Effect of Perioperative Docetaxel-induced Limb Edema on Health-related Quality of Life in Patients with Early-stage Breast Cancer: A Prospective Observational Study.

Docetaxel (DTX) is a key drug used in perioperative chemotherapy for breast cancer. Edema is a known adverse effect of DTX, but its effect on health-related QOL (HRQOL) is unclear. In this study, we evaluated the effects of edema caused by administration of DTX on HRQOL in patients with early-stage breast cancer. We prospectively investigated patients diagnosed with early-stage breast cancer (stage I-III) who received 4 cycles of DTX as preoperative or postoperative chemotherapy between September 2021 and December 2022 at Yamanashi Prefectural Central Hospital. The circumference of each extremity was measured at each administration of DTX, and limb edema was evaluated by Common Terminology Criteria for Adverse Events version 5.0. HRQOL was evaluated using SF-12 version 2, which has a range of 0-100 (national standard, 50), and compared between the presence and absence of grade 2 or higher edema and between before and after administration of DTX. Twenty patients met the eligibility criteria and were included in the study. There was no difference in the HRQOL score according to whether grade 2 limb edema was present. The median HRQOL summary scores before and after administration of DTX were 51.1 and 50.8 (p=0.763), respectively, for mental health, 52.6 and 49.4 (p=0.005) for physical health, and 38.9 and 37.5 (p=1.000) for role/social health. We found no direct effect of DTX-induced limb edema on HRQOL in patients with early-stage breast cancer. However, HRQOL summary scores indicated that administration of DTX reduced physical health in these patients.

Correction: Pterin-based small molecule inhibitor capable of binding to the secondary pocket in the active site of ricin-toxin A chain.

[This corrects the article DOI: 10.1371/journal.pone.0277770.].

Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Potential risk factors for early acute kidney injury in patients treated with vancomycin.

PURPOSE: The acute kidney injury (AKI) onset owing to vancomycin (VCM) is reported that depend on the area under the blood concentration-time curve (AUC) and occur comparison early phase (early AKI). This study aimed to investigate the occurrence of early AKI in patients treated with VCM and new indicators to avoid early AKI. METHODS: Adult patients who received VCM treatment for more than 4 days and whose trough values measured at least once on or after day 4 and serum creatinine before day 7 from the initiation of VCM administration between August 2021 and September 2022 at the Yamanashi Prefectural Central Hospital were enrolled. Early AKI (defined as AKI occurring within day 7 from VCM administration) and the association between each AUC (0-24, 24-48, 48-72, 0-48, 24-72, 0-72) were investigated. Furthermore, each AUC cut-off value for early AKI was calculated. RESULT: In total, 164 patients were enrolled; early AKI developed in 21 patients and most frequently occurred on day 4. All stratified AUC were associated with early AKI development. The AUC cut-off values were AUC0-24: 470.8 µg/mL⋅h; AUC24-48: 473.0 µg/mL⋅h; AUC48-72: 489.7 µg/mL⋅h; AUC0-48: 910.2 µg/mL⋅h; AUC24-72: 1039.2 µg/mL⋅h; and AUC0-72: 1544.0 µg/mL⋅h. CONCLUSION: The possibility of AKI development owing to the AUC accumulation of VCM was observed (accumulation toxicity). Concentration control through early-phase blood concentration measurements and a transition to AUC0-48 <910.2 µg/mL⋅h may reduce the early-phase AKI onset.

Association Between Skin Autofluorescence and White Blood Cell Counts in Older Adults.

BACKGROUND/AIM: Advanced glycation end products (AGEs) accumulate in the body with increasing age. However, their excessive accumulation may lead to various inflammatory and chronic diseases. While it is common for older adults to experience various comorbidities, there is a scarcity of published literature documenting the specific impact of ageing and comorbidities on AGEs in this population. The present study aimed to retrospectively evaluate the correlation among AGEs in the skin, calendar age, and comorbidities in older adults. PATIENTS AND METHODS: Accumulated AGEs in the skin were assessed by non-invasive measurement of skin autofluorescence (SAF) inside the forearm. This retrospective study included individuals who underwent SAF measurements at Shujitsu University Community Pharmacy with or without a prescription from October 2019 to October 2021. Subsequently, the associations between SAF, calendar age, comorbidities, and blood test parameters were investigated. RESULTS: SAF showed a positive correlation with calendar age for all enrolled participants; the correlation weakened for participants aged ≥50 years and plateaued for those aged ≥60 years. Furthermore, we observed a significant increase in SAF among all participants with comorbidities compared to those without comorbidities. By contrast, among participants aged ≥50 years, SAF did not show a significant association with comorbidities. However, SAF was significantly positively correlated with white blood cell (WBC) counts in these aged populations. CONCLUSION: The non-invasive assessment of SAF holds promise in evaluating changes in the physical condition associated with WBC counts among older adults.

