily at a patient's bedside for rapid diagnosis of A/H1N1/2009. This test will be of key importance in the control of A/H1N1/2009., (Copyright © 2011 Elsevier B.V. All rights reserved.)

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). Our method was also applicable to the human hepatoma HepG2 cells. Measurement of glycogen content in HepG2 cells revealed that GR was compensated by glycogenolysis in the basal state and was generated by gluconeogenesis in the presence of GS. The optimized conditions increased the expression of gluconeogenic genes in HepG2 cells. Insulin and metformin dose-dependently inhibited GR and 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) increased it. These results suggest that the present method is useful to evaluate the effects of nutrients, hormones and hypoglycemic agents on hepatic gluconeogenesis.

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.p.) elevated blood glucose levels in ZF rats up to 300 mg/dl within a week, and to nearly 500 mg/dl by 5 weeks after injection of STZ. Besides hyperglycemia, STZ-treated ZF (STZ-ZF) rats retained metabolic syndrome features such as hyperlipidemia and hyperinsulinemia. The stimulated insulin secretion in response to orally-loaded glucose disappeared completely in STZ-ZF rats. Although there were no significant differences in the morphology of pancreatic islets between vehicle-treated ZF (Cont-ZF) and STZ-ZF rats, the insulin content was markedly decreased in STZ-ZF rats. The hepatic gene expression for gluconeogenic enzymes was upregulated in STZ-ZF rats compared with Cont-ZF rats. Metformin lowered the blood glucose levels of STZ-ZF rats in a dose-dependent manner. These results suggest that STZ-ZF rats are useful for studies of T2DM and for the evaluation of the efficacy of anti-diabetic drugs.

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.e. Down syndrome, 22q deletion syndrome, Robinow's syndrome and cerebro-oculo-facio-skeletal syndrome, no reports of Moebius syndrome with CBVCP were found in the literature. CBVCP is often associated with central nervous system abnormalities. However, our patient had no detectable brain abnormalities. The etiology of Moebius syndrome remains unknown. It is interesting that the clinical manifestations of Moebius syndrome can include CBVCP. However, the pathophysiology of CBVCP is unknown and further investigations into the etiology of Moebius syndrome are required.

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. Therefore, the chromosome constitution is 46,XX,del(1)(q43q43), which has not previously been reported in the literature. Screening for the mutations in the candidate genes for LVNC, i.e. G4.5, CSX, Dystrobrevin, FKBP12, and Desmin, produced negative results. Interestingly, the deleted portion includes the locus for the cardiac ryanodine receptor type 2 gene (RyR2), that selectively binds to the FKBP12 homolog, FKBP12.6. The relationship between this rare myocardial abnormality and deletion of q43 is currently unknown and awaits further accumulation of cases with the same chromosomal aberration.

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 2.2-Mb common deletion encompassing NSD1 and present with frequent brain, cardiovascular, or urinary tract anomalies. The girl we described had the common deletion and showed patent ductus arteriosus, atrial septal defect, vesicoureteral reflux, and bilateral hydronephrosis. It was thus concluded that the clinical manifestations, including the Nevo syndrome phenotype, were caused by the microdeletion., ((c) 2005 Wiley-Liss, Inc.)

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. 2. Within the critical 570 kb region of the Dmo1 locus, we identified the G-protein-coupled receptor gene GPR10 as the causative gene mutated in the OLETF strain. The ATG translation initiation codon of GPR10 is changed into ATA in this strain and, so, is unavailable for the initiation of translation. 3. The GPR10 protein has a cognate ligand, namely prolactin-releasing peptide (PrRP). Centrally administered PrRP suppressed the food intake of congenic rats that have a Brown Norway derived Dmo1 region (i.e. with wild-type GPR10), but did not suppress that of the OLETF strain, indicating that GPR10 is without function and could explain hyperphagia in the OLETF strain. 4. Moreover, when restricted in food volume to the same level consumed by the congenic strain, OLETF rats showed few differences in the parameters of dyslipidaemia and obesity compared with congenic strains. 5. Taken together, these results demonstrate that the mutated GPR10 receptor is responsible for the hyperphagia leading to obesity and dyslipidaemia in the obese diabetic strain rat.

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. Construct validity was investigated by cluster analysis and multitrait scaling analysis. The results showed that three scales (physical well-being, mental well-being, and life well-being) could explain 55% of the variance in scores. The life well-being scale could be divided into subscales of Daily Functioning, Social Functioning, and Subjective QOL. Multitrait scaling analysis confirmed convergent and discriminant validity of these scales and subscales. Internal consistency and test-retest reliability were favorable. Differences in Care Notebook scores were also consistent with differences in performance status rating (known-groups validity), and Care Notebook scores correlated with EORTC QLQ-C30 and FACT-Sp-12 scores (concurrent validity). The Care Notebook allows clinical oncologists to easily collect valid and reliable QOL information of physical, mental, and life well-being repeatedly and with minimal burden on patients.

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]. L-Hcy was obtained by treatment of (4S)-TDC.HCl with hydroxylamine. D-Hcy was also synthesized from D-Met via (4R)-TDC.HCl intermediate. The obtained D- and L-Hcy were condensed with (R)- and (S)-2-amino-3-chloropropanoic acid hydrochlorides under alkaline conditions to give four stereoisomers of CYT.