Topical Betamethasone Treatment of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis with Ocular Involvement in the Acute Phase.

PURPOSE: To clarify the importance of administering topical steroids for the treatment of Stevens-Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN) with ocular involvement in the acute phase. DESIGN: Retrospective case series. METHODS: Using the medical records of acute SJS/TEN patients treated at the Kyoto Prefectural University of Medicine Hospital, Kyoto, Japan, between July 2006 and July 2017, the ocular findings, topical steroid dosage, systemic steroid dosage, and ocular sequelae were retrospectively examined. The level of cytokines in tear fluid and serum samples was also analyzed. RESULTS: This study involved 13 cases. In 10 cases in whom the clinical courses were recorded before the start of steroid therapy, the mean acute ocular severity score (AOSS: 3 = very severe; 2 = severe; 1 = mild; 0 = none) was 2.8 ± 0.4 points in the severest phase. The mean systemic steroid dose after steroid pulse therapy was 694 ± 386 mg and the mean topical steroid (0.1% betamethasone eye drop and ointment) dose was 13.4 ± 3.3 times daily in the severest phase. Analysis of cytokine levels of 4 cases showed that a cytokine storm occurred in the tear fluid after the steroid pulse therapy. At final follow-up, 16 eyes of 8 patients had a logMAR visual acuity of ≤0, and no serious ocular sequelae were observed. CONCLUSIONS: In patients with SJS/TEN, ocular surface inflammation remains strong even after systemic inflammation has improved post steroid pulse therapy, thus suggesting that both systemic and topical steroid therapy should be administered appropriately.

Weak Inhibitory Effects of Anthocyanins on Human Aldehyde Oxidase Activity: An In Vitro Study.

Aldehyde oxidase (AO) plays an important role in the metabolism of antitumor and antiviral drugs, including methotrexate, favipiravir, and acyclovir. The consumption of blueberry fruits or their extracts, which contain large amounts of anthocyanins, has recently increased. The intake of large amounts of anthocyanins occurs through the frequent consumption of blueberries or their functional foods, which may result in unwanted interactions between anthocyanins and medicinal drugs. Therefore, the present study examined the inhibition of AO by anthocyanins, anthocyanidins, and blueberry extracts in human liver cytosol using a HPLC assay. A comparison of the 50% inhibitory concentration (IC50) values of the test compounds showed that anthocyanidins slightly suppressed AO activity, whereas the inhibitory effects of anthocyanins and blueberry extracts were negligible. The inhibitory activities of the anthocyanins tested were approximately 60- to 130-fold weaker than that of the positive control menadione and were almost negligible. Furthermore, they were approximately 2,000-fold less potent than that of raloxifene, a typical AO inhibitor, and, thus, unlikely to interfere with drug metabolism by AO. In addition, since the plasma concentrations of anthocyanins after their administration were generally lower than the IC50 level, the inhibition of AO substrate metabolism by anthocyanins does not appear to be severe.

Pterin-based small molecule inhibitor capable of binding to the secondary pocket in the active site of ricin-toxin A chain.

The Ricin toxin A chain (RTA), which depurinates an adenine base at a specific region of the ribosome leading to death, has two adjacent specificity pockets in its active site. Based on this structural information, many attempts have been made to develop small-molecule RTA inhibitors that simultaneously block the two pockets. However, no attempt has been successful. In the present study, we synthesized pterin-7-carboxamides with tripeptide pendants and found that one of them interacts with both pockets simultaneously to exhibit good RTA inhibitory activity. X-ray crystallographic analysis of the RTA crystal with the new inhibitor revealed that the conformational change of Tyr80 is an important factor that allows the inhibitors to plug the two pockets simultaneously.

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Age estimation using methylation-sensitive high-resolution melting (MS-HRM) in both healthy felines and those with chronic kidney disease.

Age is an important ecological tool in wildlife conservation. However, it is difficult to estimate in most animals, including felines-most of whom are endangered. Here, we developed the first DNA methylation-based age-estimation technique-as an alternative to current age-estimation methods-for two feline species that share a relatively long genetic distance with each other: domestic cat (Felis catus; 79 blood samples) and an endangered Panthera, the snow leopard (Panthera uncia; 11 blood samples). We measured the methylation rates of two gene regions using methylation-sensitive high-resolution melting (MS-HRM). Domestic cat age was estimated with a mean absolute deviation (MAD) of 3.83 years. Health conditions influenced accuracy of the model. Specifically, the models built on cats with chronic kidney disease (CKD) had lower accuracy than those built on healthy cats. The snow leopard-specific model (i.e. the model that resets the model settings for snow leopards) had a better accuracy (MAD = 2.10 years) than that obtained on using the domestic cat model directly. This implies that our markers could be utilised across species, although changing the model settings when targeting different species could lead to better estimation accuracy. The snow leopard-specific model also successfully distinguished between sexually immature and mature individuals.

Transition From Proto-Kranz-Type Photosynthesis to HCO3 - Use Photosynthesis in the Amphibious Plant Hygrophila polysperma.

Hygrophila polysperma is a heterophyllous amphibious plant. The growth of H. polysperma in submerged conditions is challenging due to the low CO2 environment, increased resistance to gas diffusion, and bicarbonate ion (HCO3 -) being the dominant dissolved inorganic carbon source. The submerged leaves of H. polysperma have significantly higher rates of underwater photosynthesis compared with the terrestrial leaves. 4,4'-Diisothiocyanatostilbene-2,2'-disulfonate (DIDS), an anion exchanger protein inhibitor, and ethoxyzolamide (EZ), an inhibitor of internal carbonic anhydrase, repressed underwater photosynthesis by the submerged leaves. These results suggested that H. polysperma acclimates to the submerged condition by using HCO3 - for photosynthesis. H. polysperma transports HCO3 - into the leaf by a DIDS-sensitive HCO3 - transporter and converted to CO2 by carbonic anhydrase. Additionally, proteome analysis revealed that submerged leaves accumulated fewer proteins associated with C4 photosynthesis compared with terrestrial leaves. This finding suggested that H. polysperma is capable of C4 and C3 photosynthesis in the terrestrial and submerged leaves, respectively. The ratio of phosphoenol pyruvate carboxylase to ribulose 1,5-bisphosphate carboxylase/oxygenase (Rubisco) in the submerged leaves was less than that in the terrestrial leaves. Upon anatomical observation, the terrestrial leaves exhibited a phenotype similar to the Kranz anatomy found among C4 plants; however, chloroplasts in the bundle sheath cells were not located adjacent to the vascular bundles, and the typical Kranz anatomy was absent in submerged leaves. These results suggest that H. polysperma performs proto-Kranz type photosynthesis in a terrestrial environment and shifts from a proto-Kranz type in terrestrial leaves to a HCO3 - use photosynthesis in the submerged environments.

Total Anthocyanin Content, Total Phenolic Content, and Antioxidant Activity of Various Blueberry Cultivars Grown in Togane, Chiba Prefecture, Japan.

More than fifty cultivated varieties of blueberries are grown under the same processing conditions on the farm at Chiba Prefectural Agricultural College in Japan. The fruits from 51 blueberry cultivars, including 16 rabbiteye (RE) cultivars (Vaccinium ashei Reade) and 35 highbush (HB) cultivars (Vaccinium corybosum L.), were evaluated for total anthocyanin contents, phenolic contents, and their contribution to antioxidant activity among cultivars. Total anthocyanin contents varied from 0.74±0.21 ("Barkley") to 4.27±0.18 ("Suwannee") mg as cyanidin-3-glucoside (Cy-3-GC) equivalent/g fresh-weight (fw), with phenolic contents in the range of 0.77±0.14 ("Floridablue") to 3.69±0.89 ("Suwannee") mg of gallic acid equivalent (GAE)/g fw, which strongly correlated with antioxidant activities assessed using the DPPH and ORAC methods, respectively. Total anthocyanin and phenolic contents were both significantly higher (p<0.05) in RE blueberries than in HB blueberries. Furthermore, the total phenolic values were significantly higher for the RE family than for the HB family (p<0.01). In comparisons of two species, the major anthocyanidin identified were malvidin in RE blueberries and delphinidin in HB blueberries. This result suggests that some RE blueberries, especially "Suwannee," "Homebell" and "Climax," are suitable supply sources with high in vitro antioxidant capacity. This study would be helpful to the quality-oriented cultivation of blueberry.

Validation of the "My Headache Checker" that includes osmophobia in the diagnosis of migraine.

BACKGROUND: Migraine is a common headache disorder, with a 1 year prevalence rate of 6.0 %. However, less than 10% of patients with migraine receive medication in hospital. "My Headache Checker," a brief and self-administered migraine screening tool, which includes osmophobia in addition to the ID-Migraine™ three-item subset, was developed. The objective of this study was to analyze the applicability of "My Headache Checker" in Japanese patients. METHODS: A total of 238 patients visiting the outpatient department were enrolled in the study. The patients' chief complaint was not headache. "My Headache Checker" was administered to the patients. Subsequently, they were evaluated by a generalist for the diagnosis of headache. The clinical diagnosis of headache was determined based on the International Classification of Headache Disorders Ⅲ. RESULTS: Twenty (8.4%) patients satisfied the criteria for the diagnosis of migraine. Sensitivity, specificity, positive predictive value, and negative predictive value of "My Headache Checker" were 0.90, 0.83, 0.69, and 0.95, respectively. Sensitivity, specificity, positive predictive value, and negative predictive value of the ID-Migraine™ were 0.90, 0.85, 0.72, and 0.95, respectively. CONCLUSION: The majority of migraine patients are missed in busy outpatient departments. Our results suggest that "My Headache Checker" is a useful tool in diagnosing unrecognized migraine patients. However, the addition of osmophobia did not contribute to improve the screening power of the ID-Migraine™.

Role of human flavin-containing monooxygenase (FMO) 5 in the metabolism of nabumetone: Baeyer-Villiger oxidation in the activation of the intermediate metabolite, 3-hydroxy nabumetone, to the active metabolite, 6-methoxy-2-naphthylacetic acid in vitro.

Nabumetone (NAB) is a non-steroidal anti-inflammatory drug used clinically, and its biotransformation includes the major active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA). One of the key intermediates between NAB and 6-MNA may be 3-hydroxy nabumetone (3-OH-NAB). The aim of the present study was to investigate the role of flavin-containing monooxygenase (FMO) isoform 5 in the formation of 6-MNA from 3-OH-NAB. To elucidate the biotransformation of 3-OH-NAB to 6-MNA, an authentic standard of 3-OH-NAB was synthesised and used as a substrate in an incubation with human liver samples or recombinant enzymes. The formation of 3-OH-NAB was observed after the incubation of NAB with various cytochrome P450 (CYP) isoforms. However, 6-MNA itself was rarely detected from NAB and 3-OH-NAB. Further experiments revealed a 6-MNA peak derived from 3-OH-NAB in human hepatocytes. 6-MNA was also detected in the extract obtained from 3-OH-NAB by a combined incubation of recombinant human FMO5 and human liver S9. We herein demonstrated that the reaction involves carbon-carbon cleavage catalyzed by the Baeyer-Villiger oxidation (BVO) of a carbonyl compound, the BVO substrate, such as a ketol, by FMO5. Further in vitro inhibition experiments showed that multiple non-CYP enzymes are involved in the formation of 6-MNA from 3-OH-NAB.

VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction.

BACKGROUND: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. METHODS: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. FINDINGS: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. INTERPRETATION: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. FUNDING: This study was supported mainly by MEXT, Japan.

High-resolution photoreceptor imaging analysis of patients with autosomal dominant retinitis pigmentosa (adRP) caused by HK1 mutation.

PURPOSE: The hexokinase 1 (HK1) gene encodes one of the four human hexokinases that play essential roles in glucose metabolism. Recently, several cases of E847K mutation in the HK1 gene were reported to cause inherited retinal dystrophy. The purpose of this study was to identify the phenotypical characteristics of patients with a recurrent E847K mutation in the HK1 gene. METHODS: Three generations of one family with autosomal dominant retinitis pigmentosa were examined. Whole exome sequencing was performed on the DNA. Fundus imaging by an adaptive optics fundus camera was used to obtain high-resolution photoreceptor images. RESULTS: Fundus examination of the proband showed degeneration of the mid-peripheral retina, and SD-OCT images showed an absence of the ellipsoid zone (EZ) and interdigitation zone (IZ) in the parafovea and more peripherally. SD-OCT images of the mother of the proband showed an absence of the EZ and IZ, and fundus autofluorescence images showed hypo-autofluorescence surrounding the macular region. One daughter of the proband had only mild night blindness, however, the density of the cone photoreceptors was reduced in the parafoveal region. Whole exome sequencing identified a heterozygous variant, E847K, in the HK1 gene. This variant was found to co-segregate with the disease in three family members. CONCLUSIONS: Although the systemic phenotypes were found to be associated with the HK1 mutations, only the E847K mutation can cause a non-syndromic photoreceptor degeneration. Our study strengthened the hypothesis that the amino acid E847 might play a critical role in the maintenance of the morphology and function of the photoreceptors.

Effect of intranasal oxytocin on the core social symptoms of autism spectrum disorder: a randomized clinical trial.

Although small-scale studies have described the effects of oxytocin on social deficits in autism spectrum disorder (ASD), no large-scale study has been conducted. In this randomized, parallel-group, multicenter, placebo-controlled, double-blind trial in Japan, 106 ASD individuals (18-48 y.o.) were enrolled between Jan 2015 and March 2016. Participants were randomly assigned to a 6-week intranasal oxytocin (48IU/day, n = 53) or placebo (n = 53) group. One-hundred-three participants were analyzed. Since oxytocin reduced the primary endpoint, Autism Diagnostic Observation Schedule (ADOS) reciprocity, (from 8.5 to 7.7; P < .001) but placebo also reduced the score (8.3 to 7.2; P < .001), no between-group difference was found (effect size -0.08; 95% CI, -0.46 to 0.31; P = .69); however, plasma oxytocin was only elevated from baseline to endpoint in the oxytocin-group compared with the placebo-group (effect size -1.12; -1.53 to -0.70; P < .0001). Among the secondary endpoints, oxytocin reduced ADOS repetitive behavior (2.0 to 1.5; P < .0001) compared with placebo (2.0 to 1.8; P = .43) (effect size 0.44; 0.05 to 0.83; P = .026). In addition, the duration of gaze fixation on socially relevant regions, another secondary endpoint, was increased by oxytocin (41.2 to 52.3; P = .03) compared with placebo (45.7 to 40.4; P = .25) (effect size 0.55; 0.10 to 1.0; P = .018). No significant effects were observed for the other secondary endpoints. No significant difference in the prevalence of adverse events was observed between groups, although one participant experienced temporary gynecomastia during oxytocin administration. Based on the present findings, we cannot recommend continuous intranasal oxytocin treatment alone at the current dose and duration for treatment of the core social symptoms of high-functioning ASD in adult men, although this large-scale trial suggests oxytocin's possibility to treat ASD repetitive behavior.

A metabolic pathway for the prodrug nabumetone to the pharmacologically active metabolite, 6-methoxy-2-naphthylacetic acid (6-MNA) by non-cytochrome P450 enzymes.

The pathway for the transformation of the prodrug nabumetone, 4-(6-methoxynaphthalen-2-yl)butan-2-one, to the active metabolite 6-methoxy-2-naphthylacetic acid (6-MNA), a potent cyclooxygenase-2 inhibitor, has not yet been clarified in humans.To confirm the activation pathway, authentic standards of the nabumetone intermediates, 2-(6-methoxynaphthalen-2-yl)ethyl acetate (6-MNEA), 2-(6-methoxynaphthalen-2-yl)ethan-1-ol (6-MNE-ol) and 2-(6-methoxynaphthalen-2-yl)acetaldehyde (6-MN-CHO) were synthesized. High performance liquid-chromatography and gas chromatography-mass spectrometry on nabumetone oxidation revealed the generation of three metabolites.The formation of 6-MNA after a 60-min incubation of nabumetone was detected and 6-MNE-ol, an alcohol-related intermediate, was also generated by in cryopreserved hepatocytes. However, 6-MNA was below detection limit, but 4-(6-methoxynaphthalen-2-yl)butan-2-ol (MNBO) and 4-(6-hydroxynaphthalen-2-yl)butan-2-one (M3) peak were found in both the microsomes and S9 extracts with any cofactors.Nabumetone has recently been proposed as a typical substrate of flavin-containing monooxygenase isoform 5 (FMO5) and was shown to be efficiently oxidized in vitro to 6-MNEA. 6-MNA was detected in the extract obtained from a combined incubation of recombinant FMO5 and S9 fractions.The specificity of FMO5 towards catalyzing this Baeyer-Villiger oxidation (BVO) was demonstrated by the inhibition of the BVO substrate, 4-methoxyphenylacetone. Further in vitro inhibition studies demonstrated that multiple non-cytochrome P450 enzymes are involved in the formation of 6-MNA.

Quantitative facial expression analysis revealed the efficacy and time course of oxytocin in autism.

Discrepancies in efficacy between single-dose and repeated administration of oxytocin for autism spectrum disorder have led researchers to hypothesize that time-course changes in efficacy are induced by repeated administrations of the peptide hormone. However, repeatable, objective, and quantitative measurement of autism spectrum disorder's core symptoms are lacking, making it difficult to examine potential time-course changes in efficacy. We tested this hypothesis using repeatable, objective, and quantitative measurement of the core symptoms of autism spectrum disorder. We examined videos recorded during semi-structured social interaction administered as the primary outcome in single-site exploratory (n = 18, crossover within-subjects design) and multisite confirmatory (n = 106, parallel-group design), double-blind, placebo-controlled 6-week trials of repeated intranasal administrations of oxytocin (48 IU/day) in adult males with autism spectrum disorder. The main outcomes were statistical representative values of objectively quantified facial expression intensity in a repeatable part of the Autism Diagnostic Observation Schedule: the maximum probability (i.e. mode) and the natural logarithm of mode on the probability density function of neutral facial expression and the natural logarithm of mode on the probability density function of happy expression. Our recent study revealed that increases in these indices characterize autistic facial expression, compared with neurotypical individuals. The current results revealed that oxytocin consistently and significantly decreased the increased natural logarithm of mode on the probability density function of neutral facial expression compared with placebo in exploratory (effect-size, -0.57; 95% CI, -1.27 to 0.13; P = 0.023) and confirmatory trials (-0.41; -0.62 to -0.20; P < 0.001). A significant interaction between time-course (at baseline, 2, 4, 6, and 8 weeks) and the efficacy of oxytocin on the natural logarithm of mode on the probability density function of neutral facial expression was found in confirmatory trial (P < 0.001). Post hoc analyses revealed maximum efficacy at 2 weeks (P < 0.001, Cohen's d = -0.78; 95% CI, -1.21 to -0.35) and deterioration of efficacy at 4 weeks (P = 0.042, Cohen's d = -0.46; 95% CI, -0.90 to -0.01) and 6 weeks (P = 0.10, Cohen's d = -0.35; 95% CI, -0.77 to 0.08), while efficacy was preserved at 2 weeks post-treatment (i.e. 8 weeks) (P < 0.001, Cohen's d = -1.24; 95% CI, -1.71 to -0.78). Quantitative facial expression analyses successfully verified the positive effects of repeated oxytocin on autistic individuals' facial expressions and demonstrated a time-course change in efficacy. The current findings support further development of an optimized regimen of oxytocin treatment.

Determination of the Absolute Configuration of the Nabumetone Metabolite 4-(6-Methoxy-2-naphthyl)butan-2-ol Using the Chiral Derivatizing Agent, 1-Fluoroindan-1-carboxylic Acid.

The absolute configuration of (+)-4-(6-methoxy-2-naphthyl)butan-2-ol ((+)-MNBO), a nabumetone metabolite, was determined using 1-fluoroindan-1-carboxylic acid (FICA). Both enantiomers of the FICA methyl esters were derivatized to diastereomeric esters of (+)-MNBO by an ester exchange reaction. The results of 1H- and 19F-NMR spectroscopy of the diastereomeric FICA esters of (+)-MNBO confirmed the absolute configuration of (+)-MNBO was (S).